Molecular Mechanisms of Neurodegeneration: A Focus on Cholinergic Dysfunction and the Therapeutic Potential of Rivastigmine Derivatives

Neurodegenerative diseases progressively impair neuronal structure and function, leading to cognitive decline, motor dysfunction, and paralysis. Among the underlying mechanisms, cholinergic dysfunction—characterized by degeneration of cholinergic neurons and reduced acetylcholine (ACh) levels—plays a central role in disease progression, particularly in Alzheimer’s disease (AD) and Parkinson’s disease (PD). According to the cholinergic hypothesis, memory loss and cognitive impairment are directly linked to disrupted ACh-mediated neurotransmission. Rivastigmine, a dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor, enhances synaptic ACh levels but is limited by a short half-life, modest efficacy, and gastrointestinal side effects. This review highlights the molecular mechanisms underlying cholinergic dysfunction, including oxidative stress, mitochondrial impairment, protein aggregation, neuroinflammation, and synaptic dysregulation, while emphasizing rivastigmine and its derivatives as emerging therapeutic candidates. Structural modifications of rivastigmine have yielded multifunctional derivatives with improved selectivity, blood–brain barrier penetration, and neuroprotective properties, including antioxidant, anti-amyloid, and anti-inflammatory activities. These advances suggest that rivastigmine derivatives could serve as promising multi-targeted agents for neurodegenerative disorders. Future directions include integrating these compounds with nanotechnology-based delivery systems and precision medicine approaches to overcome pharmacokinetic limitations and optimize patient outcomes.