Signaling Pathways in Oxidative Stress-Induced Neurodegenerative Diseases: A Review of Phytochemical Therapeutic Interventions

Abstract

Oxidative stress, a pivotal driver of neurodegenerative diseases, results from an imbalance between the generation of reactive oxygen species (ROS) and cellular antioxidant defenses. This review provides a comprehensive analysis of key oxidative stress sources, focusing on NADPH oxidase (NOX) hyperactivity and mitochondrial Uncoupling Protein (UCP) downregulation. Critically, we examine the therapeutic potential of phytochemicals in mitigating NOX-mediated ROS generation through direct enzyme inhibition, including impacts on NOX subunit assembly and gene expression. Furthermore, we explore the ability of phytochemicals to bolster cellular antioxidant defenses by activating the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, elucidating the upregulation of antioxidant genes, such as GPx, SOD, CAT, and HO-1. This review expands beyond confined overviews; emphasizes specific molecular interactions between phytochemicals and target proteins, including NOX isoforms; and provides an in-depth analysis of the specific antioxidant genes upregulated via Nrf2. This approach aims to pave the way for targeted and translatable therapeutic strategies in neurodegenerative diseases. Ultimately, this review illuminates the intricate molecular dynamics of oxidative stress in neurodegenerative diseases; underscores the potential of phytochemicals to restore redox homeostasis and reverse pathological conditions through precise modulation of key signaling pathways.

Keywords: Alzheimer’s disease; NADPH oxidase; Parkinson’s disease; neuroprotection; phytochemicals; reactive oxygen species; therapeutic interventions.

Figure 1

The presence of Aβ protein plaques in Alzheimer’s disease (AD) is linked to the persistent activation of the NOX enzyme. This sustained activation results in excessive production of ROS. Additionally, tau tangles can disrupt the integrity of the plasma membrane, triggering calcium influx into neural cells. This initiates apoptotic cell death in the AD-afflicted brain.

Figure 2

The downregulation of UCP2 results in the dissipation of mitochondrial membrane potential (ΔΨmito) and accumulation of ROS, which subsequently inhibits the activity of ATP synthase. Overall, the consequence is a decrease in the activities of UCP2, ATP synthase, ATP production, and an excessive accumulation of ROS. The latter can induce OS and the formation of reactive astrocyte/microglial cells. This interplay stands as a significant factor in neuroinflammation and the pathogenesis of neurodegenerative diseases (NDDs).

Figure 3

This diagram illustrates the disruption of the KEAP1-Nrf2 complex by phytochemicals, preventing the degradation of Nrf2. This disruption results in the liberation of Nrf2 in the form of phosphorylated Nrf2 (p-Nrf2), which is then translocated to the nucleus. In the nucleus, p-Nrf2 binds to antioxidant response elements (AREs) in the promoter region, influencing the expression of key antioxidant genes (GPx, CAT, SOD, HO-1). This process reduces ROS and alleviates OS, thereby mitigating NDDs.

Figure 4

(A) The diagram illustrates that the majority of the phytochemicals associated with NOX inhibition and Nrf2 activation belong to the polyphenol/phenolic acid category and its subgroup, flavonoid. Notably, resveratrol, curcumin, rosmarinic acid, quercetin, and EGCG demonstrate both Nrf2 activating and NOX inhibitory activities. (B) Apocynin and fucoidan, derived from two distinct compound categories, are linked to NOX inhibitory activity. The remaining phytochemicals are categorized into diverse compound groups, each associated with Nrf2 activation.