*4.2.1.2 Parkinson's disease (PD) and OS*

The prevalence of PD is preceded only by that of AD being characterized by dopaminergic neuron degeneration in the substantia nigra [82]. A major pathological hallmark of PD is the intraneuronal aggregation of a-synuclein and the formation of Lewy bodies [93]. Crucial participation of OS in PD is intoned by convincing evidence although the exact mechanisms underlying the pathophysiology of this disease remains indescribable [96]. Singh et al., (2019) reported elevated concentration of oxidative damage markers and low concentration of glutathione (GSH) in the substantia nigra of PD patients [93]. Furthermore, high MDA plasma concentrations [97] and elevated protein carbonyl and 8-OHdG (markers of oxidative impairment to protein and DNA, respectively) in brain tissues have been reported [98]. Also, elevated concentrations of 8-OHdG and MDA, reduced activity of catalase and concentration of uric acid, and GSH have been reported in the blood of PD patients [99]. The involvement of OS in the pathobiology of PD and suggestion that targeting OS and lipid peroxidation offers a potential phytochemical therapeutic strategy for addressing this devastating brain disorder is supported.

### *4.2.1.3 Ischemic stroke and oxidative stress leads to lipid peroxidative damage*

A sudden interruption in brain blood supply due to vascular occlusion results in a stroke which is the second leading cause of death [100] and an important source of permanent disability in adults worldwide [101]. Resultantly, a portion of the brain experiences oxygen and nutrient insufficiencies, which causes depolarization of neuronal membranes and glutamate surge into synapses, resulting in a cascade of events, including calcium overload, dissipation of mitochondrial membrane potentials, OS, and inflammation [63, 102].

Inappropriate concentrations of antiapoptotic proteins [e.g., Bcl-2 (B-cell lymphoma 2)] and proapoptotic proteins [e.g., Bax (Bcl-2-associated X protein)] contribute to mitochondrial dysfunction and OS induced apoptosis [103]. Moreover, the reestablishment of blood supply immediately after ischemia exposes brain tissue to excess oxygen, which exacerbates ROS production and in turn, induces further OS-associated injury, lipid peroxidation, protein oxidation, and intracellular DNA damage [63, 104]. After ischemic stroke, oxidative damage follows with elevated OS biomarkers (NO and MDA) concentrations reported [105]. These findings indicate targeting OS and inhibiting lipid peroxidation offers a promising therapeutic strategy to reduce secondary brain injury after ischemic stroke with possible outcomes improvement [63].

#### *4.2.1.4 Traumatic brain injury builds oxidative stress and lipid peroxidation*

Traumatic brain injury (TBI) is a major cause of death and disability world over. Non-fatal TBI may lead to neurological deficits due to direct tissue damage (primary injury) or subsequent biochemical changes (secondary injury) [106]. Biochemical factors such as excitotoxicity, inflammation, mitochondrial dysfunction, and OS drive progressive neuronal degeneration in secondary damage [107]. Importantly, further damage need be reduced by targeting the secondary changes. Indications that TBI results in OS are observed by OS biomarkers (oxidized

protein moieties, lipid peroxidation products, DNA damage products) accumulating in the brain with antioxidant molecules concentrations and enzymes activities (GSH, GPx, glutathione reductase (GR), glutathione S-transferase (GST), SOD, and CAT) decline [66]. Phytochemical neuroprotective strategies, directed at salvaging injured brain tissue soon after injury and that promote regeneration during the recovery stage, are beneficial [108]. Therapeutic potentials of BDNF and its analogues have been reported in TBI and other neurological conditions [108, 109]. Therefore, phytotherapeutics targeting cellular antioxidant defense and the BDNF/TrkB signaling pathway might improve cognitive deficits secondary to TBI.
