Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer's Disease.

The dyshomeostasis of transition metal ions, accumulation of amyloid-beta (A beta) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-A beta species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced A beta aggregation in vitro and showed disassembly of A beta aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of A beta(25-35) were studied in rats. Compared to sham group, A beta(25-35) injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-alpha and IL-1 beta). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate A beta(25-35) injection-induced astrocyte activation, pro-inflammatory cytokines TNF-alpha and IL-1 beta release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1 beta production, but failed to block astrocyte activation and TNF-alpha production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.