**1. Introduction**

Neurodegenerative diseases are debilitating disorders which compromise motor or cognitive functions and are rapidly becoming a global communal disorder with over 46.8 million people suffering dementia worldwide. They are characterised by progressive damage in neural cells and neuronal loss. Common neurodegenerative diseases include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, and spinocerebellar ataxia [1]. These diseases represent major health challenges especially in the ageing population [2]. For instance, PD is the second most prevalent neurodegenerative disease affecting 1 to 2% of the population above age of 65 while AD is ranked the top 6 leading causes of death in the United States [3, 4].

It is estimated that more than 10 million individuals with the disease will be domiciled in the top 10 most populous nation in the world by 2030. In Nigeria, the most populous nation in Africa, neurodegenerative disease related cases have a significant impact on the overall hospital frequency of neurological cases reported [5]. Some of the characterised clinical features of these diseases include bradykinesia, rigidity, postural instability, resting tremor, prolonged reaction times, and freezing of gait, which may degenerate to tightened facial expression and unconscious facial movement [6, 7]. Aetiological reports have documented that individual who are exposed to industrial, occupational and environmental toxic chemicals that can interfere with the functions of the central nervous system and degenerate dopaminergic neurons are prone to developing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease [8, 9].

The complex pathogenesis of the neurodegenerative diseases remains largely unknown; however, mounting evidence suggests that oxidative stress, neuroinflammation, protein misfolding, and apoptosis are the hallmarks of the diseases (**Figure 1**). ROS may play a critical role as high levels of oxidative stress are commonly observed in the brain of patients with neurodegenerative conditions [10]. Reactive oxygen species (ROS) are chemically reactive molecules that have been implicated in the pathogenesis of neurodegenerative diseases. They are naturally generated within the biological system, playing significant functions in mediating cellular activities including stressor responses, cell survival, and inflammation. They also play pivotal role in the pathogenesis of many diseases such as cancer, allergy, muscle dysfunction, and cardiovascular disorders [11, 12]. Due to their reactivity, Presence of ROS in high quantity may lead to oxidative stress and ultimately cell death if left uncontrolled or treated. Oxidative stress is defined as the disruption of balance between pro-oxidant and antioxidant levels in biological systems [11].

#### **Figure 1.**

*Possible involvement of oxidative stress, apoptosis, and neuroinflammation in pathogenesis of neurodegenerative diseases.*

#### *Reactive Oxygen Species in Neurodegenerative Diseases: Implications in Pathogenesis… DOI: http://dx.doi.org/10.5772/intechopen.99976*

A number of experimental studies have been carried out to elucidate the significances of oxidative stress in neurodegenerative diseases [13, 14]. ROS may not be sufficient itself to induce neurodegenerative diseases but they appear to exacerbate the diseases' progression through oxidative macromolecule damage and interaction with mitochondria [10]. Interestingly, neuronal cells have been identified to be vulnerable to oxidative damage due to their high oxygen consumption, high polyunsaturated fatty acid content in membranes, and weak antioxidant defence [15]. Under basal or unstressed physiological conditions, free radicals and ROS generated from mitochondria, NADPH oxidase (Nox), and xanthine oxidase are kept at relatively low levels by endogenous antioxidants [11]. Nevertheless, abnormal mitochondrial function and/or neuro-inflammation can alter the redox status and interrupt the balance [15]. Accumulation of misfolded proteins is part of the hallmark of pathogenesis of some neurodegenerative diseases such as Alzheimer disease and Parkinson disease (**Figure 2**). The aggregation of these misfolded or modified proteins can in turn triggers inflammatory response in the brain, which induces marked ROS release and subsequent oxidative stress [16]. Mitochondrial dysfunction with concomitant aberrant ROS secretion is strongly associated with neurodegenerative disorders [17]. For instance, mutant huntingtin (mHTT) in HD may directly interact with mitochondria causing compromised and alteration in energy supply and increased production of ROS [18].

Another key player in the pathogenesis of neurodegenerative diseases is neuroinflammation. The existence of neuroinflammatory processes in human brain has also been confirmed during autopsy on a molecular basis. Mogi and colleagues reported an increase in concentrations of TNFα, β2-microglobulin, epidermal growth factor (EGF), transforming growth factor α (TGFα), TGFβ1, and interleukins 1β, 6, and 2 in the striatum of patients with Parkinson's disease [19–22]. TNFα, interleukin 1β, and interferon γ were also detected in the effects indirectly. Proinflammatory cytokines, such as TNFα, interleukin 1β, and interferon γ, can induce the expression of the inducible form of nitric oxide synthase (iNOS) [23, 24] or cyclooxygenase 2 (COX2) [25]. These enzymes produce toxic reactive species. Other enzymes involved in

#### **Figure 2.**

*Molecular mechanisms underlying pathogenesis of Parkinson's disease and Alzheimer's disease.*

neuroinflammatory processes mediated by oxidative stress such as myeloperoxidase, NADPH oxidase, and COX2, also have increased concentrations in neurodegenerative diseases [26].

Apoptosis has been implicated as the major pathway involved in the progressive neuronal cell death/loss observed in neurodegenerative diseases. Degeneration of one or more nerve cell populations is a major feature in many acute and chronic neurological diseases. Many criteria for apoptotic cell death are also fulfilled during the course of chronic neurodegenerative diseases. Therefore, the development of new therapeutic strategies for the treatment of neurodegenerative diseases requires an understanding of the molecular mechanisms underlying neuronal apoptosis. Extrinsic and intrinsic apoptosis pathways and several possible avenues for crosstalk between them can be distinguished. Whereas the extrinsic pathway is initiated by cell surface activation of cytokine receptors of the tumour necrosis factor (TNF) family, the intrinsic pathway depends on the integrity and function of mitochondria within the cell [27].

Various evidences from biochemical, genetic, cellular, and neuropathological studies have shown that protein misfolding, oligomerization, and accumulation in the brain are the main events triggering pathological abnormalities responsible for neurodegenerative diseases [28, 29]. The proteins most commonly implicated in the accumulation of cerebral misfolded aggregates in neurodegenerative diseases include: amyloid-beta (Aβ) in Alzheimer disease; tau in Alzheimer disease, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and chronic traumatic encephalopathy; alpha-synuclein (α-Syn) in PD, multiple system atrophy, and dementia with Lewy bodies; TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis and frontotemporal frontotemporal dementia; and prion proteins in PrDs (i.e., Creutzfeldt–Jakob disease (CJD), bovine spongiform encephalopathy, chronic wasting disease, and scrapie). Despite the fact that the protein aggregates involved in distinct neurodegenerative diseases are different, the process of protein misfolding, its intermediates, end-products, and main features are remarkably similar [30].

Considering the pivotal roles of oxidative stress, neuroinflammation, protein misfolding, and apoptosis in neurodegenerative diseases (**Figure 1**), the manipulation of major key players in each of the pathological mechanisms may represent a promising treatment option to slow down neurodegeneration and alleviate associated symptoms. This chapter examine the role of reactive oxygen species (ROS) and oxidative stress in the pathogenesis and progression of neurodegenerative diseases. This chapter focus on the sources of ROS in the brain, its involvement in the pathogenesis of neurodegenerative diseases and possible ways to mitigate its damaging effects in the brain.
