Vitamin E modified polyamidoamine dendrimer for piperine delivery to alleviate Aβ_1–42 induced neurotoxicity in Balb/c mice model

Abstract

In Alzheimer’s disease (AD), amyloid beta (Aβ_1-42) aggregate formation and neurofibrillary tangles are major pathological hallmarks which are related to neurodegeneration in the brain. To alleviate Aβ_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 Aβ_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 Aβ_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 Aβ_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 Aβ_1-42 content significantly. Our findings imply that PIP-TPGS-PAMAM enhanced memory and reduced cognitive deficit in mice brain induced by Aβ_1-42 toxicity.

Keywords:

• Polyamidoamine G4
• tocopheryl polyethylene glycol succinate
• piperine
• amyloid
• Alzheimer’s disease

Acknowledgments

The authors thanks to NIPER-Raebareli and department of pharmaceuticals government of India, for providing funding and research facilities. We are thankful to department of central instrument facility (CIF) NIPER-R for instrumentation facility. We would like to acknowledge NIPER, Guwahati, for providing animal studies support. The NIPER-R communication no. for this manuscript is 433.

Author contributions

Dr. Rahul Shukla: Principle investigators, conceptualization and methodology. Ajit Singh: synthesis, formulation, characterization, data curation, analysis, data interpretation, review and editing. Debarati Rakshit, and Ankit Kumar: Animal’s studies experimentation. Dr. Awanish Mishra: Animal studies supervision and data analysis.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.