Molecular Aspects of Neurodegeneration, Neuroprotection, and Regeneration in Neurological Disorders

By Akhlaq A. Farooqui

Molecular Aspects of Neurodegeneration, Neuroprotection, and Regeneration in Neurological Disorders presents readers with comprehensive and cutting-edge information on the neurochemical mechanisms of various types of neurological disorders. The book covers information on signal transduction processes associated with neurochemistry of neurological disorders, including neurodegenerative, neurotraumatic, and neuropsychiatric disorders. The book also discusses risk factors, symptoms, pathogenesis, biomarkers, and the potential treatments of neurological disorders. The comprehensive information in this monograph may not only help in early detection of various neurological disorders, but will also promote the discovery of new drugs.

• Provides a comprehensive overview of the molecular aspects of neurodegeneration, neuroprotection, and neuro-regeneration, along with therapeutic strategies for various types of neurological disorders
• Provides cutting-edge research information on the signal transduction processes associated with the neurochemistry of neurological disorders
• Discusses risk factors, symptoms, pathogenesis, biomarkers, and the potential for treatments of neurological disorders

• Language: English
• Publisher: Academic Press
• Release date: Sep 7, 2020
• ISBN: 9780128217016

Akhlaq A. Farooqui

Akhlaq A. Farooqui is a leader in the field of signal transduction processes, lipid mediators, phospholipases, glutamate neurotoxicity, and neurological disorders. He is a research scientist in the Department of Molecular and Cellular Biochemistry at The Ohio State University. He has published cutting edge research on the role of phospholipases A2 in signal transduction processes, generation and identification of lipid mediators during neurodegeneration by lipidomics. He has studied the involvement of glycerophospholipid, sphingolipid-, and cholesterol-derived lipid mediators in kainic acid neurotoxicity, an experimental model of neurodegenerative diseases. Akhlaq A. Farooqui has discovered the stimulation of plasmalogen- selective phospholipase A2 in brains of patients with Alzheimer disease (AD). Stimulation of this enzyme may not only be responsible for the deficiency of plasmalogens in neural membranes of AD patients, but also be related to the loss of synapse in the AD.

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α-Syn α-synuclein

Chapter 1: Molecular aspects of neurodegeneration and classification of neurological disorders

Abstract

Neurodegeneration is a complex, progressive, and multifaceted process that results in neural cell dysfunction and death in brain and spinal cord. These tissues require large amounts of ATP in order to maintain ionic gradients across cell membranes and maintain physiological neurotransmission. Diseases associated with metabolic dysfunction of brain, spinal cord, and nerves are called as neurological disorders. These disorders can be classified into three groups: neurotraumatic diseases, neurodegenerative diseases, and neuropsychiatric diseases. Common neurotraumatic diseases are strokes, spinal cord injury, and traumatic brain injury. Common neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Neuropsychiatric diseases include both neurodevelopmental disorders and behavioral or psychological difficulties. Examples of neuropsychiatric disorders are depression, schizophrenia, some forms of bipolar affective disorders, autism, mood disorders, attention-deficit disorder, dementia, tardive dyskinesia, and chronic fatigue syndrome.

Keywords

Stroke; Traumatic brain injury; Spinal cord injury; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; Amyotrophic lateral sclerosis; Depression; Bipolar disorders; Schizophrenia

Introduction

Brain is a highly complex organ and is responsible for a variety of tasks, including receiving and processing sensory information, housekeeping processes (e.g., macromolecule turnover and axonal transport), biosynthesis of many types of neurotransmitters, maintenance and restoration of membrane potentials, and the control of highly complex behaviors that allow for glial and neuronal cell survival, which depends on blood vessels to deliver oxygen and nutrients, for the removal of carbon dioxide and other by-products of metabolism from the brain’s interstitial space, which helps to maintain the homeostasis of the cerebral microenvironment. Brain accounts for 2% of body weight, but it receives about 15% of the cardiac output, consumes approximately 25% of glucose, and 20% of all inhaled oxygen at rest (Attwell et al., 2010). This enormous metabolic demand of glucose and oxygen is due to the fact that neurons are highly differentiated cells requiring large amounts of adenosine triphosphate (ATP) in order to maintain ionic gradients across cell membranes and maintain physiological neurotransmission. The literature relevant to brain energy metabolism and imaging is enormous. Diseases associated with metabolic dysfunction of brain, spinal cord, and nerves are called as neurological disorders. These diseases are the leading cause of disability and deaths worldwide. The burden of these diseases has increased substantially over the past 25 years because of increase in aging human population (Karikari et al., 2018) and will continue to grow in the coming decades due to the further increase in life expectancy.

There are more than 600 diseases of the nervous system that impact normal function of the brain, spine, or the nerves that connect them. Neurological disorders may cause structural, neurochemical, and electrophysiological abnormalities in the brain, spinal cord, and nerves leading to neurodegeneration, a process, which is accompanied by deterioration of cognitive or motor functions, paralysis, muscle weakness, poor coordination, seizures, confusion, and pain (Farooqui, 2010; Deleidi et al., 2015). For the sake of simplicity, I will classify neurological disorders into three groups: neurotraumatic diseases, neurodegenerative diseases, and neuropsychiatric diseases. Common neurotraumatic diseases are strokes, spinal cord injury (SCI), and traumatic brain injury (TBI) (Fig. 1.1) (Farooqui, 2010). Common neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and prion diseases (Farooqui, 2010). Neuropsychiatric diseases include both neurodevelopmental disorders and behavioral or psychological difficulties associated with some neurological disorders. Examples of neuropsychiatric disorders are depression, schizophrenia, some forms of bipolar affective disorders, autism, mood disorders, attention-deficit disorder, dementia, tardive dyskinesia, and chronic fatigue syndrome (Fig. 1.1). Neuropsychiatric diseases involve the abnormalities in cerebral cortex and limbic system (thalamus, hypothalamus, hippocampus, and amygdale). In addition, various types of brain tumors also fall under neurological disorders. Neuropsychiatric diseases not only involve alterations in serotonergic, dopaminergic, noradrenergic, cholinergic, glutamatergic, and GABA-ergic signaling within the visceromotor network (Williams and Umemori, 2014; Corvin et al., 2012) but are also associated with alterations in synaptogenic growth factors (brain-derived neurotrophic factor, BDNF), the fibroblast growth factor, and insulin-like growth factors (Williams and Umemori, 2014; Corvin et al., 2012).

Fig. 1.1 Classification of neurological disorders. AD , Alzheimer’s disease; ALS , amyotrophic lateral sclerosis; HD , Huntington’s disease; PD , Parkinson’s disease; SCI , spinal cord injury; TBI , traumatic brain injury.

Molecular aspects of neurodegeneration

Neurodegeneration in neurological disorders is a complex multifactorial process that causes neuronal death and brain and spinal cord dysfunction. The survival of neurons in the brain depends not only on blood circulation, which provides oxygen and glucose to neural and nonneural cells, but also on the removal of carbon dioxide and other toxic by-products of metabolism from the brain’s interstitial space. This process helps in maintaining the homeostasis of the cerebral microenvironment (Farooqui, 2010, 2018). The molecular mechanisms that contribute to neurodegenerative process include mitochondrial dysfunctions, proteasomal impairment, oxidative stress, axonal transport deficits, synaptic dysfunction, protein oligomerization and aggregation, excitotoxicity, calcium deregulation, neuroinflammation, reduction in antioxidative defenses, DNA damage, aberrant RNA processing, and cell cycle reentry (Farooqui, 2010, 2018). Many factors contribute to neurodegeneration, including (a) vasculature changes, (b) changes due to cellular aging, (c) neurodegeneration due to trophic factor deficiency, (d) gut dysbiosis-mediated changes, (e) protein misfolding, (f) genetic abnormalities, and (g) immune system problems (Farooqui, 2010) (Fig. 1.2). Brain damage is attributed to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. All these conditions—partially or wholly, solitary or combined, genetic or acquired, known or unknown in origin—are manifested in specific neuropathological condition, which leads to the progressive decline or even the complete loss of sensory, motor, and cognitive function. As stated previously, neurodegeneration is mediated by induction of oxidative stress, mitochondrial dysfunction, proteasomal impairment, accumulation of abnormal protein aggregates, induction of neuroinflammation, and gliosis (Srivastava et al., 2009; Farooqui, 2010; Srivastava and Bulte, 2014).

Fig. 1.2 Factors contributing to the pathogenesis of neurological disorders.

Two types of neurodegenerations have been reported to occur in human brain. Neurodegeneration that occurs rapidly (in a matter of minute to hours) is called acute neurodegeneration. Neurodegeneration that occurs slowly (in a matter of months to years) and progressively is called as chronic neurodegeneration (Fig. 1.3). Acute neurodegeneration is caused by a sudden decrease in oxygen and glucose levels, rapid reduction in production of ATP, disturbance in transmembrane potential, and sudden collapse of ion gradients leading to neuronal dysfunction. Acute neurodegeneration involves rapid interplay among excitotoxicity, oxidative stress, and neuroinflammation at very early stage of injury (Farooqui, 2010). Examples of acute neurodegeneration are neural damage in strokes, TBI, and SCI. Unlike stroke, TBI and SCI are caused by mechanical trauma to brain and spinal cord. TBI and SCI occur following falls and motorcycle and car accidents (Farooqui, 2010). Neurotraumatic diseases also cause muscle dystrophy leading to a decline in neuronal and muscular functions, which often limit quality of life as well as life span.

Fig. 1.3 Mechanistic differences between acute and chronic neurodegenerations.

Stroke is an umbrella term used for focal neurological deficits and central nervous system injuries of vascular origin. Formation of a clot in blood vessels results in the onset of stroke, a process that results not only in the deficiency of oxygen and reduction in glucose metabolism but also reduction in ATP production and breakdown of blood-brain barrier (BBB) (Farooqui, 2010, 2018). As stated previously, the survival of neurons depends on blood vessels to deliver oxygen and nutrients, for the removal of carbon dioxide and other by-products of metabolism from the brain’s interstitial space, which helps to maintain the homeostasis of the cerebral microenvironment. Therefore, for optimal function, brain requires efficient blood cerebral circulation. In addition, cerebral blood circulation provides the trophic molecules needed for the survival of neuronal cells in different regions of brain (Farooqui, 2018). Stroke-mediated brain injury is accompanied by damage to components of the neurovascular unit. This activates the innate and adaptive arms of the immune response (Famakin, 2014). Age is a prominent risk factor for stroke. Loss of synaptic spine seems to be the earliest event of cerebral ischemia and generally contributes to the subsequent brain damage (Farooqui, 2010, 2018). Diet plays an important role in the onset of stroke. Thus, as stated in this chapter, long-term consumption of Western diet is an important risk factor for ischemic stroke (Farooqui, 2015).

The onset of stroke results neuronal damage through a cascade of events including energy and sodium‑potassium pump failure, increase in intracellular calcium, depolarization, generation of free radicals, BBB disruption, and apoptosis (Kanekar et al., 2012). In stroke-mediated injury, overstimulation of N-methyl-d-aspartate receptor (NMDA) type of glutamate receptors, rapid Ca²  +-influx, and stimulation of phospholipases A2, C, and D (PLA2, PLC, and PLD), calcium/calmodulin-dependent kinases (CaMKs), mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase (JNK), nitric oxide synthases (NOS), calpains, calcineurin, and endonucleases contributes to neurodegeneration. Increase in oxidative stress promotes and supports neuroinflammation through the activation of nuclear factor-κB (NF-κB), leading to increase in expression of proinflammatory cytokines and chemokine, intracellular adhesion molecule 1, vascular cellular adhesion molecule 1, and E-selectin (Martini and Kent, 2007; Farooqui, 2010, 2018). The adhesion molecules promote leukocyte adhesion to postcapillary venule walls, obstructing blood flow (Zoppo and Mabuchi, 2003). Furthermore, the consumption of Western diet by rodents causes behavioral impairment due to decrease in levels of BDNF, a growth factor crucial for synaptic plasticity and learning and memory (Pistell et al., 2010). Long term consumption of Western diet also produces hyperglycemia, insulin resistance, hypertriglyceridemia, and low HDL-cholesterol leading to type II diabetes and metabolic syndrome (MetS). The onset of MetS increases the chances of stroke in patients of all ages, ranging from neonates through to the elderly. In addition to neuronal damage via acute oxidative stress and neuroinflammation, stroke-mediated neuronal injury exerts a powerful immunosuppressive effect that facilitates fatal intercurrent infections and threatens the survival of stroke patients. Thus, immunological alterations contribute to the ischemic cascade from the early damaging events triggered by arterial occlusion, to the late regenerative processes underlying postischemic tissue repair (Farooqui, 2010, 2018). Converging evidence suggests that multiple mechanisms contribute to neuronal injury and neural cell death following stroke-mediated brain injury (Farooqui, 2010, 2018; Heneka et al., 2010; Allaman et al., 2011).

Stroke-mediated neural injury is also accompanied by acute oxidative stress and neuroinflammation. These processes develop rapidly due to the accumulation of reactive oxygen and nitrogen species (ROS and NOS), marked increase in proinflammatory eicosanoids, and rapid expression and release of proinflammatory cytokines and chemokines (Farooqui, 2010). The onset of stroke can be confirmed by brain computed tomography (CT) and or magnetic resonance imaging (MRI) in baseline conditions and represents the second most common cause of mortality and the third most common cause of disability in developed countries (Srivastava and Bulte, 2014). Neural cells within the ischemic core are often irreversibly damaged even if blood flow is reestablished. The ischemic penumbra, however, can be defined by a moderate reduction in cerebral blood flow (CBF) where collateral blood vessels provide neural cells with limited metabolic nutrients to temporarily maintain homeostasis during the initial stages of ischemia, but it is nonfunctional (Heiss et al., 2004). At the present time, there are neither specific biomarkers nor therapeutic agents that can protect neural cells from acute neurodegeneration. Therefore, drugs to treat these pathological conditions with acute neurodegeneration effectively are not available (Farooqui, 2010; Allgaier and Allgaier, 2014; Gao et al., 2016).

TBI results from a physical blow to the head during traumatic events such as falls, motor vehicle collisions, or sports-related injuries. TBI may also be inflicted by exposure to explosive blasts. TBI are classified into mild, moderate, or severe injuries based on clinical observations and history such as duration of loss of consciousness and post traumatic amnesia. In TBI, mechanical trauma to head (primary injury) results in rupture of neural cell membranes leading in the release of intracellular contents, disruption of CBF, breakdown of the BBB, intracranial hemorrhage, brain edema, and axonal shearing, in which the axons of neurons are stretched and torn (Farooqui, 2010, 2018). In TBI, secondary injury to the brain involves the activation of microglial cells, astrocytes, and oligodendroglial cells. At the molecular level, TBI involves a complex cascade of signal transduction processes associated with the onset of oxidative stress, excitotoxicity, ischemia, edema, and neuroinflammation (Farooqui, 2010, 2018; Maas et al., 2008). Induction of mitochondrial dysfunction at the neuronal/astrocytic level is another characteristic feature of TBI pathophysiology (Motori et al., 2013). In addition, adult brain TBI is accompanied by induction of reactive gliosis and reduction in levels of BDNF leading to cognitive impairment. Processes that mediate induction of BDNF and activation of its intracellular receptors can produce neural regeneration, reconnection, and dendritic sprouting, and can improve synaptic efficacy (Rostami et al., 2014). It is important to note that moderate-to-severe TBI is accompanied by progressive atrophy of gray and white matter structures that may persist months to years after injury (Farooqui, 2010, 2018; Farkas and Povlishock, 2007).

SCI involves two broadly defined events: a primary event, which is caused by the mechanical insult. This event is instantaneous causing neuronal fiber damage and neural cell necrosis. This process is beyond therapeutic management. In contrast, the secondary event involves a series of systemic and local neurochemical changes in spinal cord after the primary events. Neurochemical changes in secondary event develop slowly (hours to days) after SCI. At the core of primary injury site, SCI involves the rupturing of neural cell membranes resulting in the release of neuronal intracellular contents (Farooqui, 2010, 2018; Fehlings and Tighe, 2008). At the molecular level, SCI results not only in the release of glutamate, induction excitotoxicity, influx of calcium ions, activation of calcium-dependent enzymes (phospholipase A2, NOS, proteases, endonucleases, and matrix metalloproteinase), release of proinflammatory cytokines and chemokines but also increase in levels of proinflammatory lipid mediators (eicosanoids) (Witiw and Fehlings, 2015; Klussmann and Martin-Villalba, 2005). These neurochemical processes are supported by the activation of microglial cells, recruitment of neutrophils, and activation of macrophages and vascular endothelial cells and T cells leading to the rapid induction of acute neuroinflammation and oxidative stress (Farooqui, 2010, 2018). Production of ROS directly downregulates proteins of tight junctions and indirectly activates matrix metalloproteinases (MMPs) that contribute to open the BBB (Farooqui, 2010, 2018). These processes contribute to a failure in normal neural function and spinal shock, and represent a generalized failure of circuitry in the spinal neural network. Hemorrhage occurs, with localized edema, loss of microcirculation by thrombosis, vasospasm, and mechanical damage, and loss of vasculature autoregulation, all of which further exacerbate the neural injury. Inhibitory elements (neurite outgrowth inhibitor, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, and chondroitin sulfate proteoglycan) in the spinal cord tissue inhibit damaged nerve fibers to exhibit regenerative sprouting (Farooqui, 2010, 2018). Converging evidence suggests that SCI is an irreversible condition that causes damage to myelinated fiber tracts that carry sensation and motor signals to and from the brain. It involves primary and secondary damages to the spinal cord. SCI also increases the risk of cardiovascular complications, deep vein thrombosis, osteoporosis, pressure ulcers, autonomic dysreflexia, and neuropathic pain (Farooqui, 2010, 2018; Sezer et al., 2015). Therefore, it is important to be aware of chronic complications of SCI and learn how to manage these complications for the recovery and rehabilitation process.

It is important to note that gut microbiota composition plays an important role in therapeutics of acute neurodegeneration-mediated brain injury (Singh et al., 2016; Rice et al., 2019). The gut microbiome is closely associated with the modulation of a multitude of cellular and molecular processes fundamental to the progression of acute neural trauma-mediated pathologies, including neuroinflammation, BBB permeability, immune system response, microglial activation, and mitochondrial dysfunction, as well as intestinal motility and permeability. These processes contribute to acute neural trauma-related neuropathology and impaired behavioral outcomes (Singh et al., 2016; Arya and Hu, 2018; Rice et al., 2019). In addition, gut dysbiosis further may aggravate behavioral impairments in animal models of TBI and SCI, as well as negatively affects health outcomes in murine stroke models. Recent studies have also indicated that microbiota transplants and probiotics may ameliorate neuroanatomical damage and functional impairments in animal models of stroke and SCI. In addition, probiotics have been shown to reduce the rate of infection and time spent in intensive care of hospitalized patients suffering from TBI. Perturbations in the composition of the gut microbiota and its metabolite profile may also serve as potential diagnostic and theragnostic biomarkers for injury severity and progression (Camara-Lemarroy et al., 2014).

In contrast, chronic neurodegeneration occurs in neurodegenerative diseases such as AD, PD, HD, and ALS. It is well known that under previously mentioned pathological conditions, changes in CBF result in limited availability of oxygen and glucose in the blood. This decreases ATP production in the brain providing limited maintenance of ionic homeostasis resulting in chronic neurodegeneration, which takes several years to develop (Fig. 1.3) (Farooqui, 2010). Chronic neurodegeneration also produces significant stress on astrocytic, microglial, and oligodendrocytic functions. This results in an increase in the expression of cytokines and chemokines, accumulation of misfolded proteins, induction of damage associated molecular patterns (DAMPs), and complement proteins (Skaper et al., 2014; Amor et al., 2014). Metabolites released from astrocytes, microglial cells, and oligodendrocytes promote the reactive astrogliosis and apoptosis (Sofroniew, 2014). The activation of microglia under these conditions not only results in neurodegeneration but also facilitates phagocytosis of dead or dying cells and debris. In chronic neurodegeneration, an increase in the expression of cytokines and neurotoxic substances exacerbates cell damage (Bonifati and Kishore, 2007). Furthermore, in AD, PD, HD, and ALS abnormalities in immune system, chronic neuroinflammation remains undetected and lingers for years, causing continued insult to the brain tissue and ultimately reaches the threshold of detection many years leading to neurodegeneration (Farooqui et al., 2007; Farooqui, 2010). At the present time, there are neither specific biomarkers nor therapeutic agents that can protect neural cells from neurodegeneration or induce neuronal regeneration or repair damage in the affected area in the brain damaged by neurotraumatic and neurodegenerative diseases. Therefore, drugs to treat these pathological conditions effectively are not available (Farooqui, 2010; Allgaier and Allgaier, 2014; Gao et al., 2016).

Biomarkers for acute neurodegeneration

Mechanisms of acute neurodegeneration in stroke, TBI, and SCI occur by different types cell death (Smith, 2004). Necrosis occurs in ischemic and traumatic core, while apoptosis dominantly takes place in the surrounding area (penumbra) (Smith, 2004; Farooqui, 2010). Acute neurodegeneration generates several metabolites (biomarkers), which can be measured in blood, cerebrospinal fluid (CSF), or tissue to determine the onset of stroke, TBI, and SCI (Farooqui, 2010). Major damage to brain and spinal cord occurs following stroke, TBI, and SCI during reperfusion (Farooqui, 2010). Biomarkers for stroke are D-dimer (a product of fibrin degradation), C-reactive protein, low-density lipoprotein, troponins, neuron-specific enolase (NSE), fibrinogen, fibronectin, ubiquitin C-terminal hydrolase-L1 (UCH-L1), S100β, von Willebrand factor (vWF), ICAM, VCAM, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), glutamate and lipid mediators, and metabolites of arachidonic acid metabolism. It is unlikely that a single biomarker will reflect the complete picture of stroke, TBI, and SCI because these pathological conditions are multifactorial (Farooqui, 2010, 2018). Among previously mentioned biomarkers, d-dimer, fibrinogen, fibronectin, vWF factor, and thrombomodulin are biomarkers of endothelial dysfunction, which also occurs in heart disease. In addition, myelin basic protein (MBP), which is one of the major components of myelin sheath, can be detected in the CSF and blood within 1 h after the onset of stroke. Unfortunately, these biomarkers are not specific because these markers are also produced following severe myocardial infarction and brain infection (García-Berrocoso et al., 2010; Liu et al., 2017). An important development in evaluating the risk of ischemic stroke is the use of lipoprotein-associated phospholipase A2 (Lp-PLA2), a circulating enzyme involved in inflammation that is an independent predictor of future stroke among healthy individuals (Oei et al., 2005). In fact, the Federal Drug Administration (FDA) has approved recently the blood measurement of Lp-PLA2 to predict the risk of cardiovascular and cerebrovascular events supporting the view that early ischemic stroke detection may permit physicians to prescribe lifestyle changes in order to reduce some risk factors or establish preventive treatments. In addition, significant changes have been reported to occur in the gene expressions in minutes to hours after the onset of stroke, TBI, and SCI (Farooqui, 2018). In animal models of stroke, it is shown that circulating miR-125b-2∗, miR-27a∗, miR-422a, miR-488, and miR-627 are markedly increased and these miRNAs can be used as biomarkers for stroke (Sepramaniam et al., 2014). miR-290 elevated at 24 h after reperfusion (Jeyaseelan et al., 2008). Similarly, miR-10a, miR-182, miR-200b, and miR-298 are increased in both blood and brain at 24 h following ischemia/reperfusion (Liu et al., 2010). Similarly, elevated hsa-miR-106b-5P and hsa-miR-4306 and decreased hsa-miR-320e and hsa-miR-320d in plasma may be novel biomarkers for the early detection of acute stroke in humans (Wang et al., 2014). Converging evidence suggests that currently there is no single biomarker approved to identify stroke etiology. However, at present in most hospitals, the diagnosis of ischemic stroke is made solely on clinical grounds after diagnosing hemorrhagic lesions by CT and MRI.

Biomarkers for severe TBI are levels of total Tau protein, NSE, S100β (a Ca-binding protein), glial fibrillary acidic protein (GFAP), UCH-L1, microtubule-associated protein 2 (MAP2), MBP, IL-6, and IL-10. These biomarkers are elevated in CSF of TBI patients. Delayed elevations in levels of some of these biomarkers are also observed in the blood after following TBI (Zetterberg et al., 2013; Adrian et al., 2016). The diagnosis of TBI can be confirmed after neurological examination by neuroimaging cranial CT scanning and MRI (Bogoslovsky et al., 2016).

Biomarkers for SCI include neurofilaments, cleaved-Tau, microtubule- associated protein 2, MBP, NSE, S100β, and GFAP (van Middendorp et al., 2011; Yokobori et al., 2015). SCI is also accompanied by microRNAs (miR-21, miR-486, miR-20). These microRNAs are synthesized in the nucleus by RNA polymerase II and contribute to cell death and astrogliosis (Nieto-Diaz et al., 2014). They are processed by a variety of proteins before entering the cytoplasm as pre-miRNA. In the cytoplasm, the enzyme coded by the gene, dicer 1 ribonuclease type III or DICER1 processes the pre-miRNA duplex into a single-stranded miRNA sequence. Studies on microRNA expression patterns at different time points following rat SCI have indicated that miRNAs regulate transcriptional changes following SCI. Bioinformatic analyses have indicated that changes in microRNA expression affect key processes in SCI physiopathology, including inflammation and apoptosis. It is proposed that miRNAs can be used as biomarkers for SCI (Yunta et al., 2012). Conventional MRI can also be used to assess macroscopic changes in the injured spinal cord; however, it does not adequately address axonal injury in the white matter.

The onset of stroke, TBI, and SCI-mediated injury to neurons is accompanied by Ca²  +  influx. This process results not only in activation of phospholipases and NOS. The activation of phospholipases A2 generates arachidonic acid (ARA), which is metabolized by cyclooxygenases and lipoxygenases to proinflammatory lipid mediators (eicosanoids and platelet activating factors). Nonenzymic oxidation of ARA produces reactive oxygen species (ROS). These metabolites interact with NF-κB and promote its migration to the nucleus, where it binds with NF-κB response element (NF-κB-RE) and promotes the expression of proinflammatory cytokines and chemokine (TNF-α, IL-1β, IL-6, MCP1, and CXCL3). The activation of NOS contributes to the generation of nitric oxide and peroxynitrite. In addition, mitochondria and endoplasmic reticulum play a central role in apoptotic neural cell death. The release of cytochrome c from mitochondria and abnormal protein processing in endoplasmic reticulum are key processes that contribute to apoptotic cell death in SCI (Farooqui, 2010, 2018). In addition, stroke-mediated acute neurodegeneration is also accompanied by the induction of endoplasmic reticulum (ER) stress, which promotes the binding of death domain of DAPK1 with the p53 DNA binding motif, followed by its phosphorylation of p53 at Ser23. The interaction between DAPK1 and p53 activates both apoptotic and necrotic signaling pathways by death-related genes such as Bax and CypD through transcriptional- and mitochondrial-dependent mechanisms. Moreover, DAPK1 directly phosphorylates tau at Ser262 resulting in accumulation in the dendritic spines, which promotes neuronal cell death (Fig. 1.2) (Kim et al., 2019). DAPK1 also enhances autophagy-associated cell death via interaction with Beclin-1, a BH3-domain-only protein (Zalckvar et al., 2009). DAPK1 is abundantly expressed in the brain. It has been linked to neuronal injury in acute neural trauma. It may serve as a target for therapeutic intervention in the treatment of stroke and epilepsy. At the molecular level, the phosphorylation of DAPK1activity contributes to the apoptotic cell death, involving Fas, TNF-α (Cohen et al., 1999), ceramide (Pelled et al., 2002), caspase (Jin and Gallagher, 2003), and p53-mediated apoptosis (Raveh et al., 2001), as well as in the disruption of matrix survival signals and suppression of integrin-mediated cell adhesion (Wang et al.,