Neuroinflammation as a Central Mechanism in Alzheimer's Disease: Therapeutic Insights from Schiff Base Derivatives.

Despite decades of intensive research, an effective cure for Alzheimer's disease (AD) remains elusive. Although AD is classically linked to amyloid-beta (Aβ) aggregation, growing evidence highlights neuroinflammation as a major driver of disease progression. Neuroinflammation forms a self-amplifying cycle involving various factors such as cytokines, chemokines, oxidative stress, and glial cell activation, emphasizing the need for multi-target therapeutic strategies. Schiff bases have emerged as promising candidates, especially metal-incorporated Schiff bases, as numerous preclinical studies have demonstrated their ability to modulate key pathological processes, including inflammation, oxidative stress, reactive oxygen species (ROS) impairment, metal dysregulation, Aβ aggregation, and cholinergic dysfunction. Additionally, some preclinical studies even revealed the neuroprotective and anti-amnesic potential of Schiff bases. Nevertheless, these activities have been investigated across diverse structures of Schiff bases, and systematic evaluation of metal-incorporated Schiff bases remains limited. Although Schiff base-based anti-AD investigations have remained exclusively at the preclinical level, the huperzine A prodrug ZT-1 progressed to early-phase clinical trials before its development was discontinued. Comprehensive studies assessing their multi-target potential with their pharmacokinetic profiles are therefore essential to advance their development as prospective anti-AD agents.