Oxidative stress and inflammation in neurodegenerative disorders

The brain's consumption of approximately 20% of the body's oxygen contributes to oxidative stress, a significant pathological factor in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This oxidative stress, linked to low levels of antioxidant enzymes, drives neuronal death by facilitating membrane peroxidation of fatty acids, proteins, and DNA. Alzheimer's disease is characterized by amyloid-beta (Aβ) plaque accumulation and hyperphosphorylated tau aggregates, both of which interact with mitochondria to generate reactive oxygen species (ROS). Aβ peptides bind metals such as iron and copper, catalyzing the formation of damaging hydroxyl radicals. Peripheral markers of oxidative damage, such as elevated malondialdehyde and protein carbonyls, are correlated with these processes in affected patients. In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra is associated with pathological iron accumulation and mitochondrial complex I dysfunction, which are worsened by misfolded α-synuclein and mutations in antioxidant genes such as PINK1 and Parkin. The autooxidation of dopamine also drives oxidative stress through the generation of hydrogen peroxide and reactive quinones. Huntington's disease involves the degeneration of medium spiny neurons in the striatum due to a polyglutamine repeat expansion in the huntingtin gene, which disrupts mitochondrial function and downregulates antioxidants, leading to excitotoxicity and ROS spikes. Amyotrophic lateral sclerosis primarily affects motor neurons due to the mutations in SOD1, which result in the production of aggregates that impair mitochondria and generate reactive nitrogen species (RNS), such as peroxynitrite. Mitigating oxidative stress in neurodegenerative disorders presents a considerable translational challenge. While low-molecular-weight antioxidant therapies for neurodegenerative disorders have shown promising results in preclinical and animal studies because they mitigate oxidative stress, their clinical efficacy is hampered by low bioavailability and difficulty in penetrating the blood‒brain barrier. To overcome these limitations, current medical research is focused on alternative delivery systems. Innovations such as nanoparticle-based drug delivery are being actively studied to help transport low-molecular-weight antioxidants across the blood‒brain barrier more safely and effectively. Several promising epidemiological trials linked high dietary intake of vitamins C and E to a reduced risk of Parkinson's disease, and plant-derived antioxidants such as polyphenols were explored for their ability to combat neuroinflammation and reduce cognitive decline. Refined oxidative stress-suppressing strategies involve the (ii) application of mitochondrial-targeted agents to preserve ATP production; (ii) boosting the Nrf2 pathway may trigger a cascade of detoxifying enzymes; (iii) supplementation with polyphenols such as quercetin, resveratrol, and curcumin can suppress oxidative stress and dampen microglial activation (neuroinflammation); (iv) and the use of substances affecting the bidirectional network linking oxidative stress and autophagy can clear ROS-generating components. Despite some promising epidemiological data, translating oral or systemic antioxidant therapy into effective clinical treatments for humans requires further effort. A survey of current knowledge of oxidative stress and antioxidant therapy in neurodegenerative diseases is the main subject of this review.