Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.
