Papaverine-Derived Dual-Active Modulator Ameliorates Alzheimer's Disease Pathology in Aged APP/PSEN1 Transgenic Mice.

Alzheimer's disease (AD) therapeutics remain a challenge due to their complex pathology and multifactorial toxicity. Advanced stages of AD are marked by rapid cognitive decline, driven by amyloid plaques, neurofibrillary tangles, neuroinflammation, synaptic dysfunction, and neuronal loss. We report the design of dual-active, prodrug-like multifunctional modulators by conjugating papaverine with butyrate, a short-chain fatty acid (SCFA) with neuroprotective properties. The lead compound, P4B, undergoes enzymatic hydrolysis to release papaverine derivative P4H and butyrate, collectively inhibiting amyloid aggregation, Aβ-oligomer-induced membrane disruption, oxidative stress, and neuroinflammation. In vivo administration of P4B to aged APP/PSEN1 mice significantly reduced the amyloid burden, neuroinflammatory markers, and microglial activation in hippocampal and cortical regions. This work introduces an SCFA-based prodrug strategy to address the multifaceted toxicity of AD, offering a novel therapeutic paradigm with potential applicability to other neurodegenerative disorders.