Co-administration of Ceratonia siliqua extract nanoparticles promotes the oral bioavailability and neurotherapeutic efficacy of donepezil in a dementia model.

Background: This study aimed to assess the herb-drug interactions between crude/silver nanoparticle (SNP)-loaded carob extract (Car, NCar, respectively) and donepezil-HCl (DPZ) and their impact on neurotherapeutic outcomes in a dementia model.

Methods: Carob pods were subjected to ethanol extraction, and their phytoconstituents were chromatographically analysed. SNP-loaded extract was synthesized and characterized, and dementia-like symptoms were induced in Wistar rats by repeated dosing with 175 mg/kg AlCl3 for 60 days, after which the animals were treated with Car, NCar, DPZ, and combinations of Car/NCar-DPZ for 30 days. The effect of carob formulations on DPZ bioavailability was in-silico profiled and the herb-drug interactions were mathematically assessed as combination indices.

Results: Different formulations significantly improved cognitive/spatial memory functions, restored dysregulated brain redox and cholinergic functions, and markedly inhibited cholinesterase, as reflected by the reduction/absence of amyloid plaques and neurofibrillary tangles. In silico profiling of the major phytoconstituents revealed their non-P-glycoprotein substrate nature and CYP3A4, 2C19, and 2C9 inhibition, which might have improved the oral bioavailability of DPZ. The combination index calculations revealed strong synergy between DPZ and both carob formulations, with the strongest effect exhibited by the DPZ/NCar combination.

Conclusion: The co-administration of carob extract/SNPs represents a promising approach for enhancing the neurotherapeutic efficacy of DPZ.