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Year : 2019  |  Volume : 8  |  Issue : 4  |  Page : 219-228

A review article: Brain damage and neuroplastic responses

1 Department of Physiology, College of Health Sciences, Arsi University, Asella, Ethiopia
2 Department of Pharmacy, College of Health Sciences, Arsi University, Asella, Ethiopia
3 Department of Anatomy, College of Health Sciences, Arsi University, Asella, Ethiopia
4 Department of Biochemistry, College of Health Sciences, Arsi University, Asella, Ethiopia

Date of Submission08-Nov-2018
Date of Acceptance05-Sep-2019
Date of Web Publication15-Oct-2019

Correspondence Address:
Mr. Debela Tolessa Yadate
College of Health Sciences, Arsi University, Asella
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijhas.IJHAS_87_18

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Globally, brain damage is becoming a major problem which can be caused by trauma, cerebrovascular disorders, brain tumors, and infectious diseases. Traumatic brain injury and cerebrovascular disorders are considered highly prevalent and given attention in this review. Their pathology is almost identical and includes oxidative damage, excitotoxicity, and several inflammatory events that lead to neurological damage and finally to death. Both traumatic brain damage and stroke induce hypoxia and glucose deprivation in brain tissue which lead to excessive accumulation of calcium and sodium ions within brain cells and release of glutamate into the extracellular compartment. All of these progress to the production of reactive oxygen species leading to oxidative damage, excitotoxicity, and inflammatory damage which can also activate cell death signaling molecules and finally to neural death. Brain regeneration (neuroplasticity) is potential future therapies in the treatment of brain damage. Neuroplasticity is the capacity of the nervous system to restore brain structure and functions. This could be due to the regrowth of axons whose peripheral projections were damaged, restoration of damaged nerve cells and production of new nerve cells which replace the lost one. This issue is especially important because most of the current drugs are not effective or are limited to symptomatic management. Oxidative damage inhibitors, glutamate inhibitors, anti-inflammatory inhibitors, anti-cell death signaling molecules, and agents promoting neural cell regeneration are among the current targeted strategies for the treatment of brain damage. Therefore, this review summarized the major cause of brain injury and mechanisms involved in the process of neuroplastic response.

Keywords: Brain damage, cerebrovascular disorders, neuroplastic response, traumatic brain injury

How to cite this article:
Yadate DT, Wari AC, Bedane KH, Gebayehu GM. A review article: Brain damage and neuroplastic responses. Int J Health Allied Sci 2019;8:219-28

How to cite this URL:
Yadate DT, Wari AC, Bedane KH, Gebayehu GM. A review article: Brain damage and neuroplastic responses. Int J Health Allied Sci [serial online] 2019 [cited 2020 Sep 27];8:219-28. Available from: http://www.ijhas.in/text.asp?2019/8/4/219/269254

  Introduction Top

The brain is committed to a continual active state which makes it unique compared with muscle tissues which shut down for a while. For this reason, it has an obligatory high level of energy consumption.[1] Any assault to the brain will quickly result in irreversible damage. New therapeutic proposals will emerge from an understanding of the interdependence of molecular and cellular responses to brain injury, in particular the inhibitory mechanisms that block regeneration and those that enhance neuronal plasticity.[2] Brain damage can be caused by trauma, cerebrovascular disorders, brain tumors, and infections.[3] Of these causes, traumatic brain injury (TBI) and cerebrovascular disorders are considered as the main causes of death. TBI can result from any blow to the head attributable to the mechanical insult itself, whereas cerebrovascular disease is caused by blood clot or rupturing of the blood vessels attributable to the series of systemic and local neurochemical and pathophysiological changes that occur in brain.[3],[4] In this article, we review TBI, cerebrovascular disease (stroke), and brain plasticity following brain damage as a means of restoring brain functions. A systematic literature search was performed using PubMed, Medline, and Web of Knowledge databases with a set of brain damage-related keywords which include traumatic brain injury, cerebrovascular disease, and neuroplastic responses.

  Traumatic Brain Injury Top

A TBI can be classified as an open or closed injury. A closed injury which is more common is caused when the brain is bounced around in the skull due to a blow to the head or severe shaking. A closed motion can cause tearing, shearing, or stretching of the brain tissue. Open injuries usually damage relatively localized areas of the brain, resulting in specific damage.[5],[6],[7] Mortality rate for severe TBI is 20%–30% in developed countries and as high as 90% in developing countries.[7],[8]

Mechanism of brain damage following traumatic brain injury

Following injury, first different forms of mechanical insult including acceleration-deceleration shearing and penetrating injury which causes a rapid deformation of brain and rupture of neural cell membranes. Release of intracellular contents, disruption of blood flow, and breakdown of the blood–brain barrier happen after TBI. Early damage following TBI often causes ischemic and the subsequent cascades. This abnormality will be the base for the next event to come into picture. The second damage to the brain stems from the primary damage to the brain and can include failure of normal energy processes and disruption of this intricate path which lead to decreased glucose utilization, lactic acid accumulation, reduced adenosine tri-phosphate (ATP) and activity of ATP-reliant ion pumps, Ca2+-induced depolarization, change in neural excitability, increased production of neurotransmitters, excitotoxicity, and finally cellular death. Demyelination involving oligodendroglia, together with the above event, leads to increased susceptibility of neurons to injury.[9],[10]

The primary trauma will cause direct tissue damage, impaired regulation of cerebral blood flow (CBF) and metabolism, and excessive release of excitatory neurotransmitters. This results in an abnormally high level of free intracellular and mitochondrial Ca2+. The consequent Ca2+ overload leads to self-digesting (catabolic) intracellular processes that involve overproduction of free radicals, activation of cell death signaling pathways, and upregulation of inflammatory mediators, which altogether ultimately lead to cell death.[11] The sequential ischemic cascade also begins with interruption of normal blood flow, and numerous experimental studies demonstrate that ischemia contributes to neuronal death to a great extent.[12] During TBI, clinical outcomes correlate with change in the cerebral perfusion pressure. During TBI, the autoregulatory mechanisms and the subsequent CBF will be disrupted, leading to compromised blood supply to the brain [Figure 1] and [Figure 2].[13] Excitotoxicity, inflammatory reactions, and oxidative stress seem to work together, leading to amplified secondary injury. Glutamate is the most abundant neurotransmitter in the brain, being utilized in 50% of the synapses in the central nervous system (CNS) overall and 90% in the cortex. Excitotoxicity refers to exposure of neurons to excess glutamate extracellularly.[14] Subsequent studies found excitotoxicity as the uncontrolled entry of calcium into the neuron through glutamate receptor-controlled calcium channels that caused the excitatory response and that the calcium which activated a number of death events by triggering cell death signaling pathways.[15] ATP availability, intracellular calcium, and extracellular glutamate determine the cascade of the interdependent molecular processes leading to neuronal death [Figure 3].[16] The metabotropic glutamate receptors [Figure 4] operate through G-protein membrane receptors and have varying responses to glutamate, both based on dose and physiology of the receptor.[17] The principal sources of glutamate are from microglia and astrocytes.[18],[19] It is utilized by neurons for neurotransmission [Figure 5]. The excitotoxic cascade involves generation of high levels of reactive oxygen species (ROS)/reactive nitrogen species, lipid peroxidation (LP) products, prostaglandins, and nitric oxide (NO), and can activate microglia.[17] Many of the pathological events described in TBIs can also be seen with excitotoxicity: calcium dysregulation plays a major role in excitotoxicity [Figure 6] and [Figure 7].[20]
Figure 1: Pathological changes of traumatic brain injury

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Figure 2: Sequential events following traumatic brain injury[13]

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Figure 3: Pathophysiology of traumatic brain injury and ischemia. (a) Kinetics of the main events taking place in the lesioned central nervous system after an acute injury. (b) Adenosine tri-phosphate availability, intracellular calcium, and extracellular glutamate determine the cascade of the interdependent molecular processes leading to neuronal death[16]

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Figure 4: Different glutamate receptors[8]

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Figure 5: Acute microglial activation and free radical generation[8]

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Figure 6: Early stage of microglial activation and neural inflammation[8]

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Figure 7: Tumor necrosis factor-α immunoexcitotoxicity following brain damage[8]

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Under conditions of trauma, hypoxia/ischemia, and in neurodegenerative diseases, there is a switch to Glu2-lacking α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors that are calcium permeable.[21] Mild frontal TBI has been shown to cause a rapid switching to calcium-permeable AMPA-type receptors within cerebellar Purkinje cells, which normally lack functional N-methyl-D-aspartate (NMDA) receptors.[22] With disturbances of brain homeostasis, some of the microglia undergo a partial activation state in which the messenger ribonucleic acids needed for generating potentially destructive elements are activated. Microglial cells have various modes of activity [Figure 8]. During the reparative mode, microglia act as phagocytic cells, cleaning up the debris from the injured neurites and secrete neurotropic substances.[8]
Figure 8: Microglia switching to reparative mode[8]

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  Cerebrovascular Disease (Stroke) Top

Cerebral ischemia is a condition of complex pathology that includes oxidative damage, excitotocicity, and several inflammatory events, such as aggregation of inflammatory cells and upregulation of cytokines. Global cerebral ischemia entails diminution in CBF over the entire brain, encountered clinically as sequelae during extracorporeal circulation following cardiac arrest from ventricular fibrillation or asystole that lasts 5–10 min. Unlike global cerebral ischemia, focal cerebral ischemia entails reduction in regional CBF in a specific vascular territory and is usually encountered clinically as an “ischemic stroke” due to thromboembolic or atherothrombotic vaso-occlusive disease.[23],[24]

Brain damage following ischemia cannot be absolutely prevented by reperfusion alone due to secondary injuries, mainly from the influx of neutrophils during reperfusion, increases in ROS, cerebral edema, and hemorrhage. Elevated levels of ROS may lead to damage of intracellular proteins and deoxyribonucleic acid (DNA) by the way of oxidation and by activating a number of pathways that lead to cell death.[25] Ischemic depolarization occurs when CBF decreases to the levels of approximately 18 mL/100 g of brain tissue per minute, and neuronal cell death ensues if CBF is <10 mL/100 g of brain tissue per minute. Core anoxic ischemic depolarizations induce release of neurotransmitters such as glutamate. Once released, glutamate generates a phenomenon of peri-infarct depolarization, which increases energy consumption and promotes Ca2+ influx into the cells.[24],[26] Increased intracellular Ca2+ in neurons and glial cells initiates a set of nuclear and cytoplasmic events that produce deep brain tissue damage. Histopathologic outcome following focal ischemia largely depends on ischemic severity and duration. Increasing durations of depolarizing ischemia are associated with a spectrum of histopathologic correlates from reversible injury to irreversible cerebral infarction [Figure 9] and [Figure 10].[26],[27]
Figure 9: In vitro and intracerebral effects of sodium nitroprusside and other nitric oxide donors on neuronal survival[26]

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Figure 10: In vitro and intracerebral effects of sodium nitroprusside and other nitric oxide donors on neuronal survival[26]

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Following cerebral ischemia, the innate immune system of CNS is activated. Microglia, the resident immune cells of the CNS, respond to CNS injuries with increased proliferation, motility, phagocytic activity, and the release of cytokines and ROS.[28],[29] Toll-like receptors (TLR) 4 participate in cerebral injury upon ischemic stroke of the CNS.[30] Similarly, TLR2 has been shown to play a role in cerebral ischemic damage.[31],[32]

  Brain Plasticity Following Brain Damage as a Means of Restoring Brain Function Top

Cytoprotection and brain regeneration are both potential future therapies in the treatment of brain damage, both based on animal research data. Since the first description of the reorganization of the sensory cortex after peripheral nerve injury by Kaas et al., it has become clear that “we can no longer consider the injured brain as a normally wired brain with a missing puzzle piece,” and thus there has been intense research subsequently focused on understanding the regeneration processes following different brain injuries.[33]

For the past 20 years, scientists had done a lot research and able to understand how the brain is changed by experience, which is referred to as neural plasticity. Neural plasticity is the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function, and connections.[34] Once believed to be fairly constant in its organization and function, it has become clear that the brain is inherently capable of changing after injury to enable at least some behavioral restoration. What is remaining and less clear, however, is what factors might potentiate (or attenuate) the endogenous response to injury and what rules might guide the reparative changes.[35] These are, as of my understanding, should lead the upcoming research, and this review looks into the current literature on factors harnessing neural plasticity as a means of treatment following brain damage in this sub title. There is a rich history of treatments on physiotherapy for skeletal–muscular dysfunctions, so it is reasonable to design treatments for brain injury based on such treatments. Historically, most therapies have been based on hunch and habit rather than preclinical studies. Even though it was difficult to conclude such studies, they showed promising effect.[35],[36] There is also change in brain mass and dendritic complexity as an indication for neuronal plasticity. Similar result was obtained for the later brain damage in animal model studies, i.e., for tactile stimulation, where the stimulation was done by using light touch with a fine brush several times daily for 15 min for 2–3 weeks after the brain injury.[35],[37],[38] Pharmacotherapeutic agents, especially psychostimulants, which boosts neural plasticity are emerging these days. Although their effectiveness is limited by lesion size, location, and route of administration, amphetamine and nicotine have showed harnessing effect on neuronal plasticity in laboratory animal studies. In another animal study, chondroitinase produced significant gains in cortical map plasticity after TBI by promoting axonal sprouting and/or changes in perineuronal nets.[35],[39] Studies have shown that inosine stimulates the projection of new axons from the undamaged side of the brain to denervated areas of midbrain and spinal cord.[36],[40] Cell-based therapy and dietary restrictions are other therapeutic options for increasing neuronal plasticity as a means of restoring brain function following neural insult.[36],[41]

Understanding the cellular and molecular mechanisms underlying the pathophysiological events after TBI and stroke, has resulted in the identification of new potential therapeutic targets and future drugs [Figure 11].[42]
Figure 11: Pathophysiological mechanisms of secondary brain injury and selected points of action of pharmacological compounds[42]

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Focusing on oxygen radical-induced oxidative damage and LP in particular, a number of potential mechanisms for its inhibition. LP inhibitor (U83836E) which directly inhibits LP can be sited as a good example.[43],[44] Another approach to block posttraumatic radical formation is the inhibition of the enzymes cyclooxygenase and 5-lipoxygenases. These enzymes play a role in the arachidonic acid cascade during which the O2•− is produced as a by-product of prostanoid and leukotriene synthesis. Hence, cyclooxygenase-inhibiting nonsteroidal anti-inflammatory agents are vaso- and neuro-protective in brain damage as they inhibit the formation of ROS (O2•−).[45],[46]

A second LP inhibitory approach involves chemically scavenging the radical species (e.g., superoxide [O2•−], hydroxyl [•OH], nitrogen dioxide [•NO2], and carbonate [•CO3] radicals) before they have a chance to steal an electron from a polyunsaturated fatty acid and thus initiate LP. This is possibly done by administering free radical scavenging superoxide dismutase.[47],[48] Another example concerns the use of the nitroxide antioxidant tempol which has been shown to catalytically scavenge the free radicals •NO2 and •CO3.[49]

A third category involves stopping the “chain reaction” propagation of LP once it has begun by the scavenging of lipid peroxyl (LOO•) or alkoxyl (LO•) radicals. The endogenous scavenger of these lipid radicals is alpha tocopherol or Vitamin E.[50],[51] One research showed that the major toxic effect of NO comes from its combination with superoxide anion, leading to peroxynitrite formation, a highly reactive and oxidant compound. Indeed, peroxynitrite mediates nitrosative stress and is a potent inducer of cell death through its reaction with lipids, proteins, and DNA [Figure 12]. Animal studies showed that inactivation of poly adenosine diphosphate ribose polymerase (PARP), either pharmacologically (PARP inhibitors which include 3-aminobenzamide and glycosylphosphatidyl inositol-6150) or using PARP knockout mice, induces neuroprotection in experimental models of TBI.[52]
Figure 12: The nitric oxide-oxidative and nitrosative stress-poly adenosine diphosphate ribose polymerase pathway in traumatic brain injury[52]

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Excitotoxicity is the major mechanism of neuronal death for both TBI and stroke. Therefore, targeting this secondary neuronal injury mechanism has got many values to save neurons from loss. The excitatory neurotransmitter participated in excitotoxicity is glutamate according to a previous study. This study confirmed that elevated glutamate activity leads to hyperexcitability and neuronal death.[53] Mechanistically, excess glutamate binds the NMDA receptor and promotes a massive influx of Ca2+ and Na+, leading to the activation of a number of enzymes responsible for ensuing cellular damage; in another study, it was found that astrocytes are prone to excitotoxicity-mediated cell death as well.[54] Indeed, administration of amantadine, an NMDA receptor antagonist, to fluid-percussion injured rats showed improved performance in the Morris water maze test and promoted neuronal survival in Corn Amon's 2/Corn Amon's 3 (CA2/CA3) pyramidal neurons of the hippocampus.[55]

Collectively, this review article highlights TBI and stroke as the major causes of brain damage. In light with this, it is critical that the processes underlying TBI and stroke as well as the processes modulating recovery are understood. Thus, it is important that knowing the basic mechanisms of brain damage helps neuroscience and its practitioners to enhance the recovery processes and ultimately patient function. Moreover, there is recently a tremendous amount of research addressing neuroplasticity at different level. As we better understand the neurological level of neuroplasticity, we can then begin to better understand how to harness treatments that enhance the recovery.

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]


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