Exploring the Neuroprotective Effects of Indole Propionate and Shikonin in STZ-Induced Diabetic Rats: A Novel Therapeutic Strategy for Cognitive Impairment in Type 2 Diabetes Mellitus

Abstract

The chronic metabolic disorder known as diabetes mellitus severely deteriorates memory function and learning while damaging hippocampal tissue. Given that impaired hippocampal insulin signaling leads to memory deficits, insulin resistance and hyperinsulinemia are considered critical links between type 2 diabetes mellitus (T2DM) and AD. This study utilized streptozotocin (STZ)-induced diabetic rat model to evaluate the therapeutic potential of indole propionate (IPA) and Shikonin as treatments for cognitive impairment. Male albino rats were divided into seven groups, three control groups receiving ddH₂O, IPA, and Shikonin, respectively, and four experimental groups treated with a high-fat diet and intraperitoneal (IP) injections of STZ (25 mg/kg) to induce diabetes. Following disease induction, diabetic rats were treated with IPA (40 mg/kg), Shikonin (10 mg/kg), and metformin (200 mg/kg) for 28 days. The study measured three critical parameters which included body weight assessment together with blood glucose levels and evaluation of hippocampal and cortical gene expression analysis related to cognitive impairment. Real-time quantitative PCR (RT-qPCR) was utilized to evaluate mRNA expression levels of genes implicated in these deficits. Our findings demonstrate that the elevated expression of Tau and APP in diabetic rats was substantially reduced with IPA treatment (p < 0.0001). Additionally, PDIA3 (ERp57), an endoplasmic reticulum (ER)-resident chaperone, was significantly downregulated in the T2DM group but restored with IPA treatment. Dysregulated expression of the mitochondrial chaperone Hsp60 was also improved with both IPA and Shikonin. Insulindegrading enzyme (IDE), a key protein linking T2DM and AD, showed substantial restoration in the T2DM+IPA-treated group. IPA and Shikonin treatments improved the body weight and blood glucose levels of diabetic rats who experienced notable decreases in both parameters initially. The results of the study demonstrate how IPA and Shikonin show promise as treatments for reducing cognitive problems in diabetes patients. However, the clinical deployment of these compounds needs confirmation through additional studies at the cellular and molecular levels.