Vitamin E modified polyamidoamine dendrimer for piperine delivery to alleviate A & beta;(1-42) induced neurotoxicity in Balb/c mice model

In Alzheimer's disease (AD), amyloid beta (A & beta;(1-42)) aggregate formation and neurofibrillary tangles are major pathological hallmarks which are related to neurodegeneration in the brain. To alleviate A & beta;(1-42) fibrils toxicity vitamin E derivative tocopheryl polyethylene glycol succinate (TPGS) was conjugated with polyamidoamine (PAMAM) dendrimer through carbodiimide reaction to synthesize TPGS-PAMAM. This TPGS-PAMAM was employed to entrap neuroprotective agent piperine (PIP) through an anti-solvent technique to prepare PIP-TPGS-PAMAM. The dendrimer conjugate was prepared to reduce A & beta;(1-42) induced neurotoxicity and increase acetylcholine levels in AD mice models. The synthesis of dendrimer conjugate was characterized through proton nuclear magnetic resonance (NMR) and Trinitrobenzene sulphonic acid assay (TNBS). Physical characterization of dendrimers conjugates were done through various spectroscopic, thermal and microscopy based techniques. PIP-TPGS-PAMAM showed 43.25 nm particle size with PIP percentage encapsulation efficiency of 80.35%. Further A & beta;(1-42) fibril disaggregation effect of nanocarrier was evaluated using Thioflavin-T (ThT) assay and circular dichroism (CD). The neuroprotection studies for PIP-TPGS-PAMAM was evaluated against neurotoxicity induced using A & beta;(1-42) intracerebroventricular (ICV) injected in Balb/c mice. The group of mice administered with PIP-TPGS-PAMAM exhibited an increase in the proportion of random alternations in T-maze test and novel object recognition test (NORT) exhibited an increase in working memory cognitive functions. The biochemical and histopathological analysis revealed PIP-TPGS-PAMAM treated groups enhanced acetylcholine levels, reduced ROS and A & beta;(1-42) content significantly. Our findings imply that PIP-TPGS-PAMAM enhanced memory and reduced cognitive deficit in mice brain induced by A & beta;(1-42) toxicity.

Automated summary

In Alzheimer's disease, the formation of amyloid beta aggregates and neurofibrillary tangles is closely associated with neurodegeneration in the brain. To mitigate the toxicity of amyloid beta fibrils, a vitamin E derivative called TPGS was conjugated with a dendrimer called PAMAM to synthesize TPGS-PAMAM. Piperine, a neuroprotective agent, was then entrapped in TPGS-PAMAM to prepare PIP-TPGS-PAMAM. The synthesized dendrimer conjugate showed promising effects in reducing neurotoxicity and improving cognitive functions in AD mouse models.