Ischemic and Traumatic Brain and Spinal Cord Injuries

Mechanisms and Potential Therapies

Akhlaq A. Farooqui

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128135969
• eBook ISBN: 9780128135976
• Topic: Biological Sciences
• Subtopic: Neurology
• Index: Biological Sciences

Ischemic and Traumatic Brain and Spinal Cord Injuries: Mechanisms and Potential Therapies presents readers with comprehensive and cutting-edge information on molecular mechanisms, including the signal transduction processes associated with neurodegeneration and neuroprotection in ischemic, spinal cord, severe and mild brain injuries. The book also covers the molecular mechanisms of drugs used for the treatment of neurotraumatic disease. Chapters are organized by molecular aspects and neuroprotective strategies by disease, including ischemic injury, spinal cord injury, traumatic brain injury, and chronic traumatic encephalopathy.The book integrates and consolidates knowledge on neurotraumatic diseases, with the hope of bringing forth more dramatic advances and developments, not only on molecular mechanisms, but also on the causes of, and treatments for, neurotraumatic diseases.- Offers a clearly written, logically organized, comprehensive overview on the molecular aspects of risk factors, pathogenesis, biomarkers, and therapeutic strategies for ischemic, spinal cord, severe and mild brain injuries- Provides cutting-edge research information on the signal transduction processes associated with neurodegeneration and neuroprotection in ischemic, spinal cord, severe and mild brain injuries- - Presents chapters that are organized by molecular aspects and neuroprotective strategies by disease, including ischemic injury, spinal cord injury, traumatic brain injury, and chronic traumatic encephalopathy

Chapter 1

Classification and Molecular Aspects of Neurotraumatic Diseases

Similarities and Differences With Neurodegenerative and Neuropsychiatric Diseases

Abstract

Neurological disorders constitute a group of diseases, which are characterized by a progressive deterioration of brain and spinal cord functions. Aging is the most important nonmodifiable risk factor for the stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Other risk factors include genes and environment.

Neurological disorders are classified into neurotraumatic, neurodegenerative, and neuropsychiatric diseases. These diseases are accompanied by induction of excitotoxicity, oxidative stress, and neuroinflammation. Neurotraumatic diseases are accompanied by rapid decrease in adenosine triphosphate (ATP), loss of ion homeostasis along with neurodegeneration that occurs rapidly (hours to days). In contrast, neurodegenerative diseases involve slow decrease in ATP, limited maintenance of ion homeostasis, and accumulation of misfolded proteins, leading to a neurodegeneration that occurs slowly (years) to develop. Neuropsychiatric diseases involve the alterations in signal transduction, changes in neurotransmitters along with induction of oxidative stress and neuroinflammation.

Keywords

Stroke; traumatic brain injury; spinal cord injury; excitotoxicity; reactive oxygen species; neuroinflammation; Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; Huntington’s disease

Introduction

Brain is a highly complex organ, which is responsible for a variety of tasks including receiving and processing sensory information and the control of highly complex behaviors that allow for survival. Brain has a very high metabolic rate. It accounts for 2% of body weight, but it receives about 15% of the cardiac output and 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. Neurodegeneration is a complex multifactorial process that causes neuronal death in the brain and spinal cord resulting in brain and spinal cord damage and dysfunction. Neurodegeneration is a progressive process associated with the loss of selective populations of vulnerable neurons. Neurodegeneration is regulated by many factors, including genetic abnormalities, immune system problems, and metabolic or mechanical insults to the brain and/or spinal cord tissues (Farooqui, 2010; Deleidi et al., 2015). Neurodegeneration is accompanied by oxidative stress, axonal transport deficits, protein oligomerization, aggregation, calcium deregulation, mitochondrial dysfunction, abnormal neuron–glial interactions, neuroinflammation, DNA damage, and aberrant RNA processing (Farooqui, 2010).

Diseases associated with brain, spinal cord, and nerves damage and dysfunction are called neurological disorders. The neurological consequences of neurodegeneration in patients can have devastating effects on mental and physical functioning. Several hundred neurological disorders have been described in the literature. These disorders may cause structural, neurochemical, and electrophysiological abnormalities in the brain, spinal cord, and nerves causing paralysis, muscle weakness, poor coordination, seizures, confusion, and pain (Farooqui, 2010; Kempuraj et al., 2016). Several hundreds of distinct neurological and psychiatric diseases have been reported to occur in human population. These diseases can be classified into three major groups: neurotraumatic diseases, neurodegenerative diseases, and neuropsychiatric diseases. Common neurotraumatic diseases include strokes, traumatic brain injury (TBI), spinal cord injury (SCI), chronic traumatic encephalitis (CTE), and epilepsy. Common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) (Farooqui, 2010). In AD, neurons of the hippocampus and entorhinal cortex are the first to degenerate, whereas in PD, dopaminergic neurons in the substantia nigra degenerate. HD is characterized by neuronal death in the basal ganglia and cortex. Amyotrophic lateral sclerosis (ALS) is accompanied by mutations in superoxide dismutase 1 (SOD1) in motor neurons. These diseases represent a primary health problem especially in the aging population (Hamer and Chida, 2009). For example, AD ranks as the sixth leading cause of death in the United States. PD, the second most prevalent neurodegenerative disease, affects 1%–2% of the population above 65 years (Bekris et al., 2010; Alzheimer’s Association, 2011). Reactive oxygen species (ROS) are chemically reactive molecules, which are closely associated with the pathogenesis of neurotraumatic and neurodegenerative diseases. ROS are naturally metabolites, which are generated within the biological system. They not only play important roles in cellular activities such as inflammation, cell survival, and stressor responses, but are also associated with cardiovascular diseases, muscle dysfunction, onset of allergies, and induction of various types of cancers (Zuo et al., 2015). Owing to their reactivity, high-concentration generation of ROS in the brain can lead to oxidative stress-mediated neural cell death (Farooqui, 2010; Dias et al., 2013; Zuo et al., 2015). A common characteristic of virtually all neurodegenerative diseases is that the consequences are often devastating, with severe mental and physical effects. This is due in large part to the loss or dysfunction of neurons—a highly specialized cell type that is typically postmitotic—lost cells are not replaced. Thus, once a neuron is lost, it typically gone forever, along with its associated function. Due to aging of global population, prevalence of AD, PD, HD, and ALS is expected to increase, imposing a social and economic burden on society (Hebert et al., 2003; Kowal et al., 2013). 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. Neuropsychiatric diseases involve abnormalities in cerebral cortex and limbic system (thalamus, hypothalamus, hippocampus, and amygdala). Neuropsychiatric diseases not only involve alterations in serotonergic, dopaminergic, noradrenergic, cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)-ergic signaling within the visceromotor network, but are also associated with alterations in synaptogenic growth factors (brain-derived neurotrophic factor [BDNF]), fibroblast growth factor, and insulin-like growth factors (Farooqui, 2010; Williams and Umemori, 2014).

In strokes, TBI, and SCI, neurodegeneration occurs rapidly (in a matter of hours to days) because of sudden lack of oxygen, rapid decrease in ATP, disturbance in transmembrane potential, sudden collapse of ion gradients, and rapid interplay among excitotoxicity, oxidative stress, and neuroinflammation at very early stage (Farooqui, 2010). In addition, in strokes, TBI, and SCI, acute neuroinflammation develops rapidly due to the accumulation of eicosanoids and the release of proinflammatory cytokines (Farooqui, 2010). In contrast, in AD, PD, HD, and ALS, oxygen, nutrients, and reduced levels of ATP continue to be available to the neurons, and ionic homeostasis is maintained to a limited extent resulting in a neurodegenerative process, which takes many years to develop (Farooqui et al., 2010). Furthermore, in AD, PD, HD, and ALS due to abnormalities in immune system, chronic inflammation remains undetected and lingers for years, causing continued insult to the brain tissue and ultimately reaches the threshold of detection many years after the onset of the neurodegeneration (Farooqui et al., 2007; Farooqui, 2010). Currently, there are no therapeutic agents that can induce neuronal regeneration or repair damage in the affected area in the brain damaged by neurotraumatic, neurodegenerative, and neuropsychiatric diseases. Therefore, drugs to treat these pathological conditions effectively are not available (Farooqui, 2010; Allgaier and Allgaier, 2014; Gao et al., 2016).

Neurodegeneration in Ischemic Injury

To function normally, brain needs an uninterrupted supply of glucose and oxygen through cerebral blood flow (CBF). Glucose and oxygen are needed for the synthesis of ATP, which is required not only for maintaining the appropriate ionic gradients across neural membranes (low intracellular Na⁺, high K⁺, and very low cytosolic Ca²⁺), but also for creating optimal cellular redox potentials. Stroke is a metabolic insult caused by severe reduction or blockade in CBF, leading not only to a deficiency of oxygen and reduction in glucose metabolism, but also to a decrease in ATP production and accumulation of toxic products (Farooqui, 2010). Two major types of strokes have been described in humans: ischemic and hemorrhagic. Ischemic strokes are brought about by critical decrease in blood flow to various brain regions causing neurodegeneration. Hemorrhagic strokes are caused by a break in the wall of the artery resulting in spillage of blood inside the brain or around the brain. Ischemic stroke is subclassified into thrombotic or embolic strokes. A thrombotic stroke or infarction occurs when a clot forms in an artery supplying the brain, whereas an embolic stroke is the result of a clot formed elsewhere in the body and subsequently transported through the bloodstream to the brain. The onset of stroke is often subtle and accompanied by the breakdown of the blood–brain barrier (BBB), overstimulation of glutamate receptors by extracellular glutamate leading to neuronal excitotoxicity (Table 1.1). This process results in calcium influx and mitochondrial dysfunction resulting in the deficiency in energy (ATP) supply as well as generation of high levels of oxidants which are the key contributors to neurodegeneration through necrotic and apoptotic cell death. Excessive glutamate receptor stimulation may also produce increase in nitric oxide production which can be detrimental to neural cells, as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite (Farooqui, 2010). High-level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, high levels of oxidants can induce endoplasmic reticulum stress pathways which may further contribute to induction of apoptosis. At the injury site, vascular cells (endothelial cells, vascular smooth muscle cells, adventitial fibroblasts, and neurons) promote the generation of ROS primarily via cell membrane-bound nicotinamide adenine dinucleotide phosphate oxidase (Sun et al., 2007). Other sources of ROS include uncontrolled arachidonic acid cascade and production of ROS by mitochondria during respiration. Stroke-mediated injury also triggers a robust inflammatory reaction characterized by the activation of endogenous microglia, leading to increase in expression of cytokines and chemokines (Allan et al., 2005; Farooqui and Horrocks, 2007). Stroke also results in increased cerebrovascular permeability and leakage. These processes support secondary ischemic brain injury (Brouns and De Deyn, 2009). The common stroke-mediated deficits include motor impairment (including limb spasticity), sensory impairment, language impairment (aphasia and/or dysarthria), dysphagia, cognitive impairment, visual impairment, and poststroke depression (O’Keefe et al....

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• About the Author
• Preface
• Acknowledgments
• List of Abbreviations
• Chapter 1. Classification and Molecular Aspects of Neurotraumatic Diseases: Similarities and Differences With Neurodegenerative and Neuropsychiatric Diseases
• Chapter 2. Molecular Aspects of Ischemic Injury
• Chapter 3. Potential Neuroprotective Strategies for Ischemic Injuries
• Chapter 4. Molecular Aspects of Spinal Cord Injury
• Chapter 5. Potential Neuroprotective Strategies for Experimental Spinal Cord Injury
• Chapter 6. Neurochemical Aspects of Traumatic Brain Injury
• Chapter 7. Potential Neuroprotective Strategies for Traumatic Brain Injury
• Chapter 8. Molecular Aspects of Concussion and Chronic Traumatic Encephalopathy
• Chapter 9. Potential Neuroprotective Strategies for Concussion and Chronic Traumatic Encephalopathy
• Chapter 10. Summary, Perspective, and Direction for Future Research on Neurotraumatic Diseases
• Index