A Review of AChE Inhibitors as Therapeutic Neuromodulators in Neurodegenerative and Neuroinflammatory Conditions

Acetylcholinesterase inhibitors (AChEIs) have long been used as symptomatic treatments in neurodegenerative disorders, particularly Alzheimer’s disease. However, emerging evidence highlights their broader therapeutic potential beyond cholinergic enhancement, extending into neuroprotection, anti-inflammatory modulation, and neuronal repair. This review explores the multifaceted mechanisms by which AChEIs act as therapeutic neuromodulators in both neurodegenerative and neuroinflammatory contexts. We discuss the classical and non-classical roles of acetylcholinesterase (AChE), the current landscape of AChEI pharmacotherapy, and novel approaches aiming to develop multitarget-directed ligands (MTDLs). Challenges, including blood-brain barrier penetration, adverse effects, and disease heterogeneity, are addressed alongside future perspectives emphasizing personalized medicine and combinatorial strategies. Harnessing the full neuromodulatory potential of AChE inhibition could lead to more comprehensive therapies for a range of neurological diseases.