Neurochemical Aspects of Neurological Disorders

Neurochemical Aspects of Neurological Disorders

C H A P T E R 1 Neurochemical Aspects of Neurological Disorders Akhlaq A. Farooqui Department of Molecular and Cellular Biochemistry, The Ohio State ...

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C H A P T E R

1 Neurochemical Aspects of Neurological Disorders Akhlaq A. Farooqui Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States

INTRODUCTION Neurological disorders constitute a group of diseases, which are characterized by a progressive loss of neurons and synapses in the brain and spinal cord leading to the deterioration of functions,1,2 due to site-specific premature and slow death of specific neuronal populations and loss of synapses in brain and spinal cord modulating thinking, skilled movements, decisionmaking, cognition, and memory.3 The onset of neurological disorders is often subtle and usually occurs in mid-to-late life.1,2 The loss of neurons in the brain and spinal cord is called neurodegeneration, a multifactorial process that involves genetic, environmental, and endogenous factors related to aging.1,2,4 Neurodegeneration is also regulated by problems of the immune system, aging, age-related alterations in microbiota, and mechanical insults to the brain or spinal cord tissues. At the molecular level, neurodegeneration is accompanied by biochemical changes such as induction of oxidative stress, onset of neuroinflammation, loss of adenosine triphosphate (ATP), increase in calcium influx, and disruption of ion homeostasis, axonal transport deficits, stimulation of Ca21-dependent enzymes, protein oligomerization, and aggregation, calcium deregulation, mitochondrial dysfunction, and abnormal neuron glial interactions in the brain and spinal cord.

CLASSIFICATION OF NEUROLOGICAL DISORDERS Several hundred of distinct neurological disorders have been reported to occur in human population. Neurological disorders are Curcumin for Neurological and Psychiatric Disorders DOI: https://doi.org/10.1016/B978-0-12-815461-8.00001-3

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classified into three major groups: neurotraumatic diseases, neurodegenerative diseases, and neuropsychiatric diseases. Common neurotraumatic diseases include stroke, traumatic brain injury (TBI), spinal cord injury (SCI), and chronic traumatic encephalopathy (CTE).5 Common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).2 In AD, neurodegeneration occurs in the hippocampus and entorhinal cortex, whereas in PD, dopaminergic neurons degenerate in the substantia nigra. HD is characterized by neuronal death in the basal ganglia and cortex. Multiple sclerosis is a chronic inflammatory demyelinating autoimmune disease of the brain, which is accompanied by breakdown of myelin sheath (Fig. 1.1). It is the leading cause of neurological deficits and disability in young adults in the Western countries.6 Amyotrophic lateral sclerosis (ALS) is a major motor neuronal disorder, which is accompanied by progressive loss of neurons leading to muscle loss, paralysis, and death from respiratory failure. Neuropsychiatric diseases involve abnormalities and alterations in neurotransmitters (dopamine, serotonin, glutamate, and gammaaminobutyric acid (GABA)) along with induction of mild oxidative stress and neuroinflammation. Examples of neuropsychiatric disorders are major depressive disorder, anxiety, attention-deficit/hyperactivity disorder (ADHD), posttraumatic stress disorder, autism, and schizophrenia (Fig. 1.1). The molecular mechanisms contributing to neurodegeneration in neurotraumatic, neurodegenerative, and neuropsychiatric diseases are not fully understood. However, the pathogenesis of

FIGURE 1.1 Classification of neurological disorders. AVM, Arteriovenous malformation; ADHD, Attention-Deficit/Hyperactivity Disorder.

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neurotraumatic diseases involves a rapid decrease in ATP, loss of ion homeostasis along with rapid induction of oxidative stress and neuroinflammation, and abnormal neuron glial interactions. Neurotraumatic diseases are associated with acute neurodegeneration that develops rapidly (minutes to hours). In contrast, chronic neurodegeneration, which occurs in neurodegenerative diseases, involves slow decrease in ATP with limited maintenance of ion homeostasis, axonal transport deficits, and accumulation of misfolded proteins and their aggregation. Chronic neurodegeneration is also associated with chronic neuroinflammation and oxidative stress, which occurs slowly and takes years to develop. Neuropsychiatric diseases involve abnormalities and alterations in neurotransmitters (dopamine, serotonin, glutamate, and GABA) with induction of mild oxidative stress and neuroinflammation. The pathogenesis of neurotraumatic, neurodegenerative, and neuropsychiatric diseases may also involve alterations in blood brain barrier (BBB) permeability, decrease in brain-derived neurotrophic factor (BDNF), and insulin-like growth factors.2 It is interesting to note that there is considerable overlap in neurochemical changes that occur among neurotraumatic, neurodegenerative, and neuropsychiatric diseases. Thus stroke, AD, PD, HD, and ALS are accompanied by agitation, delusions, hallucinations, sleep disturbance, and depression.7

Stroke Stroke is a highly dynamic multifactorial metabolic insult caused by severe reduction or blockade in cerebral blood flow resulting not only decrease in oxygen and glucose delivery to brain tissue but also results in the breakdown of BBB and buildup of potentially toxic products in brain.2 Two major types of strokes have been reported to occur in human population. They are called ischemic stroke and hemorrhagic stroke (Fig. 1.1). Ischemic strokes are caused by critical decrease in blood flow to various brain regions inducing 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 overstimulation of glutamate receptors by extracellular glutamate leading to neuronal excitotoxicity (Fig. 1.2). This process results in calcium influx and mitochondrial dysfunction resulting in the deficiency in energy (ATP) supply as well as generation of high levels

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Clot formation and reduction in blood flow

Stroke/reperfusion

Induction of excitotoxicity

Mitochondrial damage Activation of cPLA2 Oxidative stress

Ca2+

Cyct c and Ap af-1, Caspase9, ap optosome formation

Generation of ARA and eicosanoids

Activation of calpains

Activation of microglia, infiltration of leukocytes, inflammasome activation

Activation of NOS RNS and ROS

Proteolysis

DNA damage

Cytoskeletal changes

PARP-1 activation

Activation of caspase 3

Increase in expression of cytokines and chemokinines

Neuroinflamination

Apoptosis

Neurodegeneration

FIGURE 1.2 Pathways contributing to neuronal injury by ischemic stroke. cPLA2, Cytosolic phospholipase A2; NOS, nitric oxide synthase; PARP-1, poly [ADP-ribose] polymerase-1; ARA, arachidonic acid; ROS, reactive oxygen species; RNS, reactive nitrogen species; Cyto c, cytochrome c; and Apaf-1, apoptotic protease activating factor-1.

of oxidants which are 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.2 High level peroxynitrite and other oxidant promote neuronal apoptosis (Fig. 1.2). Stroke-induced injuries include motor impairment (including limb spasticity), sensory impairment, language impairment (aphasia and/or dysarthria), dysphagia, cognitive impairment, visual impairment, and poststroke depression.8

Spinal Cord Injury SCI consists of two broadly defined events: a primary event that is mediated by the mechanical trauma itself and a secondary event, attributable to the series of systemic and local neurochemical and pathophysiological changes that occur in spinal cord after the initial traumatic insult.9 The primary event produces the acute stretching of the spinal

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cord tissue leading to rupturing of neural cell membranes and alterations in BBB permeability leading to the release of intracellular contents.10 In contrast, secondary event produces many neurochemical alterations (ischemia, edema, increase in excitatory amino acids, and reactive oxygen species) in the spinal cord tissue (Fig. 1.3). These neurochemical alterations are supported by not only the activation of glial cells (microglia, astrocytes, and oligodendrocytes) but also result in leukocyte infiltration, activation of macrophages, and vascular endothelial cells.11 These processes result in acute neurodegeneration. SCI also triggers a systemic, neurogenic immune depression syndrome characterized by a rapid and drastic decrease of CD14 1 monocytes, CD3 1 T-lymphocytes, and CD19 1 B-lymphocytes and MHC class II (HLA-DR) 1 cells within 24 hours reaching minimum levels within the first week.12 In addition, SCI also induces the synthesis of autoantibodies that bind nuclear antigens including DNA and RNA.13 At the molecular level, SCI results in the release of glutamate, generation of reactive oxygen and nitrogen species (ROS and RNS), activation of

FIGURE 1.3 Pathways contributing to spinal cord injury. Glu, Glutamate; cPLA2, cytosolic phospholipase A2; NOS, nitric oxide synthase; ARA, arachidonic acid; PAF, platelet activating factor; ROS, reactive oxygen species; RNS, reactive nitrogen species; Cyto c, cytochrome c; IL-1β, tumor necrosis factor-α, interleukin-1β; COX-2, cyclooxygenase-2; FFA, free fatty acid; ONOO2, peroxynitrite.

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NF-κB, increased expression and release of TNF-α, IL-1β, IL-6, and activation of proteases at the vicinity of injury site (Fig. 1.3). Thus collective evidence suggests that secondary event of SCI is supported by the induction of excitotoxicity, oxidative stress, and neuroinflammation.14 18 These neurochemical events are followed by alterations in ion homeostasis, changes in cellular redox, mitochondrial dysfunction, induction of neurodestructive and neuroprotective genes, alterations in enzymic activities, and upregulation in expression of proinflammatory cytokines and chemokines.18

Traumatic Brain Injury TBIs are caused not only by blow to the head by an external force, motorcycle, and car accidents but also by contact sports (American football, boxing, wrestling, rugby, hockey, lacrosse, soccer, and skiing) among young adults (15 and 24 years). In addition, military veterans (20 and 30 years) expose themselves to repetitive concussions or mild traumatic brain injuries (mTBIs) throughout their careers. Among seniors (75 years and older), fall is an important cause of TBI.19 Like SCI, the pathophysiology of TBI is biphasic. The primary injury in TBI occurs rapidly while secondary TBI is initiated at later time points. The primary injury in TBI is accompanied by an increase in intracranial pressure, rupturing of microvessels and neural cells, diffuse axonal shearing, disruption of BBB permeability, and necrosis of neural cells. In contrast, secondary injury results in Ca21 influx, activation of microglial cells and astrocytes, onset of cellular stress, induction of neuroinflammation, and apoptotic cell death (Fig. 1.4).20 Cerebral edema is another process, which is induced by water imbalance, substance P release, and the development of functional deficits in response to TBI.21 Secondary injury in TBI results in induction of excitotoxicity, increase in Ca21-influx, activation of Ca21-dependent enzymes (cPLA2, COX-2, NOS, MMPs, and calpains) induction of oxidative stress, decrease in ATP, disruption of BBB, increase in the expression of proinflammatory cytokines and chemokines, and changes in cellular redox (Fig. 1.4). Cerebral ischemia also contributes to the pathogenesis of secondary TBI. It results in a decrease in cerebral blood flow within the first hours after TBI.22 The decrease in cerebral blood flow not only results in mitochondrial damage, alterations in ion homeostasis, and development of edema but also in the disruption of interactions between neurons and glial cells along with induction of neuroinflammation.23 25 Clinical symptoms of secondary injury appear slowly (days/week/months) after TBI. Although TBI occurs in a matter of milliseconds, the biological consequences of TBI last a lifetime. In fact, TBI is recognized as an

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FIGURE 1.4 Pathways contributing to traumatic brain injury. Glu, Glutamate; cPLA2, cytosolic phospholipase A2; NOS, nitric oxide synthase; ARA, arachidonic acid; ROS, reactive oxygen species; RNS, reactive nitrogen species; Cyto c, cytochrome c; IL-1β, tumor necrosis factor-α; interleukin-1β; IL-6, interleukin-6; COX-2, cyclooxygenase-2; FFA, free fatty acid; CTE, chronic traumatic encephalopathy; ONOO2, peroxynitrite.

environmental risk factor for many neurodegenerative diseases such as AD, PD, concussion, and chronic traumatic encephalopathy (CTE).5 Very little is known about the molecular mechanisms that link TBI to development of neurodegenerative diseases. Concussion is a complex neurological syndrome produced by mild traumatic biomechanical acceleration and deceleration forces initiated by either a direct blow to the head, face, or neck or via excessive force elsewhere on the body transmitted to the head.26,27 In concussionmediated brain injury, the brain elongates and deforms, stretching neurons, glial cells, and blood vessels. This not only results into altered neural cell membrane permeability but also disruption of BBB. These processes may cause unconsciousness, memory and motor impairment, and cognitive decline leading to increase in dementia risk.28 30 At the molecular level, concussion is accompanied by pathophysiology of concussion involves a complex cascade of neurochemical changes, which include potassium efflux, and sodium and calcium influx, in

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discriminant release of excitatory neurotransmitter (glutamate) leading to neuronal membrane depolarization, acute hyperglycolysis and subacute metabolic depression,31 along with reduction in cerebral blood flow and uncoupling or mismatch between energy supply and demand. This is followed by influx of calcium, which persists longer than other ionic disturbances. This leads to sequestration of calcium into mitochondria producing mitochondrial dysfunction and induction of oxidative stress along with neuroglial energy crisis in the injured brain. In addition, concussion also produces changes in intracellular redox state. This puts additional stress on neurons and glial cells through the generation of free radicals (superoxide anions; hydroxyl, alkoxyl, and peroxyl radicals; and hydrogen peroxide) producing more oxidative stress triggering long-lasting impairments in neuronal function, which is particularly relevant for the clinical setting of sports-related concussion.32 Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative tauopathy associated with repetitive mild brain trauma (RMBT). Because millions of athletes and thousands of military veterans are exposed to RMBTs and subconcussive insults and TBI, CTE represents an important public health issue.33,34 The relationship between concussion and CTE is not clear. However, it is reported that the number of concussions does not significantly correlate with pathology of CTE.35 37 The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition. At late stages, CTE is characterized by activation of microglia and astrocytes, release of cytokines, and induction of neuroinflammation along with induction of movement and speech disorders. CTE can be distinguished from other neurodegenerative diseases by a distinctive topographic location and cellular pattern of tau neurofibrillary tangles (NFTs) (Fig. 1.4).35 37 CTE is also accompanied by alterations in BBB and in postmortem tissues, CTE is diagnosed by using antibodies directed against phosphorylated tau (p-tau) protein.29,38

NEURODEGENERATIVE DISEASES Risk factors for neurodegenerative diseases include old age, genetic disposition, environmental factors, immune system alteration, and unhealthy lifestyle (Fig. 1.5). Neurological disorders are accompanied by the accumulation of misfolded proteins, mitochondrial and proteasomal dysfunction, loss of synapses, and progressive premature and selective slow death of specific neuronal populations in a specific region of the brain due to the induction of oxidative stress and neuroinflammation.2,39 In addition, interplay among pathological factors (aging, environmental factors, genetic

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FIGURE 1.5 Factors contributing to the pathogenesis of neurodegenerative diseases. IL-1β, interleukin-1β; IL-6, interleukin-6; BBB, blood brain barrier; Aβ, beta-amyloid; α-syn, alpha-synuclein.

predisposition, and cellular redox status) along with increase in metal ionlike iron and expression of cytokines and chemokines may also play a major role in the pathogenesis of neurodegenerative diseases (Fig. 1.5).2,40 42 Majority of cases of neurodegenerative diseases ( . 93% 95%) are of sporadic and only 5% 7% cases appear to be primarily genetic origin. The onset of neurodegenerative diseases is often subtle and usually occurs in mid-to-late life and their progression depends not only on genetic but also on environmental factors.39 The onset occurs when neurons fail to respond adaptively to age- and lifestyle-related increase in oxidative and nitrosative stress and neuroinflammation. Persistence presence of oxidative stress and neuroinflammation in neurodegenerative diseases is accompanied by significant decline in glutathione, glutathione peroxidase, glutathione-S-transferase, and superoxide dismutase.2

Alzheimer’s Disease AD is characterized by the accumulation of extracellular β-amyloid (Aβ) plaques (senile plaques) and intracellular NFTs composed of Tau

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amyloid fibrils,2,43 leading to the loss of synapses and degeneration of neurons in multiple brain regions (cortical and subcortical areas and hippocampus). Aβ plaques (senile plaques) first appear in the frontal cortex and then spread over the entire cortical region, while hyperphosphorylated Tau and insoluble tangles initially appear in the limbic system (entorhinal cortex, hippocampus, and dentate gyrus) and then progress to the cortical region. NFTs appear before the deposition of plaque in AD brains and that tangle pathology is more closely associated with disease severity than the plaque load.44 Aβ peptides are produced from the proteolytic cleavage of amyloid precursor protein (APP) by α-secretase or β-secretase (BACE-1). The action of α-secretase produces APPsα (C83), whereas degradation of APP by β-secretase generates APPsβ (C99) along with the formation of membrane-tethered α- or β-carboxyl-terminal fragments (CTFs). CTF processing by γ-secretase generates the harmless P3 peptide (nonamyloidogenic pathway) or Aβ peptides ranging in size from 35 to 42 amino acids (amyloidogenic pathway), plus the APP intracellular domain (AICD) fragment.45 Accumulation of Aβ and its aggregation contribute to a variety of cytotoxic effects. For example, Aβ not only affects the mitochondrial redox activity, increases the production of ROS, damages the intracellular calcium homeostasis, and induces the formation of selective calcium channels but also promotes the increase in lipid mediators and release of cytokines through the stimulation of phospholipases A2, COX-2, and NOS activities, whereas Tau hyperphosphorylation and NFT formation contribute to the increase in rate of protein misfolding, generation of amyloidogenic oligomers, underactivity of repair systems such as chaperones and ubiquitin proteasome system, or a failure of energy supply and antioxidant defense mechanisms.46,47 These processes result in abnormal and unbalanced functional activities leading to neuronal dysfunction and ultimately causing neural cell death and cognitive dysfunction.2,43,48 Majority of AD cases ( . 90% 95%) are of sporadic (lateonset form). These patients are older than 65 years. Only 5% 7% cases are primarily genetic (early-onset familial form) involving apolipoprotein E, APP, presenilin 1 (PS 1), and presenilin 2 (PS 2) genes.49,50 TBI in childhood increases the risk of AD later in life.51 53 In addition, many animal studies have indicated that TBI not only enriches the metabolism od APP but promotes the production and accumulation of Aβ and pathological tau following TBI.52,54 Furthermore, accumulation of APP and extracellular deposition of the 40- to 42-amino acid Aβ peptide occurs in senile plaques in human brain tissue soon after severe TBI supporting the view that there are molecular links between TBI and AD.55

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Parkinson’s Disease PD is a chronic, multifactorial, and progressive neurological disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta as well as the formation of intracellular inclusion bodies, also known as Lewy bodies (Fig. 1.6). The molecular mechanisms contributing to the pathogenesis of PD remain unknown. However, it is proposed that the neurodegeneration of dopaminergic neurons may be result in the depletion of dopamine leading to abnormal dopaminergic neurotransmission in the basal ganglia motor circuit. This process not only promotes resting tremor, muscular rigidity, akinesia, bradykinesia, and posture but also produces ambulation difficulty, sleep disorder, depression, dementia, and gastrointestinal dysfunction.56,57 Mutation in several genes contributes to familial and sporadic forms of PD. These genes include α-synuclein, Parkin, PINK1, DJ-1, LRRK2, and UCHL1.57 Lewy bodies, the key hallmarks of PD, are

FIGURE 1.6 Involvement of α-synuclein in the pathogenesis of Parkinson’s disease. Glu, Glutamate; NMDA-R, NMDA receptor; PtdCho, phosphatidylcholine; Lyso-PtdCho, lyso-phosphatidylcholine; cPLA2, cytosolic phospholipase A2; COX-2, cyclooxygenase-2; 5LOX, 5-lipoxygenase; ARA, arachidonic acid; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; I-κB, inhibitory subunit of NFκB; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; Cyto c, cytochrome c; Bcl2, B-cell lymphoma 2

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mainly composed by α-synuclein (Fig. 1.6). Among PD-associated proteins, α-synuclein and PTEN-induced putative kinase (PINK)1 are two critical proteins associated with the pathogenesis of PD. α-Synuclein-induces mitochondrial deficits and apoptosis. PINK1 alleviates α-synuclein-mediated toxicity. However, the mechanistic details remain obscure. PINK1 interacts with α-synuclein mainly in the cytoplasm, where it initiates autophagy. These interactions depend on the kinase activity of PINK1 and are abolished by deletion of the kinase domain or a G309D point mutation, an inactivating mutation in the kinase domain.58 Interaction between PINK1 and α-synuclein stimulates the removal of excess α-synuclein, which prevents mitochondrial deficits and apoptosis.58 Another protein whose mutations have been found to induce rare forms of autosomal recessive PD is DJ-1. This protein acts as a redox-sensitive molecular chaperone, whose loss of function may induce oxidative stress and consequently mitochondrial damage.59 Sporadic PD cases may be caused by the environmental and genetic risk factors provoking oxidative stress, excitotoxicity, mitochondrial dysfunction, energy failure, neuroinflammation, misfolding and aggregation of α-synuclein, impairment of protein clearance pathways, cell-autonomous mechanisms, and deficits in proteasomal function or autophagy lysosomal degradation of defective proteins (e.g., α-synuclein).57,60,61 Among these processes, protein misfolding and subsequent accumulation of misfolded proteins in intracellular spaces have become a leading hypothesis for PD.62 Misfolded α-synuclein not only undergoes phosphorylation, nitration, and truncatation but also has abnormal solubility. It has ability to prompt the production of oligomeric species, aggregates into fibrils, and can be ubiquitinated.63 Like misfolded Aβ protein inclusion in AD, in the intracellular spaces of substantia nigra pars compacta neurons in PD contain aggregated α-synuclein.57 As stated above, substantia nigra pars compacta neurons contain intracytoplasmic inclusions called Lewy bodies and Lewy neurites which contain several misfolded amyloid proteins, including aggregated and nitrated α-synuclein, p-tau, and Aβ protein.64 α-Synuclein-induces neurodegeneration not only through the mitochondrial thiol oxidation and activation of caspases downstream of mitochondrial outer membrane permeabilization but also by promoting apoptosis.65 α-Synuclein also modulates activities of microglial cells. Thus interactions between nitrated and aggregated α-synuclein with microglia result in secretion of inflammatory, regulatory, redox-active, enzymatic, and cytoskeletal proteins.66,67 The interactions between α-synuclein and microglial cells not only increase the levels of extracellular glutamate and cysteine but also decrease the levels of intracellular glutathione and other secreted exosomal proteins.66,67 Increase in redox-active proteins

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suggests regulation of microglial responses by misfolded, nitrated α-synuclein. These changes are linked with the discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation in animal models of PD.67 Extracellular α-synuclein is also known to induce neuroinflammatory reactions in glial cells leading to neurodegeneration. High levels of α-synuclein in blood can contribute to CNS pathology, since the plasma levels of α-synuclein are significantly higher than in the CSF levels.68

Huntington’s Disease HD is an autosomal dominant neurodegenerative disorder, which is characterized by the selective loss of medium spiny projection neurons mainly in the striatum and cortex, although other regions including the hippocampus are also affected. Symptoms of HD include midlife onset of involuntary movements, cognitive, physical and emotional deterioration, personality changes, and dementia leading to premature death.69 The mean age of HD onset is between 30 and 50 years, with a range of 2 85 years. The mean duration of the disease is 17 20 years. The progression of the disease leads to more dependency in daily life and finally death. The most common cause of death is pneumonia, followed by suicide. HD is caused by an expanded cytosine adenine guanine (CAG) repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product called huntingtin (Htt). This protein is expressed ubiquitously in the human body.70 Its highest levels occur in the brain, where it is expressed in all neurons and glial cells.71 Wild-type Htt is largely localized in the cytoplasm, but in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, suggesting that mutant Htt (mutHtt) may contribute to a transcriptional dysfunction resulting in multiple cellular dysfunctions such as intracellular signaling pathway alterations, protein trafficking defects, synaptic transmission impairments, proteasome dysfunction, and mitochondrial alterations (Fig. 1.7).71 73 It is also proposed that mutHtt produces toxicity through protein aggregation, transcriptional dysregulation, defective energy metabolism, oxidative stress, excitotoxicity, and inflammation,74 76 as well as to the loss of beneficial functions of wild-type Htt, which includes BDNF translation, vesicle transport, and as scaffold for autophagic machinery.77 79 Growing evidence suggests that mutHtt disrupts mitochondrial functions, resulting in energetic defect, reactive oxygen species overload, and release of proapoptotic molecules (Fig. 1.7). More specifically, the respiratory chain is affected with impairment of the mitochondrial complex II/III activity in the caudate

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FIGURE 1.7 Involvement of α-synuclein in the pathogenesis of Huntington’s disease. Glu, Glutamate; NMDA-R, NMDA receptor; PtdCho, phosphatidylcholine; Lyso-PtdCho, lyso-phosphatidylcholine; cPLA2, cytosolic phospholipase A2; COX-2, cyclooxygenase-2; 5LOX, 5-lipoxygenase; iNOS, inducible nitric oxide; ARA, arachidonic acid; PAF, platelet activating factor; ONOO2, peroxynitrite; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; I-κB, inhibitory subunit of NF-κB; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; Cyto c, cytochrome c; Bcl2, B-cell lymphoma 2; Cyto c, cytochrome c; NOS, nitric oxide synthase.

and putamen samples of HD patients.69 The maintenance of functional mitochondria requires biogenesis as well as mitochondrial fusion/ fission dynamics to replenish stores of damaged components. Peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) is a key transcriptional coactivator that controls mitochondrial biogenesis and energy metabolism. PGC-1α is downregulated by mutHtt through interference with the CREB/TAF4-dependent transcriptional pathway.80 More recently, fragmented mitochondria were linked to HD,81 due to increased dynamin-related protein 1 activity.82,83 The accumulation of mitochondrial damages in postmitotic neurons is therefore considered as a key process in HD pathogenesis.

Amyotrophic Lateral Sclerosis ALS is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5% 10% of the ALS CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

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has familial form of this disease and rest of the ALS patients are sporadic. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS patients.84 Familial forms of ALS are classified into two subtypes: classical fALS in which degeneration occurs only in motor neurons and familial ALS, which is characterized by the degeneration of the posterior column in addition to the lesion of the motor neuron system.84 How mutations in SOD1 cause motor neuron death remains uncertain. However, several mechanisms have been proposed to explain the gain of toxic property.85 One of the proposed mechanisms is the formation of protein aggregates, which have been proposed to interfere with one or more critical cellular processes.86 SOD1 positive inclusions are found not only in spinal cord tissue of fALS patients87 and in spinal cords of transgenic mice that express SOD1-linked fALS mutant proteins.88,89 It is reported that there is a strong correlation between the aggregation of mutant SOD1 and toxicity.90 The etiology of sporadic ALS remains unclear. However, disturbances in calcium homeostasis and protein folding are essential features of neurodegeneration that occurs in ALS. The progressive loss of upper and lower motor neurons leads to muscle loss, paralysis, and death from respiratory failure. Other possible mechanisms of neurodegeneration in ALS include91 excessive production of ROS and RNS,92 mitochondrial dysfunction,93 induction of endoplasmic reticulum stress, axonal deterioration, and deposition of toxic ubiquitinated neuronal inclusions, where transactive response DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are major protein components.93 Most of the abovementioned mechanisms are interconnected and interactions among excitotoxicity, oxidative stress, and neuroinflammation may play a major role in pathogenesis of ALS.92,94 In addition, there is evidence not only for the involvement of immune system in the ALS but also for the activation of components of the classical complement pathway in the serum, cerebrospinal fluid, and neuronal tissue of individuals with ALS.91,93

NEUROPSYCHIATRIC DISORDERS As stated above, neuropsychiatric diseases are accompanied by mild chronic oxidative and neuroinflammation.95 At the nuclear level, abnormalities in neuropsychiatric diseases may be caused by neuronal network-mediated abnormalities, disbalanced neurotransmission, and overexpression or underexpression of genes that modulate behavioral symptoms.96 In addition, environmental factors (exposure to heavy metals or other toxins) and hormonal impairments can also contribute

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to the pathogenesis of neuropsychiatric diseases. In addition, neuropsychiatric diseases also involve gray-matter atrophy caused by reduction in neuronal and glial size, increase in cellular packing density, disruption in neuronal connectivity, particularly in the dorsolateral prefrontal cortex, and distortions in neuronal orientation.97

Depression Depression is a multisystem and multifactorial mental disorder characterized by depressed mood, anhedonia (reduced ability to experience pleasure from natural rewards), irritability, difficulties in concentrating, and abnormalities in appetite and sleep (neurovegetative symptoms).98 Many studies on depression have indicated that depressed patients show reduced gray-matter volume and glial density in the prefrontal cortex and the hippocampal regions, elevated levels of blood IL-6 and TNF-α,99 low levels of magnesium, overactivity of hypothalamic pituitary adrenal axis, and alterations in cerebral structures. The molecular mechanism of depression is not fully understood. However, it is proposed that the pathogenesis of depression may involve the disturbance in neurotransmitters (dopamine, norepinephrine, and serotonin), increase in inflammatory processes, defects in neurogenesis, decrease in synaptic plasticity, mitochondrial dysfunction, and redox imbalance. In addition, changes in neuropeptides (vasopressin), cytokines, and gene environmental interactions may contribute to the pathogenesis of depression.99,100

Autism Spectrum Disorder Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, which is characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Symptoms of ASD are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. The molecular mechanisms contributing to the pathogenesis of ASD are not fully understood. However, it is proposed that an abnormal immune response, chronic neuroinflammation, and autoimmunity may exert a negative influence on neurodevelopment, potentially contributing to the etiology of autism.101 Structural abnormalities have also been described in the cerebellum, hippocampus, amygdala, and insular cortex of autistic patients.102 Animal model studies indicate that stress reduces BDNF expression or activity in the hippocampus and that this reduction can be prevented by treatment with antidepressant drugs.103 Recent

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evidence supports the view that pathogenesis of autism may involve not only genetic factors but supported by strong environmental components along with persistent neuroinflammation.104 Collective evidence suggests that autism is a neuropsychiatric disorder of unknown pathogenesis. ASD is characterized by neuroinflammation, peripheral immune abnormalities, and environmental factors. Interactions among these factors may explain symptomatology of ASD.

CONCLUSION Neurological disorders constitute a group of brain and spinal cord diseases characterized by a progressive deterioration of structure and/ or function of neuronal cells. Neurological disorders not only show different symptoms but may also be caused by multitude of unknown causes and factors. Most neurological disorders are accompanied by induction of oxidative stress and onset of neuroinflammation along with mitochondrial and proteasome system dysfunctions. Neurological disorders are classified into three groups, namely, neurotraumatic diseases, neurodegenerative diseases, and neuropsychiatric diseases. The major basic mechanisms leading to neurodegeneration are multifactorial caused by genetic, environmental, and endogenous factors related to aging. Aging is the most important nonmodifiable risk factor for the stroke, AD, PD, and HD.

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