Objectives: Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species, along with the failure of balancing effects of endogenous antioxidant defenses result in destruction of cellular structures, lipids, proteins, and genetic material, which lead to oxidative stress. Oxidative stress-induced neuronal apoptosis plays a pivotal role in pathogenesis of neurodegeneration. Antioxidants represent one of the medical choice strategies for protecting against this unbalanced oxidation-antioxidation status. Recently, natural compounds with neuroprotective potential that can scavenge free radicals and protect cells from oxidative damage have received extensive attention.

Methods: In this review, we summarized the detailed research progress on the medicinal plants-derived natural compounds with potential anti-oxidation effects and their molecular mechanisms on modulating the neurotoxin (6-OHDA, H₂O₂, glutamate, Aβ)-induced oxidative stress and cell apoptosis.

Results: The natural compounds that efficacious in modulating reactive species production and mitochondrial function include flavonoids, glucosides, alkaloids, polyphenols, lignans, coumarins, terpenoids, quinones and others. They decreased the neurotoxin-induced oxidative damage and apoptosis by (1) decreasing ROS/RNS generation, lipid peroxidation, caspase-3 and caspase-9 activities, LDH release, the ratio of Bax/Bcl-2, Ca²⁺ influx and cytochrome c release, (2) elevating MMP, and (3) restoring endogenous antioxidant enzymatic activities (CAT, GSH-Px, GSR, SOD). And they exerted neuroprotective effects against cell damages and apoptosis by modulating the oxidative cascades of different signaling pathways (Nrf2/HO-1, NF-κB, MAPKs, PI3K/Akt, GSK-3β) and preventing mitochondria-dependent apoptosis pathways.

Discussion: The present work reviews the role of oxidative stress in neurodegeneration, highlighting the potential anti-oxidation effects of natural compounds as a promising approach to develop innovative neuroprotective strategy.