Neuromodulatory Targets for Neuroprotection: Bridging Acetylcholinesterase Inhibition and Neuronal Health

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s are marked by progressive neuronal loss and impaired synaptic function, often exacerbated by oxidative stress, excitotoxicity, and neurotransmitter imbalances. Among the promising therapeutic strategies, modulation of acetylcholinesterase (AChE) activity has garnered significant attention not only for its symptomatic relief through enhanced cholinergic transmission but also for its emerging role in broader neuroprotective pathways. This review delineates the dual role of AChE as both an enzymatic regulator of synaptic acetylcholine and a non-catalytic modulator involved in apoptosis, neurite outgrowth, and synaptic remodeling. Furthermore, we explore the interconnected signaling cascades involving neurotrophic factors, inflammatory mediators, and oxidative stress modulators that intersect with AChE regulation. Natural and synthetic AChE inhibitors, such as donepezil, galantamine, huperzine A, and novel multitarget compounds, are examined for their efficacy, blood-brain barrier permeability, and off-target effects. Finally, we propose a systems pharmacology approach integrating AChE inhibition with secondary neuromodulatory targets, such as NMDA receptors, nicotinic receptors, and neurotrophin signaling, to enhance therapeutic precision. This integrative model offers a conceptual bridge between symptomatic management and disease-modifying interventions in neurodegeneration. Keywords: Acetylcholinesterase inhibition; Neurodegeneration; Synaptic plasticity; Neuroinflammation; Multitarget therapy