Parkinson’s disease (PD) is the world’s fastest-growing neurodegenerative disorder, presenting a significant burden on patients, caretakers, and healthcare systems. Despite advances in symptomatic management, disease-modifying therapies remain inaccessible, underscoring the need to focus on prevention and neuroprotection. Estrogen has emerged as a potential neuroprotective agent due to its diverse effects on neuronal survival and function. This review examines the neuroprotective role of estrogen in the pathogenesis of PD. A comprehensive literature search was conducted using the PubMed, Scopus, and Web of Science databases, with a focus on studies published within the last 10 years. The combinatorial keyword strategies, including “estrogen,” “parkinson’s disease,” “estrogen receptor alpha (ERα),” “estrogen receptor beta (ERβ)”, “G-protein coupled estrogen receptor 1 (GPER1),” “neurodegeneration,” “oxidative stress,” “neuroinflammation,” “neuroprotection,” and “preclinical studies.” Findings indicate that estrogen deficiency promotes Parkinson’s-like pathology, which includes oxidative stress, mitochondrial impairment, synaptic dysfunction, and neuroinflammation. Activating ERα, ERβ, and GPER1 through both genomic and non-genomic mechanisms slows disease progression by reducing oxidative damage, inflammatory cytokine release, and neurodegeneration. Preclinical evidence suggests that several natural, synthetic, and semisynthetic estrogen compounds protect neurons by modulating PI3K/Akt, MAPK/ERK, and NF-κB signalling pathways, thereby reducing dopaminergic neuronal loss and improving behavioural outcomes. Estrogen protects the brain from neurotoxic insults, while a deficiency of estrogen exacerbates oxidative stress, mitochondrial dysfunction, and neuroinflammation. While activation of ERα, ERβ, and GPER promotes antioxidant, anti-inflammatory, and anti-apoptotic effects, reducing PD pathogenesis. These findings support estrogen receptors as potential therapeutic targets for PD management.
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