AD, a leading cause of dementia, is characterized by a progressive decline in cognitive function [48]. Amyloid beta (Aβ) plaques, neurofibrillary tangles (NFTs), hyperphosphorylated microtubule-associated protein tau, and neuronal loss within the brain are specific histopathological hallmarks of AD patients [49]. Prior to the development of plaque pathology, oxidative stress has been recognized as the key player in the etiology of AD, contributing to mitochondrial dysfunction in synapses and neurons, and in Aβ production [50,51]. In fact, the concept of oxidative stress in AD was originally derived from the “free radical theory of aging”, meaning that free radicals play a central role in the aging process [52]. Mitochondrial dysfunction in AD includes impaired mitochondrial complexes [53,54,55,56], malfunctioning of F1Fo adenosine triphosphate (ATP) synthase, which is involved in oxidative phosphorylation [57,58], and damage to the promoter of the mitochondrial ATP synthase gene that controls ATP generation [59,60]. Further, dysfunctional mitochondria produce 4-HNE that upregulates γ-secretase complex and promotes cleavage of the amyloid precursor protein (APP), leading to Aβ accumulation [61,62]. In addition, increased Ca²⁺ and ROS levels lead to a buildup of p-tau aggregates which are toxic and are considered as one of the defining pathological hallmarks of AD patients [63]. ROS also play a pivotal role in the stress kinases like the phospho-c-Jun N-terminal kinase 1 (p-JNK) pathway which is linked to tau hyperphosphorylation and cell death in response to Aβ accumulation [64]. Further, oxidative stress reduces the activities of antioxidants, i.e., superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST), thus weakening the endogenous antioxidant defense of the CNS [65]. Further, oxidative stress increases The increased levels of LPO under oxidative stress are strongly associated with neurotoxicity in AD [50] as it leads to an increase in amyloidogenesis through upregulation of β-secretase expression [66]. Although there are several downstream degenerative events, it appears that mitochondrial dysfunction and oxidative stress are the key triggering factors in the pathogenesis of AD.

PD is the second-most common neurodegenerative disease after AD that causes both motor and nonmotor symptoms [67]. The pathology of PD is driven by the accumulation and aggregation of α-synuclein, a presynaptic neuronal protein in the nervous system [68]. The mechanisms associated with the pathogenesis of PD include aberrant protein homeostasis, bioenergetic impairment, and oxidative stress [69]. Oxidative stress is associated with α-synuclein protein aggregation [64]. The cascade of events leading to degeneration of dopaminergic neurons in PD is also linked to oxidative stress [70]. Analysis of the postmortem brain tissue of the victims of PD shows elevated levels of oxidative stress markers such as 4-HNE, protein carbonyl, 8-hydroxy-2′-deoxyguanosine, and 8-hydroxy-guanosine [71]. In addition, oxidative stress is associated with the formation of Lewy bodies, which are the clumps of protein in the PD brain [72]. Experimental evidence in PD models suggests that oxidative stress in the dopaminergic neurons activates p38 mitogen-activated protein kinase (p38 MAPK) pathway that ultimately leads to apoptosis of the brain cells [73].

ALS is also known as Lou Gehrig’s disease, in which motor neurons in the brain, brain stem, and spinal cord are damaged, resulting in muscle weakness, atrophy, paralysis, and premature death [74]. Oxidative stress, mitochondrial dysfunction, and mutations in the genes that act on mitochondrial processes are involved in the pathophysiology of ALS [75,76]. Most of the familial ALS patients (15–20%) have mutations in the superoxide dismutase 1 (SOD1) gene, which plays an important role in the defense mechanism against oxidative stress [77]. More than 150 ALS-related SOD1 gene mutations have been discovered in various parts of the enzyme, which result in protein misfolding and aggregation, increased ROS production, and redox system disequilibrium, ultimately resulting in nerve cell loss [77,78]. ALS is also linked to several interrelated risk factors, such as neuroinflammation, excitotoxicity, mitochondrial dysfunction/dysregulation, and endoplasmic reticulum stress [79,80,81]. Considerably high oxidative stress biomarkers such as MDA, 8-hydroxyguanosine, and advanced oxidation protein products are found in ALS patients [82]. In sporadic ALS patients, cystine/glutamate antiporter overexpression was observed that causes increased oxidative stress and extracellular glutamate accumulation [83]. In addition, dysregulation of the retinoic acid (RA) signaling pathway, a product of vitamin A, contributes to the death of motor neurons [84].

In stroke, thrombus formation in cerebral blood vessels creates an ischemic condition, triggering free radical formation and tissue damage (Figure 2) [85]. Resumption of blood supply to the ischemic region further exuberates the condition as more free radicals are formed, termed “reperfusion injury or reoxygenation injury” [86]. Collectively, it is referred to as the ischemia/reperfusion (I/R) injury [86]. Oxidative stress leads to mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity, resulting in the blood-brain barrier (BBB) damage, apoptosis/necrosis of neurons, and supporting cellular elements (glial cells and vessels) [87,88,89]. These are the prominent features of neurodegeneration in stroke-related cerebral pathology [90,91,92,93]. Further, excessive ROS production or impaired ROS degradation [94,95] stimulates vasoconstriction, increased platelet aggregation, and endothelial cell permeability, thereby affecting cerebral blood circulation [96]. Activation of matrix metalloproteinases (MMPs) disrupts the cerebral extracellular matrix (ECM), which causes immunocyte infiltration and neuroinflammation, culminating in the breakdown of the neurovascular unit (NVU), leading to hemorrhage and edema [97,98].

SCI is another common form of neuronal injury that causes neurological dysfunctions [99] and is characterized by an initial primary injury followed by the secondary phase of injury (Figure 3) [100]. Primary injury results immediately from the initial trauma causing damage to the blood vessels and axons [101]. In contrast, secondary injury is the indirect result of the primary injury that involves inflammation and oxidative stress [10]. The secondary injury progression occurs not only at the site of impact, but it spreads along the entire spinal cord, including the faraway segments of the spinal cord that are not impacted, making the condition more devastating and debilitating with time [101]. Following injury, the elevated levels of ROS and the consequent oxidative stress are considered critical events associated with the secondary injury progression [102]. Under oxidative stress condition, dysfunctional mitochondria become the source of ROS [103] that cause a further cascade of degenerative processes, particularly curtailing ATP production required for normal cellular functioning, thus promoting apoptosis [103]. The excess ROS alters cell functions by modulating ion channels, followed by excessive accumulation of intracellular calcium ions that eventually causes excitotoxicity [104]. Oxidative stress damages the microvascular endothelium that reduces the spinal cord white matter blood flow, resulting in ischemic injury [105].

The peripheral nervous system (PNS) is a bundle of long nerve fibers that connect different parts of the body with the CNS. Damage to the peripheral nerves due to trauma and compression can cause impairment in the brain’s communication with the target organs [106]. These injuries affect motor and sensory behaviors, perception, consciousness, and sensations of the skin and joints [106]. The most common symptoms of PNI are defects in sensory and motor function that can lead to complete paralysis of the affected limb or the development of intractable neuropathic pain [107]. Many surgical procedures, such as oral and maxillofacial surgery, can also cause injury to the peripheral nerves [108]. The major component of the mechanism and pathogenies of PNI involves oxidative stress and inflammation that exacerbates neural damages and plays a negative role in the regeneration process [109]. Experimental evidence at the preclinical level has demonstrated that inhibiting oxidative stress could help improve functional recovery by accelerating the repair processes [110,111,112,113,114].

Other neurodegenerative diseases implicated due to oxidative stress are: vascular dementia [115], Down syndrome [116], Autism [117], attention-deficit/hyperactivity disorder (ADHD) [118], Huntington’s disease (HD) [119], multiple sclerosis (MS) [120], depression [121], and epilepsy [122]. Similarly, in traumatic brain injury (TBI) [123], progressive degeneration occurs due to the accumulation of excessive free radicals, glutamate release, Ca²⁺ overload, mitochondrial dysfunction, leading to apoptosis/necrosis [123].