Designing Multi-functional Antioxidants for Neurodegenerative Disorders.

Abstract

Neurodegenerative disorders (NDs), including Alzheimer's disease, Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS), pose a major global health threat due to complex pathology, increased prevalence, and lack of effective therapies. Numerous findings have indicated that oxidative stress (OS) is a central and unifying pathological mechanism driving neuronal dysfunction and degeneration across these disorders. Excessive reactive oxygen species (ROS) and nitrogen species (RNS) generation, coupled with impaired endogenous antioxidant defenses, leads to lipid peroxidation, protein misfolding, nucleic acid damage, mitochondrial dysfunction, neuroinflammation, metal dyshomeostasis, and disruption of the blood-brain barrier (BBB). These interconnected processes form self-perpetuating pathogenic cycles that accelerate synaptic failure and neuronal loss. This review is a compilation of thoroughly searched literature from the last 20 years (2006-2026) on OS-mediated neurodegeneration and emerging antioxidant-based therapeutic strategies for neurodegenerative disorders, sourced from PubMed, Scopus, ScienceDirect, Google Scholar, and Web of Science. Relevant articles were selected using specific keywords "Neurodegenerative Disorders", Neurodegenerative disorders and antioxidants", "Alzheimer's Disease and Oxidative Stress", "Parkinson's Disease and Oxidative Stress", "Alzheimer's Disease and Multi-functional Antioxidants", "Parkinson's Disease and Multifunctional Antioxidants", "Neurodegenerative Disorders and Antioxidant therapies". Despite strong mechanistic support, conventional antioxidant-based therapies have demonstrated limited clinical success, largely due to poor bioavailability, inadequate BBB penetration, and failure to address the multifactorial nature of neurodegeneration. Consequently, there is a paradigm shift toward the development of multi-functional antioxidants capable of simultaneously targeting multiple redoxdriven pathways. Such agents are designed to combine free-radical scavenging, metal chelation, mitochondrial protection, modulation of redox-sensitive signaling pathways, and regulation of neuroinflammatory responses within a single therapeutic framework. By restoring redox homeostasis while preserving physiological redox signaling, multi-functional antioxidants offer a rational and promising disease-modifying strategy. This review critically examines OS-mediated mechanisms underlying major NDs and emphasizes the therapeutic potential of designed multi-functional antioxidants as next-generation neuroprotective agents.