biomedicines

Review
Understanding Acquired Brain Injury: A Review
Liam Goldman 1,† , Ehraz Mehmood Siddiqui 2,† , Andleeb Khan 3, * , Sadaf Jahan 4 , Muneeb U Rehman 5 ,
Sidharth Mehan 6 , Rajat Sharma 1,7 , Stepan Budkin 1,8 , Shashi Nandar Kumar 9 , Ankita Sahu 10 ,
Manish Kumar 1 and Kumar Vaibhav 1,11, *

1 Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
2 Department of Pharmacology, Buddha Institute of Pharmacy, CL-1, Sector 7, Gorakhpur 273209, India
3 Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University,
Jazan 45142, Saudi Arabia
4 Medical Laboratories Department, College of Applied Medical Sciences, Majmaah University,
Majmaah 15341, Saudi Arabia
5 Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
6 Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga 142001, India
7 Center for Undergraduate Research and Scholarship, Augusta University, Augusta, GA 30912, USA
8 The Graduate School, Augusta University, Augusta, GA 30912, USA
9 Environmental Toxicology Laboratory, ICMR-National Institute of Pathology, New Delhi 110029, India
10 Tumor Biology Lab, ICMR-National Institute of Pathology, Safdarjung Hospital Campus,
New Delhi 110029, India
11 Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University,
Augusta, GA 30912, USA
* Correspondence: [email protected] (A.K.); [email protected] (K.V.); Tel.: +706-721-4691 (K.V.)
† These authors contributed equally to this work.

Abstract: Any type of brain injury that transpires post-birth is referred to as Acquired Brain Injury
(ABI). In general, ABI does not result from congenital disorders, degenerative diseases, or by brain
Citation: Goldman, L.; Siddiqui,
E.M.; Khan, A.; Jahan, S.; Rehman,
trauma at birth. Although the human brain is protected from the external world by layers of tissues
M.U.; Mehan, S.; Sharma, R.; Budkin, and bone, floating in nutrient-rich cerebrospinal fluid (CSF); it remains susceptible to harm and
S.; Kumar, S.N.; Sahu, A.; et al. impairment. Brain damage resulting from ABI leads to changes in the normal neuronal tissue activity
Understanding Acquired Brain and/or structure in one or multiple areas of the brain, which can often affect normal brain functions.
Injury: A Review. Biomedicines 2022, Impairment sustained from an ABI can last anywhere from days to a lifetime depending on the
10, 2167. https://doi.org/10.3390/ severity of the injury; however, many patients face trouble integrating themselves back into the
biomedicines10092167 community due to possible psychological and physiological outcomes. In this review, we discuss ABI
Academic Editors: Bruno Meloni and pathologies, their types, and cellular mechanisms and summarize the therapeutic approaches for a
Jun Lu better understanding of the subject and to create awareness among the public.

Received: 15 June 2022

Keywords: Acquired Brain Injury (ABI); post-birth; brain impairment; brain functions; pathologies;
Accepted: 26 August 2022
cellular mechanisms; therapeutic approach
Published: 2 September 2022

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in
published maps and institutional affil- 1. Introduction
iations.
Acquired Brain Injury (ABI) is an umbrella term encapsulating its two main categories:
Traumatic Brain Injury (TBI) or Non-Traumatic Brain Injury (Non-TBI) [1]. TBI is an
external traumatic event in which injury to the brain is sustained, while Non-TBI occurs
Copyright: © 2022 by the authors. due to an internal disease process that also leads to damaged brain tissue. Causes of TBI
Licensee MDPI, Basel, Switzerland. include motor vehicle accidents, falls, sports-related injury, and violence, whereas Non-TBI
This article is an open access article could be triggered by a stroke, neoplasm, infection, and anoxia [1]. Clinical outcomes of
distributed under the terms and both categories of ABI vary, depending on the specific disease process and the premorbid
conditions of the Creative Commons circumstances such as age, genetics, and socioeconomic background. Risk rates for TBI
Attribution (CC BY) license (https:// are the greatest in the elderly at and above 75 years, and male individuals are at greater
creativecommons.org/licenses/by/ odds of getting TBI [2–5]. The vectors of brain damage in both TBI and Non-TBI include
4.0/).

Biomedicines 2022, 10, 2167. https://doi.org/10.3390/biomedicines10092167 https://www.mdpi.com/journal/biomedicines

 TBI could be triggered by a stroke, neoplasm, infection, and anoxia [1]. Clinical outcomes
of both categories of ABI vary, depending on the specific disease process and the premor-
Biomedicines 2022, 10, 2167 bid circumstances such as age, genetics, and socioeconomic background. Risk rates2 of for31
TBI are the greatest in the elderly at and above 75 years, and male individuals are at
greater odds of getting TBI [2–5]. The vectors of brain damage in both TBI and Non-TBI
include vascular
vascular abnormalities,
abnormalities, broadinjury,
broad axonal axonalfocal
injury, focal or disseminated
or disseminated atrophy, atrophy, and
and neuronal
neuronal circuit disruption [6]
circuit disruption [6] (Figure 1).(Figure 1).

Figure 1. ABI: Etiopathology, classifications, the brain region affected, and related complications.
Figure 1. ABI: Etiopathology, classifications, the brain region affected, and related complications.
The pictorial presentation of ABI describes its type (purple) and etiology of the disease (in orange
The pictorial presentation of ABI describes its type (purple) and etiology of the disease (in orange
texts). ABI is mainly divided into TBI and Non-TBI injuries. Non-TBI can arise from tumors, vessel
texts). ABIinfection,
occlusion, is mainlyor divided
alcoholinto TBI and Non-TBI
consumption. ABI caninjuries. Non-TBI
affect different can arise
regions from
of the tumors,
brain vessel
depending
occlusion, infection, or alcohol consumption. ABI can affect different regions of the brain
on impact, insult, infection, or blockage (shown in pink) and may show related signs and symptomsdepending
on impact,ininsult,
(depicted infection,
green). HR: Heartor blockage
rate. (shown in pink) and may show related signs and symptoms
(depicted in green). HR: Heart rate.
ABI describes a wide range of diseases, establishing it as a vastly important area in
ABI describes
medicine and publica health.
wide range of diseases,
According to the establishing it as a vastly
Centre for Disease Controlimportant area in
and Prevention
medicine
(CDC), TBI and
is public
one of health.
the major According
groups of to ABI
the Centre
and is for Disease Control
a principal cause ofand Prevention
mortality and
(CDC),
lifelong TBI is one[7,8].
disability of the
Asmajor groups
per CDC of ABI
reports and is a the
(2006–2014), principal
frequencycause
of of mortalityhos-
TBI-related and
lifelong disability [7,8]. As per CDC reports (2006–2014), the frequency
pitalizations, emergency department visits, and deaths had increased by 53 percent [9]. In of TBI-related
hospitalizations,
2013, roughly 2.8emergency
million TBIdepartment
cases occurredvisits,
in and deaths had
the United increased
States by 53Among
of America. percentthe
[9].
In 2013, roughly 2.8 million TBI cases occurred in the United States
2.5 million emergency department visits, there were approximately 300,000 TBI hospital- of America. Among
the 2.5 million
izations emergency
and about department
60,000 deaths [2,10]. Itvisits, there were
is important approximately
to keep in mind that300,000 TBI hos-
these numbers
pitalizations
only refer to one-half of the diseases associated with ABI. Non-TBI also plays a largethese
and about 60,000 deaths [2,10]. It is important to keep in mind that role
numbers
in the number of individuals ending up in the hospital. The CDC reports that every year,a
only refer to one-half of the diseases associated with ABI. Non-TBI also plays
large role in the800,000
approximately number of individuals
people will have ending
a strokeup and,in in
the2018,
hospital.
one inThe CDC
every sixreports that
cardiovas-
every year, approximately 800,000 people will have a stroke and, in 2018,
cular-disease-related deaths was due to stroke [11,12]. These epidemiological data on ABIs one in every six
cardiovascular-disease-related deaths was due to stroke [11,12]. These
elucidate the necessary interventions that hospitals and researchers need to accomplish to epidemiological
data
serveon theABIs
largeelucidate
extent ofthe necessaryaffected
individuals interventions
by ABI.that hospitals and researchers need to
accomplish to serve the large extent of individuals
While both TBI and Non-TBI carry many different affected by ABI.
disease processes and medical
While both TBI and Non-TBI carry many different disease
problems (Figure 2), the patients usually receive treatment and rehabilitation processes and medical
in the same
problems (Figure 2), the patients usually receive treatment and rehabilitation in the same
facilities in the hospital. This is important to mention because demographic characteristics
facilities in the hospital. This is important to mention because demographic characteristics
of TBI and Non-TBI vary considerably. For example, the Toronto Rehabilitation Institute
of TBI and Non-TBI vary considerably. For example, the Toronto Rehabilitation Institute
demonstrated that the patient population for TBI compared to Non-TBI were significantly
demonstrated that the patient population for TBI compared to Non-TBI were significantly
younger, tended to be male, and lived in metropolitan areas [13]. In addition, the global
younger, tended to be male, and lived in metropolitan areas [13]. In addition, the global
population is aging, so leaders in the medical profession need to anticipate larger demand
for units and specially trained staff to treat patients with TBI and Non-Traumatic Brain
Injuries with possible comorbidities [14,15]. Nevertheless, to ensure exceptional clinical
outcomes for patients with ABI, physicians, and nurses must be able to provide person-
alized and specific treatments to the patients. To achieve that, a good understanding of
 population is aging, so leaders in the medical profession need to anticipate larger demand
for units and specially trained staff to treat patients with TBI and Non-Traumatic Brain
Biomedicines 2022, 10, 2167 Injuries with possible comorbidities [14,15]. Nevertheless, to ensure exceptional clinical
3 of 31
outcomes for patients with ABI, physicians, and nurses must be able to provide personal-
ized and specific treatments to the patients. To achieve that, a good understanding of ABI
and its pathology in different categories is preferred. Therefore, the present review aims
ABI and its pathology in different categories is preferred. Therefore, the present review
to give a comprehensive and clear description of ABI, its types, mechanism, and treatment
aims to give a comprehensive and clear description of ABI, its types, mechanism, and
strategy.
treatment strategy.

Figure 2. Poor outcomes post-ABI. A variety of parameters related to the ABI mechanism play a
Figure 2. Poor outcomes post-ABI. A variety of parameters related to the ABI mechanism play a role
role in predicting the outcome. ABI can develop as a result of a stroke or disease or an iatrogenic
in predicting
cause, the outcome.
and there ABI can develop
is some indication as awho
that those result of a stroke
suffer from aorhead
disease or an
injury areiatrogenic cause,
a self-selecting
and there is some indication that those who suffer from a head injury are a self-selecting
group, with poor attention, impulsivity, and overactivity being associated with poor road-crossing group, with
poor
skills.attention,
These may impulsivity, andother
interact with overactivity being
premorbid associated with
characteristics thatpoor road-crossing
are predictors skills.post-in-
of poor These
jury prognosis.
may interact with other premorbid characteristics that are predictors of poor post-injury prognosis.

2.
2. Acquired
Acquired Brain
Brain Injury
Injury and
and Its
Its Types
Types
As
As mentioned above, ABI is abroad
mentioned above, ABI is a broadclassifying
classifyingterm
termencompassing
encompassing any non-congenital
any non-congen-
brain injury; therefore, ABI is inherently diverse in the populations it affects,
ital brain injury; therefore, ABI is inherently diverse in the populations it affects, in the mech-
in the
anisms by which brain injury ensues, and in prognosis. The following paragraphs
mechanisms by which brain injury ensues, and in prognosis. The following paragraphs break
down the different types of TBI and Non-Traumatic Brain Injuries that
break down the different types of TBI and Non-Traumatic Brain Injuries that make make up ABIs
up
(Figure 1).
ABIs (Figure 1).
2.1. Traumatic Brain Injuries (TBIs)
2.1. Traumatic Brain Injuries (TBIs)
TBI arises because of a hit or jolt to the brain and comprises mild to severe injury. TBI
TBIshow
patients arisessymptoms
because ofsuch
a hitas
orunconsciousness,
jolt to the brain and comprises
confusion, mild dizziness,
nausea, to severe injury. TBI
headache,
patients show symptoms such as unconsciousness, confusion, nausea, dizziness,
or incoordination and receive symptomatic and stabilizing treatment. Patients keep vis- head-
ache, clinics
iting or incoordination
with chronic and receive symptomatic
symptoms and stabilizing
even after weeks or months treatment. Patients
post-initial keep
traumatic
visiting clinics with chronic symptoms even after weeks or months post-initial
experiences. If either symptoms continue or neurologic impairments appear, routine radio- traumatic
experiences.
logical If either
re-imaging maysymptoms continue
be required or the
to assess neurologic
situationimpairments appear,
[16]. There is routine ra-
a comprehensive
review published by our group that might be of interest to the TBI audience to obtain more
insight [17].
Biomedicines 2022, 10, 2167 4 of 31

2.1.1. Concussion
A concussion is one of the most widely recognized forms of TBI. It occurs due to a
sudden strike or whip to the head that causes the brain to bounce or twist within the skull.
Symptoms can range from minor confusion and disorientation to complete amnesia, nausea,
vomiting, and loss of consciousness [18]. These symptoms occur due to abnormal brain
movement upon impact, which at the molecular level disrupts neuronal cell membranes
and axonal stretching. This, in turn, causes the extensive flux of ions across neuronal
membranes resulting in diffuse waves of depolarization, which precipitate the classic
concussion symptoms [18]. In 2006, a study on concussion epidemiology in Canada noted
that 110 individuals per 100,000 had had a concussion within the previous year [19]. In
2014, 2.87 million cases of TBI in the United States were recorded by the CDC, and of those,
812,000 cases were children diagnosed with concussion alone or in combination with other
injuries [2]. Similarly, according to a US study carried out in 2017, approximately 19.5% of
adolescents (in grades 8–12) reported a minimum of one concussion, while 5.5% had more
than one concussion in their lives [20].

2.1.2. Skull Fractures

A skull fracture results from any impact to the head that surpasses the bone’s capability
to withstand the pressure. Although a fracture of the skull itself is not a brain injury, over
75% of all skull fractures are associated with some form of brain injuries, such as intracranial
hemorrhages or subdural or epidural hematomas [21]. Fractures that occur at the basilar
skull are more problematic as this area of the skull harbors essential areas of the brain that
allow us to eat, breathe, and walk [22].

2.1.3. Epidural or Subdural Hematomas and Subarachnoid Hemorrhage

In general, a hematoma is a bruise, and a hemorrhage is a bleeding blood vessel.
In the case of TBI, it is called an epidural or subdural hematoma if the insult occurs
above or below the dura matter. Hematomas mostly occur from blunt force trauma to the
head and are typically found in the temporal brain; however, they may also occur from a
penetrating TBI or spontaneously (the spontaneous type would not be considered TBI) [23].
A subarachnoid hemorrhage is divided into two groups: aneurysmal vs. non-aneurysmal.
The non-aneurysmal hemorrhage most often occurs due to blunt force trauma to the brain
or sudden acceleration changes. Epidural hematomas account for roughly 2% of injuries to
the head and 5–15% of fatal head injuries. Subdural hematomas are more common, with an
estimated rate of 5–25% in patients with head trauma [21].

2.1.4. Penetrating Brain Injury

Penetrating brain injuries can be caused by assaults, collisions, or even suicide at-
tempts [24] and may be defined from mild to severe TBI based on the Glasgow coma
scale (GCS). Following a patient’s preliminary examination, neurosurgical examination
starts with a clinical exam and documentation of raised intracranial pressure (ICP). In the
case of suspected arterial or venous injury, a CT scan is the first choice for diagnosis. As
the possibility of post-TBI epilepsy is 45–53%, a prophylactic anticonvulsant is given to
patients [25].

2.2. Non-Traumatic Brain Injuries (Non-TBI)

2.2.1. Infections
Due to the multiple layers of protection from the skull, meninges, and the blood-
brain barrier (BBB), the brain is relatively repellent to any pathogenic invaders [26,27].
However, when bacteria and other pathogens breach the brain’s defenses, the damage
can be devastating. Two major types of brain infections are meningitis and encephalitis.
Meningitis occurs when a bacterial agent infects the meninges and encephalitis is the
infection of the brain tissue itself [28,29]. Approximately 1.2 million cases of meningitis
occur globally each year [30], while the incidence of encephalitis infection tends to vary
Biomedicines 2022, 10, 2167 5 of 31

between studies, but the 2019 census estimated 1.4 million cases with 89,900 deaths and
4.80 million DALYs [31].

2.2.2. Anoxia
The brain needs a lot of oxygen and energy in the form of glucose. Anoxic brain injury
results when the brain is completely denied of oxygen in incidences such as drowning,
heart attack, carbon monoxide poisoning, and much more. As a result, the metabolic
homeostasis of the brain is destroyed resulting in major neuronal injury and cell death.
Since there are many different causes of anoxic brain injury, rates are hard to gauge [32].

2.2.3. Stroke
There are two main types of stroke: ischemic and hemorrhagic. Ischemic strokes result
from occluded cerebral arteries, which prevent nutrient-rich blood from supplying the
surrounding brain tissue. This results in permanent tissue damage. Transient ischemic
attack (TIA), also referred to as a mini ischemic stroke, only lasts for a short amount of time.
Ischemia that affects more than two-thirds of the middle cerebral artery (MCA) territory
is termed malignant cerebral infarction (MCI) and causes space-occupying edema and
neurological deterioration [33]. Swelling and symptomatology peak in the first 48 h after
a stroke. The first step in treatment is to reduce risk factors and keep ICP under control.
Although there are no precise surgical recommendations, a hemicraniectomy is generally
recommended [34]. Hemorrhagic strokes result from cerebral artery leakage into the brain,
causing elevated ICP and cellular damage [35]. The incidence of stroke among adults aged
between 35 to 44 years is roughly 30 to 120 per 100,000 per year. This number increases
drastically for individuals aged between 65 to 74 years, where the yearly incidence is about
670–970 per 100,000 [36]. A detailed account of brain hemorrhage for further reading can
be found here [37].

2.2.4. Alcohol and Drug Use

The usage and abuse of alcohol and drugs are highly prevalent in modern-day lifestyles
estimating a high lifetime risk for either drug or alcohol abuse and dependence [38].
There are many mechanisms through which drugs and alcohol can have negative effects
on the normal functioning of the brain. These include disturbing nutrient distribution
to brain tissue, direct cellular damage, altered chemical homeostasis of the brain, and
hypoxia [38,39].

2.2.5. Neoplasm
In a similar way to anoxia and infectious Non-TBI, brain cancers (neoplasm) are
vastly diverse in pathophysiology and epidemiology. Gliomas are the most prevalent
class of brain neoplasm, accounting for roughly 78% to 80% of all malignant brain tumors.
These cancers stem from the supporting neuronal cells of the brain called glia. Gliomas
include astrocytomas, ependymomas, glioblastoma multiforme, medulloblastomas, and
oligodendrogliomas [40].
Meningiomas are the most prevalent primary tumors and are also classified as ABIs [41].
Patients with genetic predispositions to disorders, such as neurofibromatosis type 2 or
multiple endocrine neoplasia type 1, are more likely to develop meningioma [42]. The pre-
ponderance is asymptomatic and histologically benign [43]. Initially, generalized symptoms
(nausea, headache, or altered mental status) may be present, with localized neurological
abnormalities developing later [44]. In situations with subtotal meningioma extraction,
adjuvant therapy in combination with postoperative radiation may be recommended. Pa-
tients with meningioma have a good prognosis, albeit those with a higher WHO grade or
partial resection have a higher chance of continuation [45].
Biomedicines 2022, 10, 2167 6 of 31

3. Mechanism of ABI
A sort of physical trauma from an external entity may lead to a brain injury. The
medical field has acquired tremendous success in the treatment of head injuries over the
last few decades. A clearer understanding exists of the causes of tissue damage and the
biophysical, biochemical, or physiological repercussions that culminate in a variety of
clinical manifestations such as scalp laceration, syncope, and progression to a persistent
vegetative state [46–51]. Various sorts of pathologies, such as skull fracture, hematoma
(intracerebral, epidural, subdural, or intraventricular), as well as different types of contusion
and brain injuries, could be recognized and their clinical and functional repercussions could
be defined by contemplating the mechanisms of injury to the head [50].

3.1. Biophysical Mechanism of ABI

The physical characteristics of the intruding substance, such as density, size, speed,
and length of loading, determine how much energy is delivered to the cranium in ABIs [52].
When a harmful energy burden or mechanical response is exerted to the head, the length of
the energy loading will be the first determinant to determine the severity of the injury [53].
This period has been set between 50 and 200 milliseconds. Static loads are defined as those
lasting more than 200 milliseconds, while dynamic loads are defined as those lasting less
than 200 milliseconds [54,55]. Static injuries are extremely rare and mainly occur when the
head is ensnared between two hard objects. These enormous weights may cause distortion
and injury to the skin and bones. The dynamic load could be caused by the passage of
energy to cerebral tissue via impetuous loads, which are variable in speed. When the head
does not receive direct impact but is put into motion as a result of an impulse generated by
a force exerted on different parts of the body, this is known as impulsive loading [56]. In
such cases, the injury is caused by inertial shifts in the head. In the next category, called
impact loads, when an infringing object strikes the head, it may cause tissue injury in-depth,
depending on the surface area, density, size, and speed of the object. It has the potential to
alter the head’s pace and induce acceleration or deceleration and may cause inertial shifts
in the head too.
The influence of an object on the head can cause changes in the tissue’s arrangement,
including the skin, bone, and deep frameworks. If the adjustment is greater than the
tissue’s elasticity, it will lead to permanent disfigurement, skin laceration, or a bone fracture.
With higher weights, the aggravating agent may produce depressed skull fractures and
destruction of underlying tissue, such as the dura, brain, and arteries. This often results
in an epidural hematoma, subdural hematoma, contusion, or intracerebral hemorrhage.
Perforation and permeation may occur in more extreme situations, specifically at fast
speeds, and with small agent sizes. The transmission of energy to the skull and cerebral
tissue may be related to the collision. The brain tissues distort, and contusion could be
because of this energy burden [57,58].

3.2. Injury to the Tissues

Tissue distortion is caused by deformation, shock waves, and acceleration/deceleration,
which all impose energy on the tissue. These can cause damage to the tissues in the skull,
which include neural components, vessels, and bone. Injuries arise when the stress applied
to the tissue exceeds the threshold. The physical properties of tissues, the amount of energy,
the length of energy loading, and the magnitude of the load all influence their endurance.
More intense activities, while still within the continuum, are at the brink of physiologic
endurance and, if repeated, will cause progressive or even acute brain malfunction. In
normal physiological conditions, the tissues’ physical tolerance to injury is substantially
lower, resulting in a variety of outcomes depending on the implicated components of
pathological injury [59].
Biomedicines 2022, 10, x FOR PEER REVIEW 7 of 32

substantially lower, resulting in a variety of outcomes depending on the implicated com-

Biomedicines 2022, 10, 2167 7 of 31
ponents of pathological injury [59].

3.2.1. Primary and Secondary Injuries

3.2.1. Primary and Secondary Injuries
The mechanism that causes the initial injury is a direct outcome of the delivered en-
ergyThe mechanism
to the that causes
head [17,60]. They maythe initial
cause injury is a direct
additional outcome
injuries of theof
as a result delivered
themselves,energy
ei-
to the head [17,60]. They may cause additional injuries as a result of themselves,
ther as sequelae of the original event or by exacerbating it, resulting in secondary injuries, either
as
thesequelae of the original
most prevalent of whichevent or by exacerbating
are hypotension it, resulting
and hypoxia. Secondaryin secondary
injury caninjuries,
include
the most prevalent of which are hypotension and hypoxia. Secondary
excitotoxicity, free radical formation, mitochondrial dysfunction, induction of injury can include
damaging
excitotoxicity, free radical
intracellular enzymes, andformation, mitochondrial
other pathways inside thedysfunction,
wounded neural induction
tissues,ofall
damaging
of which
intracellular
can cause continued system dysfunction (Figure 3) [17,61–63]. Certain tertiary of
enzymes, and other pathways inside the wounded neural tissues, all which
damages
can cause continued system dysfunction (Figure 3) [17,61–63]. Certain tertiary
are also included, which are frequently secondary results of the head’s energy loading. damages are
also
Thisincluded, which are imbalance
includes electrolyte frequentlyduesecondary
to renalresults
issues,of the head’s
various typesenergy loading.
of cardiac abnormal-This
includes electrolyte imbalance due to renal issues, various types of cardiac abnormalities,
ities, hepatic insufficiency, and so on.
hepatic insufficiency, and so on.

Figure 3.
Figure 3. Schematic
Schematic representation
representation of ofpathophysiology
pathophysiologyof ofABI.
ABI.BBB
BBBdysfunction
dysfunction caused
caused byby injury
injury
allows the transmigration of activated leukocytes into the injured brain parenchyma,
allows the transmigration of activated leukocytes into the injured brain parenchyma, which is facili- which is facil-
itated by the upregulation of cell adhesion molecules. Activated leukocytes, microglia, and astro-
tated by the upregulation of cell adhesion molecules. Activated leukocytes, microglia, and astrocytes
cytes produce ROS and inflammatory molecules such as cytokines and chemokines that contribute
produce ROS and inflammatory molecules such as cytokines and chemokines that contribute to de-
to demyelination and disruption of the axonal cytoskeleton, leading to axonal swelling and accu-
myelination
mulation of and disruption
transport of the
proteins at axonal cytoskeleton,
the terminals. On theleading to axonal
other hand, swelling
excessive and accumulation
accumulation of glu-
of transport
tamate proteins atneurotransmitters
and aspartate the terminals. Oninthe theother hand,
synaptic excessive
space due toaccumulation
spillage fromofsevered
glutamate and
neurons
aspartate neurotransmitters
activates NMDA and AMDAinreceptors
the synaptic space
located on due to spillagemembranes,
post-synaptic from severed neurons
which allowactivates
the pro-
ductionand
NMDA of ROS.
AMDA As receptors
a result oflocated
mitochondrial dysfunction,
on post-synaptic molecules
membranes, suchallow
which as apoptosis-inducing
the production of
factorAs
ROS. (AIF) and of
a result cytochrome
mitochondrialc aredysfunction,
released intomolecules
the cytosol.
suchThese cellular and molecular
as apoptosis-inducing factorevents
(AIF)
including the interaction of Fas with its ligand Fas ligand (FasL) ultimately lead
and cytochrome c are released into the cytosol. These cellular and molecular events including to caspase-depend-
ent interaction
the and -independent neuronal
of Fas with cell death.
its ligand BBB: blood-brain
Fas ligand barrier;lead
(FasL) ultimately NMDA: N-methyl-D-aspartate
to caspase-dependent and
receptor; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ROS: Reactive
-independent neuronal cell death. BBB: blood-brain barrier; NMDA: N-methyl-D-aspartate receptor;
oxygen species; Cyt c: Cytochrome c; ICP: Intracranial pressure; AIF: Apoptosis-inducing factor.
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ROS: Reactive oxygen
species; Cyt c: Cytochrome c; ICP: Intracranial pressure; AIF: Apoptosis-inducing factor.
Biomedicines 2022, 10, 2167 8 of 31

Various types of clinical cases can be distinguished based on the above-mentioned

aspects in the formation of a head injury. It can begin with a bone injury, since prolonged
static loading causes a change in the normal structure of the skull, ultimately leading to a
fracture when the flexibility of the bone toleration is exceeded. The amount of force and
the timing of the fracture determine the severity of the crack. When a large load is applied,
the entire skull is severed into segments, and the brain tissue is ruptured, causing it to
leak from the punctured nose, ear canals, and scalp. The sufferer may present with severe
impairment of cerebral and brain stem function. Death is often the result [64–66].
If the injury occurs in an acoustic region, neurological deficits may occur as a result
of damaged brain function. These could be the injury’s direct or major consequences.
There are certain further occurrences of the above-mentioned events, which are referred
to as secondary traumatic effects. Various types of intracranial hematomas, as well as
intraventricular hematomas and brain tissue contusions, can occur from injury to the
cerebrovasculature in the affected areas. These particulate lesions can cause a mass effect,
as well as an upsurge in ICP and brain herniation [17,65,67,68]. As a primary injury, brain
laceration may predispose the sufferer to convulsions and epilepsy [69,70].
Infections of the bone and cerebral contents are another serious result of this type of
injury, as the overlaying skin is punctured, allowing bacteria to enter the deeper structures.
These later occurrences are also secondary impacts. Lesions can occur as a result of the
expansion of a hematoma or contusion, or as a result of the mass effect caused by various
subsequent effects of damage, such as edema around the lesions. Cerebral herniation,
concussions, diffuse axonal damage, subdural hemorrhage, intracerebral hemorrhage, and
intraventricular hemorrhages are some of the other problems [71–73]. Severe injuries can
range from a short period of disorientation and cognitive impairment to concussion or loss
of consciousness to a long-term coma or persistent vegetative state (PVS) due to extensive
harm to brain neurons and axons [17,74].

3.2.2. Prenatal and Birth Damage

Early prenatal injury can result in the embryo’s mortality. On other hand, insuffi-
cient growth (agenesis of the corpus callosum or anencephaly) or abnormal development
(lissencephaly or microcephaly) could be the possible outcomes of late injuries [75–78].
During a period of heightened development, trauma (such as fetal stroke in the womb or
damage to the mother) will result in more structural issues than when progression has
slowed or has ended. Intricate stent delivery or hypoxia may result in birth failure [79–82].

3.2.3. Post-natal Injury

Pediatric patients may have acquired ABI from metabolic disturbances (phenylke-
tonuria), systemic illness (sickle cell disease, diabetes), trauma, central nervous system
tumors, infections (meningitis or encephalitis), toxins (use of alcohol or anticonvulsants
during pregnancy), and clinical treatment such as radiotherapy or chemotherapy for
leukemia [83–89].

3.2.4. Injuries in Adulthood

According to recent CDC data, people aged 75 years or older had the highest rate of
hospitalizations (325 of total TBI-related hospitalizations) and mortality (28% of TBI-related
deaths) [90,91]. The CDC further stated that males are two times more likely to get TBI-
related hospitalization and have three times higher mortality than females [90,91]. Alcohol
intake is identified as a major risk factor for TBIs, with effects on assessment, intensity, and
prognosis. It was discovered that 16 percent of brain injury patients aged 15 and above
were intoxicated at the time of injury. The alcohol group had a fatality rate of 14.5 percent
compared to 9 percent in the non-alcoholic group [92]. Individuals with an older ABI have
a higher chance of poorer physical, intellectual, and psychosocial outcomes, as well as
a lengthier recovery period and more comorbidities. The major cause of brain injuries
that comes under this category is fall. More than half of all fatal falls and 8% of nonfatal
Biomedicines 2022, 10, 2167 9 of 31

fall-related hospitalizations were caused by these brain injuries. ABIs have the highest
incidence of death and hospital admittance among fall-related injuries in adults and older
adults during the first year after the injury. Furthermore, even after controlling for age and
gender, there are rising tendencies in the incidence and mortality of trauma-induced ABIs
in older persons. According to several studies, those who take anti-arrhythmic medications
are more prone to suffer from brain damage. Several studies show that men had a higher
chance of serious brain injuries during a fall than women, despite the possibility of a reverse
relationship with nonfatal brain injuries [92,93].
The number of elderly persons hospitalized for a fracture has decreased over the last
decade, whereas the percentage of those with a TBI, subarachnoid hemorrhage, and/or,
subdural, in particular, has risen dramatically [94]. TBIs are becoming more common, which
appears to be linked to the increased use of anticoagulants and antiplatelet medicines like
clopidogrel and warfarin. Chronic illnesses related to equilibrium disturbance (Stroke and
Parkinson’s disease), scenarios of falls likely to result in an ABI, and risky behaviors may
happen more frequently in men, in contrast to the use of anticoagulants and antiplatelet
drugs. There is a need for more investigation into the underlying principles [95,96]. It
is reasonable to assume that elderly adults with chronic diseases that affect the joints,
nervous system, cardiac system, and cognition are at a higher risk of falling and developing
ABIs. These may also be exacerbated by a lack of visual perception and visuo-motor
reflexes [97,98].

3.3. Physiological Mechanisms of ABI

There are different mechanisms that arise from primary and secondary injury and
contribute to ABI pathology (Figure 3). We briefly described the pathological events here to
understand the pathology of ABI.

3.3.1. Excitotoxicity
Glutamate, an excitatory amino acid neurotransmitter is primarily responsible for
triggering cellular damage during brain ischemia. It has a multifaceted role in synap-
tic plasticity, brain development and maturation, axon guidance, and general neuronal
growth [17,99]. In ABI, restricted blood flow to the brain diminishes energy reserves
and causes membrane depolarization, thus leading to the reduced uptake of glutamate
from the surroundings. Under stable conditions, glutamine activates multiple receptors
such as N-methyl-D-aspartic acid (NMDA), kainic acid receptors, and alpha-amino-3-
hydroxy-5-methylisoxazole-4-propionate (AMPA), while its clearance is managed by active
ATP-dependent transporters [100,101]. During ABI, glutamine triggers the activation of
sodium channels (causes brain swelling), calcium channels (causes neuronal death), and
intracellular catabolic enzyme activity via glutamate receptors thus leading to cell death,
which further cascades into the generation of oxygen free radicals, membrane depolariza-
tion, and intracellular toxicity leading to brain injuries [102,103]. Preclinical studies suggest
a protective effect of suppressing NMDA and AMPA receptors post-ABI but have undesir-
able side effects [104,105]. To overcome this, Memantine (partial NMDA antagonist) was
tested, along with death-associated protein kinase and calcium-calmodulin-dependent pro-
tein kinase, and showed potential therapeutic efficacy without many side effects [100,106].
Another dopaminergic agonist, Amantadine was found to be promising in several brain
injuries. It triggers the dopamine release in neurons and delays the reuptake of dopamine
by neural cells and also inhibits the NMDA receptor signaling, thus proving its poten-
tial effect in the brain injuries [107–110]. A non-psychotropic cannabinoid (Dexanabinol),
which acted as a potent NMDA receptor antagonist was also reported to have a potential
effect in glutamate injury, but also showed unwanted side effects that impaired normal
brain functioning [37,111]. Additionally, metabotropic glutamate receptors (mGluRs) were
also reported to express a promising response in retarding excitability thus hindering
excitotoxicity [112].
Biomedicines 2022, 10, 2167 10 of 31

3.3.2. Oxidative Stress

A possible precursor to the pathogenesis of cerebral injury has been identified as oxida-
tive stress. Several reactive oxygen species (ROS), such as superoxide, hydrogen peroxide,
hydroxyl radicals, and per hydroxyls can be generated, followed by the development of
several reactive nitrogen species (RNS), which can cause brain tissue damage through a
variety of cellular and molecular pathways [17,37,102]. The reaction of nitric oxide along
with superoxide forms peroxynitrite, which can also bind to DNA directly, altering its
structural integrity and causing cell damage as well as apoptosis [17,113]. These highly
reactive radicals can degrade nucleic acids, proteins, and lipids, leading to neuronal cell
death. Edaravone and NXY-059, two promising antioxidants, were used to treat stroke but
did not produce significant effects [102,114,115]. Polyethylene glycol (PEG)-conjugated
SOD (PEG-SOD or pegorgotein) was reported to have promising effects in several studies
but failed in a larger phase III clinical trial [17]. Another study with lecithinized superoxide
dismutase (PC-SOD) showed that it inhibited secondary neuronal loss after brain injury
and enhanced survival rates [116]. As a result, novel therapeutic strategies for minimizing
the devastation caused by ROS are desired. Incipient interventions, such as modulation
of transient receptor potential melastatin-2 channels or poly (ADP ribose) polymerase-1
control endogenous facilitators of oxidative stress [117,118]. More investigation into the
neurological effects of oxidative stress could lead to new targeted therapies for the reduction
of several brain injuries, especially ABIs [118].

3.3.3. Acidosis
When mitochondrial respiration is disrupted, acidosis may arise as a result of lactate
buildup in the cells. Acid-sensing ion channels (AICs) are activated by protons and serve as
pH sensors in the body. They are amiloride-sensitive cation ports that relate to the epithelial
sodium group and enable calcium and sodium to enter neurons [37,119]. About six AIC
domains have been reported, with AIC1a, AIC2a, and AIC2b being expressed in the brain
and spinal cord. AIC1a and AIC2s are present in high-synaptic-density areas of the brain
to help with excitatory signaling and are involved in several brain injuries [119]. With their
activation, neuronal cell death occurs through sodium, zinc, and calcium influx into the cell.
In experimental stroke models, the inhibition of AIC1a has a longer therapeutic window,
which was much more effective than currently available drug therapies [100].

3.3.4. Inflammation
Inflammation may sometimes lead to brain injuries of several types including ABI [120].
Conversely, the pathogenesis of ABIs is further complicated by inflammation [121,122].
During brain injuries, there is an intense and long-lasting inflammatory response that
includes the activation of microglia, development of pro-inflammatory mediators, and
penetration of different kinds of immune cells into the brain tissue [17,123]. Cytokines
such as interleukin IL-6, IL-1β, tumor necrosis factor-alpha (TNFα), transforming growth
factor beta (TGFβ), and chemokines such as monocyte chemoattractant protein-1 (MCP-1)
and cytokine-induced neutrophil chemoattractant play an important role in the patho-
genesis of inflammation in neuronal cells. Depending on the type of inflammatory re-
sponse and when it happens, the immune response in the brain might have a variety
of outcomes [17,102]. While chronic inflammatory activities may contribute to secondary
ABIs and more prolonged detrimental events, inflammation early point may be beneficial.
However, elucidating the exact mechanisms of inflammatory responses is challenging,
as it is a diverse set of perceptions involving inflammatory cellular components, all of
which may be harmful or beneficial [124]. Broad-spectrum blockers of inflammation (AT1
receptor blockers, PPAR gamma blockers, beta-blockers, etc.), not shockingly, minimize
neuronal cell damage [125–127]. The lack of systematic implementation progress highlights
the need for a deeper knowledge of the numerous molecular and cellular pathways after
inflammation. In addition, a better understanding of the different structural profiles of
diverse inflammatory mediators is needed.
 (AT1 receptor blockers, PPAR gamma blockers, beta-blockers, etc.), not shockingly, mini-
mize neuronal cell damage [125–127]. The lack of systematic implementation progress
highlights the need for a deeper knowledge of the numerous molecular and cellular path-
Biomedicines 2022, 10, 2167 ways after inflammation. In addition, a better understanding of the different structural
11 of 31
profiles of diverse inflammatory mediators is needed.

3.3.5. Tauopathies
3.3.5. Tauopathies
Abnormal aggregation of tau proteins inside brain cells leads to several disorders
Abnormal aggregation of tau proteins inside brain cells leads to several disorders
including ABI [128–130]. The concentrations of a particular tau protein in brain tissue,
including ABI [128–130]. The concentrations of a particular tau protein in brain tissue,
CSF, and serum change in ABI pathogenesis (Figure 4) [131,132]. The events that lead to
CSF, and serum change in ABI pathogenesis (Figure 4) [131,132]. The events that lead to
tau release can be numerous and complicated, as can the types of modified tau species.
tau release can be numerous and complicated, as can the types of modified tau species.
Tau’s basic role is to promote microtubule flexion and saturation, which is dependent on
Tau’s basic role is to promote microtubule flexion and saturation, which is dependent on
its post-translational modifications [133–135]. When Tau attaches to microtubules with a
its post-translational modifications [133–135]. When Tau attaches to microtubules with a
poor or no phosphorylation state; microtubule flexion is hindered; phosphorylated tau
poor or no phosphorylation state; microtubule flexion is hindered; phosphorylated tau has
has a low potential for microtubules (Figure 1) [136,137]. Alternative splicing, which re-
a low potential for microtubules (Figure 1) [136,137]. Alternative splicing, which results in
sults in different-sized
different-sized tau isoforms,
tau isoforms, might besignificant
might be another another significant tau modulation
tau modulation [138–
[138–140]. Tau’s
140]. Tau’s capacity to disperse amongst cells is also steered by its accumulation
capacity to disperse amongst cells is also steered by its accumulation feature [141,142]. feature
[141,142]. Oligomeric
Oligomeric tau speciestaudisperse
species disperse
betweenbetween cells, whereas
cells, whereas integrated
integrated insoluble
insoluble tau
tau does
does not [143,144]. Tau spreads because of illness, and this property may express
not [143,144]. Tau spreads because of illness, and this property may express pathophysio- patho-
physiological
logical conditions
conditions triggeredtriggered
by ABI by ABI [145,146].
[145,146].

Figure 4. Expected molecular mechanism of brain injury on tau in the nervous system. Neurons,
Figure 4. Expected molecular mechanism of brain injury on tau in the nervous system. Neurons,
glia, oligodendrocytes, and blood vessels are damaged by the impact load that arises after a head
glia, oligodendrocytes, and blood vessels are damaged by the impact load that arises after a head
injury. Injury to some or more of these cells causes intracellular unfolding, which causes the entire
injury.
device Injury to some orTau,
to malfunction. morewhich
of these cells causes
is highly intracellular
correlated unfolding, which
with microtubules, causes the
is abundant entire
in axons.
device to malfunction. Tau, which is highly correlated with microtubules, is abundant
Impact forces devastate cell membrane integrity, as well as the microtubule framework in the axon.in axons.
Impact forces devastate
Tau disengages from thecell membraneas
microtubule integrity, as well
it becomes as the Tau
unstable. microtubule framework
would then in the phos-
be misfolded, axon.
phorylated,
Tau develop
disengages from athe
porous oligomeric
microtubule as itconformation, accumulate,
becomes unstable. or disperse
Tau would then bein a dysfunctional
misfolded, phos-
pathway. Tau
phorylated, may also
develop invadeoligomeric
a porous other neighboring cells (glia,
conformation, serum, or
accumulate, or CSF) as itin
disperse spreads.
a dysfunctional
pathway. Tau may also invade other neighboring cells (glia, serum, or CSF) as it spreads.

Due to the extreme sudden TBI-induced protein abundance, protein catabolic path-
ways such as autophagy and proteasomal degradation may become exhausted [147–149].
When the plasma membrane of a compromised cell is disrupted, leftover cytoplasmic
proteins such as tau which leave the cell can be absorbed by neighboring cells, confirming
trophic rearrangement [149,150]. Tau can cross into the cerebrovasculature, and CSF, relying
on where the weakened, tau-releasing cell is located, which further tends to contribute to
brain injuries [151–153].
Biomedicines 2022, 10, 2167 12 of 31

4. Injury and Outcome

Issues may occur as a result of an ABI in a variety of ways, either directly from the
injured brain or implicitly from the response of an individual to the injury. Due to changing
perceptions, family factors (pre-injury family functioning and managing), psychological
background, as well as social exclusion lead to an abrupt cessation of current issues [154]
(Figure 2).
The foreseen consequence is aided by a variety of factors related to the mechanism
of insult. Given a severe brain injury, the duration and extent of coma with a duration of
post-traumatic amnesia for less than 20–30 min and with a level of the coma of 12 or less on
the Glasgow Coma Scale are common characteristics of an ABI [155]. The magnitude of the
damage and the functional loss normally has a dose-response correlation. Many adults and
infants with traumatic complications do better than expected, whereas those with relatively
minor injury issues can encounter problems. There might be conflicts between parents and
professionals. Even if the injuries are minor, it is crucial not to ignore the complaints [96].
Brain injuries can attribute to low concentration, impulsivity, and overactivity which can
associate with other comorbid parameters that indicate poor post-injury performance.
Learning difficulties that exist pre- and post-trauma can put many individuals of discrete
ages at a heightened risk, exacerbating difficulties. The most critical thing to evaluate is the
observed change in behavior or educational progression [156].

4.1. Physical Outcomes

Aside from apparent gross motor problems, disabilities in the brain may have a
significant effect on intellectual and behavioral performance. Sensory loss, weakness,
tremors, seizures, excessive sweating, intermittent vision issues, ground abnormalities, and
hearing problems are also possible side effects. All of these factors affect well-being, social
interactions, and self-esteem [157]. Further longitudinal studies investigating these features
of ABI are needed to uncover underlying mechanisms.

4.2. Cognitive Outcomes

Mental manifestations are among the most obscure but recurrent issues which can lead
to a variety of information-processing skills—thought, speed, as well as the ability to react to
tasks—being slowed down. High levels of impulsivity and impaired judgment are normal,
and they have important long-term consequences [158]. Verbal communication issues
may not be apparent, but there may be impaired language abilities in word searching,
interpretation, and comprehension [159]. Reading, painting, structural skills, and job
performance can be challenging for patients with ABIs, as well as activities and knowing
physical differences. Cognition and listening abilities are often harmed. The ability to
prepare, specify objectives, coordinate, and implement a plan to achieve an intended goal
are examples of executive skills. This also includes expertise in efficiency surveillance and
planning. Any of these issues can affect individuals or some combination of them. The
severity of these functional disabilities is determined not only by the extent of the injury
but also by the age at the time of concussion [160,161].

4.3. Educational Outcomes

Given the neuropsychological impact, the majority of rehabilitation emerges in the
starting years, but developmental problems continue and can worsen. After the injury,
issues about a lack of improvement in learning, speaking, and reading, as well as an
inability to understand intelligent concepts and conceptualization [162]. More research is
in demand to explore the underlying mechanisms.

4.4. Emotional and Behavioral Outcomes

Unidentified cognitive episodes and a lowered self-image linked to an understanding
of logical and technical difficulties can suggest behavioral and emotional issues [163].
Making rude remarks about others may be connected with impulsivity and this behavior
Biomedicines 2022, 10, 2167 13 of 31

can be incredibly embarrassing and disconcerting for other people in society [164]. Elevated
anxiety, rage, utterances of violence, fatigue, and inertia are the common and normal parts
of the recovery stage and can last a significant amount of time. This is marked by a lack
of enthusiasm and interest in everything, as well as difficulties maintaining focus and
working at a fast pace, as well as passively carrying out recommendations rather than
initiating activity. Both the extent of the incident and pre-existing symptoms can be linked
to oppositional defiant disorder [165,166]. This is frequently linked to the realization of
a lack of skill in certain things and being able to cope with everyday life less well [161].
The assumption by patients that they will be able to catch up with things soon can cause
a lot of anxiety. Patients may be conscious of actual or potential losses, regardless of the
circumstances of ABIs. Serious personal trauma can be humiliating and have a significant
effect on one’s self-esteem. Fear of failure might be really serious, and it could be the origin
of depression and anxiety [161]. Post-traumatic stress disorder can occur even though there
is no continuous recollection of head trauma [167].

5. Pre-Existing Medications
Nimodipine, triamcinolone, polyethylene glycol-conjugated superoxide dismutase,
and mild hypothermia have all shown positive results in phase II clinical trials [162].
Excitatory amino acid inhibitors, calcium channel blockers, NMDA receptor antagonists,
corticosteroids, free radical scavengers, magnesium sulfate, and growth factors have all
been used in preclinical research to evaluate the therapeutic effects of drugs in various
animal models [168,169]. Regretfully, none of the formulations or methods that have been
examined in phase III trials have shown to be successful [167,170]. Mannitol has been
shown to help reduce brain swelling after a brain injury [171]. However, its efficacy in the
long-term treatment of serious TBI is unknown. Inordinate mannitol injection has been
shown to be dangerous, as mannitol passes through the circulation and the brain, increasing
pressure inside the skull and worsening internal brain injuries [171]. A new meta-analysis
backs up earlier reports that hypothermic treatment is a good cure for brain injuries in
some situations. Health professionals should continue to use vigilance when assessing
hypothermia for TBI care before more data from well-conducted trials become clear [172].
After an extreme brain injury, elevated ICP is still the leading cause of disability and death.
When estimated within any intracranial space, an accelerated ICP is usually characterized
as 15–20 mmHg [173]. Raised ICP has been linked to increased mortality and morbidity
after extreme brain injuries. A rise in brain size at the cost of one or more intracranial
resources is the cause of high ICP [174]. In ABI, increased ICP is caused by mass lesions,
edema, and increased cerebral blood flow. Fortunately, there is no proof to substantiate the
regular use of decompressive craniotomy in any brain injuries in adults with high ICP to
increase survival and the standard of living [175]. A decompressive craniotomy can be a
valuable choice when optimum medical care has failed to stop ICP. One randomized trial
of decompressive craniotomy (DECRA) with extreme brain injury is currently underway,
which could provide more information on the procedure’s effectiveness in adults [175].

6. Plausible Drug Therapies

6.1. S100B
The S100B protein is a member of a phenotypic family of low molecular weight
calcium-binding S100 proteins that are primarily developed by glial cells. It also functions
as a neurotrophic agent and a neuronal protection protein [176]. Excess supply of S100B by
triggered glia, on the other hand, may exacerbate neuroinflammation and cause neuronal
disruption. The brain and the serum S100B levels are scarcely associated, with serum
concentrations largely determined by the blood-brain barrier’s consistency contrary to the
amount of S100B in the brain [177]. Cerebrospinal S100B can be valuable as an indicator of
consequence in adults with serious brain injury. Long-term functional restoration after ABI
was shown to be aided by intraventricular S100B implementation [178,179]. Five weeks
after brain injury, it significantly boosted hippocampal neurogenesis. The Morris water
Biomedicines 2022, 10, 2167 14 of 31

maze used to test spatial learning capacity on days 30–34 after injury, showed that an
S100B injection improved cognitive efficiency [180,181]. S100B has not been used for the
clinical care of any brain injury. S100B was used in a clinical trial called S100B as a Pre-
Head CT Scan Screening Test After Mild TBI (NCT00717301) to see whether a serum can
anticipate traumatic anomalies on a brain CT scan after a mild TBI. A change in serum S100B
suggested whether the patient’s neurological condition had improved or deteriorated [182].
Finally, surgical therapy resulted in lower levels of S100B. Serum S100B protein represented
the seriousness of the injury and aided in the prediction of outcomes after a serious brain
injury [183]. S100B was also useful in determining the effectiveness of treatment following
a serious TBI [184].

6.2. Statins
Statins, which are powerful inhibitors of cholesterol synthesis, can also help peo-
ple with brain injuries [185]. Many of its effects, such as increased NO bioavailability,
immunomodulatory activities, improved endothelial function, antioxidant properties, up-
regulation of endothelial nitric oxide synthase, suppression of inflammatory responses, and
platelet actin reduction are cholesterol-independent [186]. Simvastatin treatment signifi-
cantly increased Akt, cAMP response element-binding proteins (CREB) phosphorylation,
and GSK-3; amplified the production of BDNF and VEGF in the dentate gyrus (DG);
enhanced tissue regeneration in the DG; and improved cognitive and memory restora-
tion [187]. In rats with traumatic brain injury, atorvastatin injection decreased cognitive
brain abnormalities, enhanced neuronal survival and synaptogenesis in the glioma pa-
rameter range and the CA3 areas of the hippocampus, and promoted angiogenesis in
these areas [188]. Pre-treatment of rats with lovastatin enhanced mental outcomes and
decreased the severity of brain injury, with a concurrent decline in serum concentrations of
TNF-α and IL-1β mRNA and protein [189]. In addition, statin therapy increased cerebral
hemodynamics in mice after a severe brain injury [190]. Statins helped animals regain
their spatial memory quickly after a brain injury. A double-blind controlled clinical trial
was conducted on 21 patients with TBI (aged 16 to 50 years) who had Glasgow Coma
Scale scores of 9 to 13 and intracranial deposits as evidenced by a computed tomography
(CT) scan [191]. Despite the overwhelming usefulness of statins, their desirable healthcare
quality profile, and comprehensive preclinical research showing both neurorestoration and
neuroprotection, further clinical trials are needed to assess statins’ neuroprotective and
neurorestorative properties after any type of brain injury [192].

6.3. Role of Phytochemicals in Brain Injury

Plants develop metabolic systems that generate hazardous and/or antinociceptive bioac-
tive molecules as a result of their static existence and exposure to herbivores and other
pathogens [193,194]. Among phytochemicals, sulforaphane (isothiocyanato-4-(methylsulfinyl)-
butane) has been demonstrated to have neuroprotective effects in several experimental
paradigms. Sulforaphane has shown to have a protective effect on the neurological disorder
and reduces Aβ1-42-induced inflammation via nuclear factor erythroid-2-related factor 2
(Nrf2) signaling [195,196]. The putrid phytonutrients have many other effects, particularly
neuroprotective, anti-proliferative, neurogenerative, anti-microbial, and allelopathic proper-
ties, in addition to their bitter taste [197]. The majority of phytochemicals formed by plants
to contend with environmental factors are classified as alkaloids, phenolics, or terpenoids.
There are a variety of functions and ecological positions shared by these three classes [198].
Other phytonutrients, on the other hand, readily penetrate the brain when consumed
(or inhaled), where they have the capability of altering brain functions, as psychoactive
phytochemicals like cannabinoids, psilocybin, and mescaline have shown [199]. These
behavior-altering phytonutrients are extremely potent, acting at subtherapeutic levels and
connecting explicitly to particular neurotransmitter receptors. Neuroactive phytonutrients
found in widely eaten fruits, vegetables, and nuts, on the other hand, contain a bitter or
sour taste that is usually well-tolerated [200,201]. Nephrotoxic phytochemicals are found
Biomedicines 2022, 10, 2167 15 of 31

in the body at concentrations much lower than their harmful level in the volume usually
ingested, which explains their positive benefits [202]. Curiously, many phytochemicals
are synthesized using cytochrome p450 (CYP450) enzymes [203]. It is worth noting that
phytochemicals have emerged to stimulate all of the same cellular processes in mammalian
cells as they have in plants. Signaling pathways involving Nrf2, SIRT1, and AMPK that
developed in insects and other herbivores before humans in response to phytochemicals
have been retained in human neurons [204–206]. Several of the compounds incorporated in
the skins of fruits, according to new research, will boost cognitive function and safeguard
against cognitive dysfunction in animal models of dementia, Alzheimer’s disease, and
many other neurodegenerative diseases [207]. Image recognition ability was improved in
old rats fed a blueberry-augmented diet, and administering green tea catechins to mice
alleviated age-related contextual memory formation decline [208]. By optimizing the ex-
pression of the transcription factor CREB, both blueberry and green tea phytochemicals can
strengthen cognitive performance [209,210]. Caffeine, the most commonly consumed psy-
choactive phytochemical, has been shown to improve cognitive performance by enhancing
intracellular calcium and cyclic AMP levels, which stimulate kinases that phosphorylate
and thus activate the cAMP-response element binding protein (CREB) [211].

6.4. Magnesium
Magnesium’s impact on calcium channels, NMDA receptors, and neuron membranes
makes it a potential clinical weapon [212]. In animal studies, magnesium has been shown to
improve conditions such as intellectual and sensorimotor control after a brain injury [213].
Furthermore, because of the lack of side effects and proportional effectiveness to corticos-
teroids, the magnesium sulfate approach has proved to be the most appropriate move [214].
Clinical trials with patients with mild or extreme TBI who reported to a level-1 community
trauma unit and were assigned randomly one of two magnesium doses or placebo within
8 h of injury continued for 5 days in a double-blind study. Consistent magnesium infusions
for 5 days given to patients within 8 h of a mild or extreme TBI displayed less significant
effects [215].

6.5. Barbiturates
ICP is a risk factor for extreme ABI, and it is linked to a high risk of death. Barbiturates
(pentobarbital and thiopental) are thought to lower ICP by preventing cerebral prolifera-
tion, which lowers cerebral physiological requirements and blood volume [174,216,217].
Barbiturates also lower blood pressure and can thus have an adverse impact on cerebral
blood flow [218]. In one analysis, pentobarbital was considered less efficient than mannitol
in lowering the ICP. In 25% of ABI patients, barbiturate therapy causes a drop in blood
pressure. Any lowering ICP impact on cerebral blood flow would be compensated by this
hypotensive effect [219]. Despite the fact that barbiturate coma is the secondary treatment
for post-traumatic adjuvant ICP, and persistent hypotension is the most common side
effect of it, recent studies indicate that low-dose corticosteroid therapy can be used in a
fraction of patients to prevent hypotension [220]. ABI patients, who are plunged into a
barbiturate coma, are more likely to experience adrenal insufficiency [221,222]. Some ABI
patients who received barbiturates experienced adrenal dysfunction and needed higher
concentrations of norepinephrine to manage cerebral blood flow than those who did not
receive barbiturates [169,223].

6.6. Glutamate Receptor Antagonist

Neuronal cells, as a result of TBI, may become excitotoxic, which is when there is a
buildup of the excitatory neurotransmitter, glutamate. This results in the overactivation
of glutamate receptors causing brain damage to occur at multiple levels such as loss of
the blood-brain barrier (BBB), neuron cell membrane integrity, cerebral edema, and cell
death [224]. To quell the excitotoxic effects of glutamate, researchers have tried introducing
a glutamate receptor antagonist (Dizoclipine), in rats with TBI [225] or topiramate in an
Biomedicines 2022, 10, 2167 16 of 31

epilepsy model in rodents [226]. The receptor antagonist was shown to alleviate continued
brain damage in rodents; however, the drug was associated with an inadequate therapeutic
window [227,228]. This research, although in its infancy, shows that glutamate receptors
could be a viable target for TBI therapy.

6.7. Antioxidants
Another prominent process of secondary brain injury in TBI is through the presence
of free radicals in the cerebral tissue. There are many complex mechanisms through which
the injured brain produces free radicals; however, in TBI, the balance of oxidants and
antioxidants is shifted [229]. The shifted balance toward oxidant production results in
increased membranous lipid peroxidation, oxidized proteins, DNA damage, and mito-
chondrial respiration leading to neuronal cell death [17,37,230]. Researchers have demon-
strated that melatonin and N-acetylserotonin have anti-inflammatory, antioxidant, and
anti-apoptotic effects [231]. The administration of melatonin was shown to up-regulate
antioxidant enzymes in rodent studies, which could provide a possible neuroprotective
effect in humans [232].

6.8. Targeting Inflammation

Upon receiving a TBI, the immune system is already at work. Drugs such as dexam-
ethasone, pioglitazone, indomethacin, or ibuprofen have shown to have prominent effects
on ABI-induced inflammation [233,234]. Damage-associated molecular patterns (DAMPs),
chemokines, and cytokines flush through the neural tissue, recruiting armies of white
blood cells to help clean up the injury. While the intent of the WBCs is to save the brain
from further disastrous damage, activated microglia (macrophages in the brain) release
reactive oxidative species and excitatory neurotransmitters that contribute to further cell
death [235]. Researchers are targeting inflammatory cytokines such as IL-1β and TNF-α.
These studies show some promise as they were able to reduce neurologic damage and
even improve cognition and motor ability [236]. Another avenue of research of neurologic
immunology in TBI is through the endocannabinoid system, which has been shown to play
an essential role in the homeostasis of the cell and may play a prominent role in cellular
repair mechanisms after or during disease processes [237]. Endocannabinoid clinical trials
failed to show significant protective effects; however, tests of synthetic endocannabinoid
receptors showed some therapeutic promise in rodent studies [17,238].

6.9. Programmed Cell Death Inhibitors

Apoptosis of neuronal cells is another result of TBI and is considered a poor prog-
nostic factor. Studies are targeting different areas of the apoptotic cascade. The design of
drugs that inhibit cyclin-dependent kinases (regulators of the cell cycle) showed poten-
tial therapeutic outcomes as they slowed the progression of neuron death and improved
health outcomes in TBI mice [239]. Another area of the programmed cell death pathway
researchers are targeting for therapies is that of caspase-dependent apoptosis. Caspase-3
and 12 inhibitors (peptide-based inhibitors such as z-VAD-fmk, and qVD-oph and the small
molecule inhibitors, IDN-6556 and p35) have improved health outcomes in a hemorrhagic
and TBI model of rodents and can be used as an effective therapy due to its wide therapeutic
window [17,240].

7. Future Prospective
Because of the breadth of diseases and pathophysiological mechanisms, ABI encom-
passes there is a range of different therapeutic options specified for each disease process.
These treatments range from chemotherapies to surgical interventions. However, when it
comes to TBI, contemporary treatment options are limited due to the innate complexity of
TBI pathophysiology [241]. Due to this complicated nature of TBI care, modern-day inter-
vention plans are generalized approaches that may be able to address the primary brain
damage (occurring due to direct brain damage after immediate impact) but customarily
Biomedicines 2022, 10, 2167 17 of 31

fail to impede secondary neuronal tissue damage (damage that continues months to years
after the traumatic episode) from the brain’s response to the traumatic event. The following
covers the current treatments for TBI and their strengths and weaknesses, in addition to
identifying promising future therapies.

7.1. ICP Monitoring and Management

ICP is the pressure that results from the closed system of the craniospinal compartment.
Increasing pressure can produce disastrous amounts of stress on the brain tissue causing
neuronal damage and possible brain herniation. Within the skull, there is a precious balance
in secretion, composition, and volume of CSF [242]. Increased ICP is a pervasive result
of TBI and is a significant result of secondary brain injury; therefore, monitoring and
managing its levels is established as a critical aspect of TBI treatment. There are multiple
methods healthcare providers use to monitor ICP. Computed tomography (CT) scans are
often used to visualize the increase in pressure while intraventricular catheters are the
“gold standard” for ICP monitoring. The catheter is usually surgically placed into the
lateral ventricle where a standard pressure transducer will monitor pressure changes [243].
The catheter can also double as a drain, which can be used for the therapeutic draining of
the intracranial space or, as mentioned above, for diagnostic objectives [244]. In addition to
catheter use as a means of ICP therapy, head elevation is used to displace much of the CSF
from the cranium and encourage venous return to the heart. With head elevation, ICP may
be reduced without the disruption of cerebral blood flow [245]. Hyperventilation is another
means through which ICP can be reduced medically. Hyperventilation lowers the ICP by
increasing the intraarterial CO2 partial pressure which signals the sympathetic nervous
system to vasoconstriction; however, it is only used for brief periods, when the brain tissue
is under stress [246].

7.2. Medically Induced Coma

The brain is the single largest organ in the form of glucose consumer in the body.
Accounting for roughly 2% of the body’s weight, it nonetheless consumes 20% of the body’s
glucose [247]. This shows how active the human brain is. In traumatic episodes, it is
important to preserve its function by reducing the metabolic demand of the brain. To do
this, physicians often administer benzodiazepines or infuse barbiturates to induce a coma
in the patient. This can save brain tissue from excitotoxic events and seizures, saving a
great amount of neuronal tissue [246,248].

7.3. Surgical Intervention

As mentioned above, hematomas and hemorrhages are often associated with TBI. If the
significant mass effect from a hematoma or bleeding is appreciated in imaging, then surgery
is warranted. A hematoma may continue to grow, which could apply large amounts of
pressure to the brain tissue resulting in neuronal death. If the hematoma begins to expand
rapidly this is considered a neurosurgical emergency and pressure must be relieved via
decompressive craniotomy [244].
ICP monitoring and management, medically induced comas, and surgical interven-
tions are adequate means of immediate therapy; however, their limitation is that they fail
to address the secondary effects of TBI. These effects can last from months to years and can
result in neuronal cell dysfunction and neurodegeneration. There are currently little to no
therapies that adequately address the main pathophysiologic mechanisms of secondary
brain damage; nevertheless, many researchers are working to address this aspect of TBI
treatment by addressing the different aspects of disease phenomenon such as excitotoxicity,
oxidative stress, inflammation, and programmed cell death [17].

7.4. Remote Ischemic Conditioning as an Adjuvant Therapy

Remote Ischemic Conditioning (RIC) is a non-invasive adjuvant therapy particu-
larly useful in treating ischemic and hemorrhagic injuries [249,250]. Recent studies val-
Biomedicines 2022, 10, 2167 18 of 31

idated the therapeutic effect of RIC on the treatment of several brain disorders such
as focal ischemia [251,252], acute ischemic stroke [253,254], aneurysmal sub-arachnoid
hemorrhage [255–257], and intracranial arterial stenosis [258] and in the prevention of
stroke-associated pneumonia [259]. It consists of repeated cycles of temporary ischemia-
reperfusion in the arms or legs. The procedure involves a manual or electronic tourniquet,
which applies a pressure of 30 mm of Hg above the systolic blood pressure to establish
repeated cycles of occlusion and reperfusion [249,250].
The principle of RIC, as both pre-and post-conditioning, has been validated in differ-
ent in vitro, preclinical, and clinical studies in distinct disease models such as myocardial,
pulmonary, and endothelial injury [260,261]. Multiple mechanisms have been put forward
to explain the therapeutic effect of RIC and might involve the release of humoral factors
such as nitric oxide or biogenic amines such as ornithine, glycine, kynurenine, spermine,
carnosine, and serotonin [262]. These factors modulate the systemic immune response
by regulation neutrophils activation [263,264], macrophage polarization [265], and/or T
cell activation [266]. These mediators are also transported through the bloodstream to-
wards the site of injury, where they attenuate disease progression by regulating multiple
pathways at cellular and molecular levels [267]. This involves changes in mitochondrial
metabolism characterized by a reduction in the levels of glycerol, a decrease in the lac-
tate/pyruvate ratio, and a reduction in the rate of ATP depletion through the regulation
of KATP channels [268]. At the molecular levels, it regulates distinct pathways such as
AMPK [269], opioid pathway [270], Notch signaling [271], and peroxisome proliferator-
activated receptor (PPAR) gamma [272]. RIC also regulates gene expression at the site
of injury at both genetic and epigenetic levels. It downregulates the expression of genes
associated with the regulation of metabolism, molecular transport, oxidative stress, and
cell cycle regulation [273]. In the case of brain injury, its clinical relevance produced results
in several clinical trials and was discussed in detail in the recently published review article
by Baig S et al. [249]. While the research on the effect of the RIC on ABI is still in its infancy,
further progress in this area requires investigating which patient groups respond best to
RIC, identifying the optimal protocol such as dose and duration of therapy, and establishing
biological and radiological biomarkers of the conditioning response.

7.5. Elastin Derived Peptides in Acquired Brain Injury

Elastin-derived peptides (EDPs), the fragmented product of elastin protein, have been
implicated in the progression of neurological degeneration during acquired brain injury.
EDPs are detectable in CSF and blood in healthy people and patients after ischemic in-
jury [274,275]. Elastin is the major structural matrix protein found on the surface of arteries,
lung tissue, cartilage, elastic ligaments, brain vessels, and skin. Due to extensive crosslink-
ing, elastin is highly insoluble and has a long half-life [276,277]. However, under normal
and disease conditions, it is degraded by serine protease (also known as elastase) [278],
cathepsins [279], and matrix metalloproteases (MMPs) particularly MMP-2, -3, -7, -9, -10,
and -12 [280,281].
During brain injury, elastase is released from interstitial and inflammatory cells, and
together with cathepsins and MMPs degrades elastin to release EDPs [276,282]. EDPs bind
to the cell-surface protein complex consisting of elastin-binding protein (EBPs), cathepsin
A, and neuraminidase (Neu1) [283,284]. Another EDP receptor, Galactin-3, is expressed
in inflammatory cells and is associated with tumor progression and metastasis [285–287].
Other less characterized EDP-binding proteins are integrins αvβ3 and αvβ5 [288,289].
The immune cells recognize EDPs as a foreign antigen and produce anti-elastin antibod-
ies that result in an autoimmune reaction as seen during psychiatric diseases and other
neurodegenerative disorders such as Alzheimer’s disease [290–292].
The binding of EDPs to their receptors in astrocytes activates various intracellular sig-
naling pathways such as peroxisome proliferator-activated receptor gamma (PPARγ) [293]
and AHR [294]. Together, these pathways regulate cellular activities such as cytotoxicity,
apoptosis, cell proliferation, and metabolism [295]. Limited studies have investigated the
Biomedicines 2022, 10, 2167 19 of 31

effect of EDPs on nervous system cells, particularly in astrocytes. An in vitro study sug-
gested that astrocytes express EBPs, which might be involved in the process of astrocytoma
invasion [296]. In the mouse cortical glial cells, EDPs peptide decreased the expression
of Mmp-2 and Mmp-9, whereas it increased the expression of Timp-2, Timp-3, and Timp-4
mRNA indicating its inhibitory effect on neovascularization [297]. The EDPs also decreased
NO production and increased ROS production in astrocytes [298]. Further studies sug-
gested that EDPs reduce the proliferation of undifferentiated neuroblastoma cells, thereby
promoting aging which may underlie several neurodegenerative diseases [299].
Taken together, the studies so far indicate pro-inflammatory and anti-angiogenic
effects of EDPs in brain injury. How EDPs levels in different pre-clinical and clinical ABI
models affect the outcome of the diseases is worth further investigation.

7.6. Stem Cell—Contemporary Clinical Trial

Early studies of stem cell therapies in brain injury focus on the restoration and reha-
bilitation of damaged neuronal connections. Recently, the paradigm of stem cell therapy
has shifted from the reconstruction of neural networks to the reduction of the secondary
immune response, responsible for secondary brain injury and neurodegeneration [300].
Studies showed that hematopoietic stem cells attenuated proinflammatory markers like
TNF-α and IL-β. In turn, this resulted in lower immune cell infiltration of the brain and
decreased activation of microglia [301]. In cellular therapy studies, researchers found that
the infusion of multipotent adult progenitor cells (MAPCs) after TBI in rodents achieved
some level of neuroprotection from the secondary immune response. The results showed
that MAPCs led to the efflux of IL-4 and IL-10 cytokines which stimulated the M2-microglial
phenotype and MAPCs led to modulated microglial activity in neural tissue [302]. Cur-
rently, the same researchers are carrying out clinical trials with the use of mononuclear cells
derived from bone marrow as a treatment for TBI. In phase 1, the bone marrow mononu-
clear cells were delivered intravenously to pediatric patients with a severe traumatic brain
injury which showed some central nervous system preservation. Phase 2 clinical trials were
completed in adults with the same functional, structural, and neurocognitive outcomes
measured as in phase 1 [302].
The new developments of different therapies, targeting different aspects of the complex
nature of TBI are important as they will help save the lives of millions worldwide. These
possible treatment options will also give physicians more options in treatment which may
be personalized to the patient’s specific injury and bodily response to said damage.

8. Conclusions
The established medical treatment of ABI patients consists primarily of advanced
prehospital treatment, comprehensive clinical care, and long-term recovery; however,
there is no scientifically validated successful management of neuroprotective agents to
prevent subsequent injury or improve healing. The massive impact of ABI, on the other
hand, clearly demonstrates the need for certain neuroprotective and/or neurorestorative
strategies or therapies.
Combining therapies can lead to improved results. Several agents and cells or even
other strategies may be used in these possible permutations. Inadequacies in clinical trial
designs and analyses can affect the outcome. In new clinical trials, a more responsive
interpretation of the outcome is needed with substitute performance indicators and new
forms of outcome analyses. Certain phytochemicals’ potential to stimulate certain beneficial
stress response mechanisms that exercise and energy restriction suggests that they can
enhance brain performance and reduce the risk of neurodegenerative diseases. These
neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, show that
oxidative stress, reduced immune bioenergetics, mitochondrial function, and the aggrega-
tion of protein aggregates all play a role in the malfunction and continued degeneration
of the brain. There are mounting results showing that neurohormetic phytochemicals
have the capability to stimulate mechanisms that resist or restore oxidative damage, boost
Biomedicines 2022, 10, 2167 20 of 31

bioenergetics, and improve the elimination of proteopathic proteins like amyloid peptide
and synuclein, which is helpful in improving the patient’s condition. Additionally, stem
cell therapy and non-invasive RIC showed promise in improving ABI. However, extensive
and robust research is needed to investigate a number of significant, unanswered questions
about the underlying neural mechanisms of action of particular phytochemicals, as well as
their therapeutic effectiveness in animal experimental models and human beings. Further
advancement of scientific proof therapies and application of these recommendations is
likely to increase the likelihood of quantitatively effective agents showing promising effects
in potential clinical trials.

Funding: This study was supported in parts by AURI research fund and by grant from the National
Institutes of Neurological Disorders and Stroke NS114560.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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