Murine model preclinical assessment of PEGylated block copolymer targeting cognition and oxidative stress insults of Alzheimer’s disease

Abstract

Misfolded peptide amyloid beta (Aβ42), neurofibrillary tangles of hyper-phosphorylated tau, oxidative damage to the brain, neuroinflammation are distinguished determinants of Alzheimer’s disease (AD) responsible for disease progression. This multifaceted neurodegenerative disease is challenging to cure under a single treatment regime until the key disease-determinants are traced for their sequential occurrence in disease progression. In an early report, a novel side-chain tripeptide containing PEGylated block copolymer has been tested thoroughly in vitro and in silico for the early inhibition of Aβ42-aggregation as well as degradation of preformed Aβ42-fibril deposits. The present study demonstrates a preclinical assessment of the PEGylated block copolymer in colchicine-induced AD mimicking murine model. The colchicine induced Wistar rats receiving an intranasal delivery of the block copolymer at a daily dosage of 100 µg/kg and 200 µg/kg body weights respectively for 14 days manifested a notable attenuation of behavioral deficit pattern, oxidative stress, and neurotransmitters’ deficiency as compared to the untreated ones. The current study also reports the ameliorative property of the PEGylated compound for progressive neuroinflammation and decreased mitochondrial bioenergetics in astrocytoma cell line viz. U87. A closer look into the drug mechanism of action of a compact three-dimensional PEGylated block copolymer confirmed its disintegrative interaction with Aβ42 fibril via an in silico simulation. The results obtained herein this study signify the potential of the novel PEGylated block copolymer to ameliorate the cognitive decline and progressive oxidative insults in AD, and may envision a successful clinical phase trial.