Related Experiment Video
Updated: Aug 10, 2026
Osmotic Minipump Implantation for Increasing Glucose Concentration in Mouse Cerebrospinal Fluid
Published on: April 7, 2023
Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis
Xiaoqin Tan1, Yanru Gao2, Lingyu Zhang3
1Medical Department, City University of Wuhan, Wuhan, Hubei Province, China. xqtan@wic.edu.cn.
Abstract:
Type 2 diabetes-associated cognitive dysfunction (TDACD) is a recognized metabolic brain disorder with limited therapeutic options. This preclinical study investigated whether isoorientin (ISO) confers neuroprotection in TDACD and examined the involvement of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in its effects. A mouse model of TDACD was induced by high-fat diet and streptozotocin. Mice were administered ISO for six weeks. The systemic metabolism and cognitive behavior were evaluated. The synaptic protein expression, apoptosis, tau phosphorylation, oxidative stress in the brain were detected to identify the pathological signature. The activity of GSK3β and the expression of its downstream targets Nrf2 and heme oxygenase-1 (HO-1) were analyzed to elucidate the mechanism. ISO improved systemic glucose metabolism and alleviated hepatic steatosis, and reversed cognitive deficits. In the brain, ISO restored synaptic proteins (PSD-95, BDNF, soluble α-synuclein), exerted anti-apoptotic effects (increased Bcl-2/Bax ratio, decreased cleaved caspase-3), and attenuated oxidative stress and mitochondrial damage. Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear accumulation, upregulated HO-1 expression, and reduced tau phosphorylation at Ser396. These findings demonstrate that ISO exerts a neuroprotective effect in TDACD model by inhibiting oxidative stress via GSK3β/Nrf2 pathway, and highlight ISO as a potential therapeutic candidate for TDACD.
Insights
Isoorientin (ISO) shows neuroprotective effects against type 2 diabetes-associated cognitive dysfunction (TDACD). This study reveals ISO improves brain health by targeting the GSK3β/Nrf2 pathway, offering a potential therapeutic strategy for TDACD.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Pharmacology
Background:
- Type 2 diabetes-associated cognitive dysfunction (TDACD) is a metabolic brain disorder with few treatment options.
- The underlying mechanisms of TDACD and potential therapeutic targets remain under investigation.
Purpose of the Study:
- To investigate the neuroprotective potential of isoorientin (ISO) in a mouse model of TDACD.
- To elucidate the role of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in ISO's effects.
Main Methods:
- A TDACD mouse model was established using a high-fat diet and streptozotocin.
- Mice received ISO treatment for six weeks, followed by assessments of metabolic function, cognitive behavior, synaptic integrity, apoptosis, oxidative stress, and GSK3β/Nrf2 pathway activity.
Main Results:
- ISO treatment improved systemic glucose metabolism, reduced hepatic steatosis, and reversed cognitive deficits in TDACD mice.
- ISO restored synaptic protein levels, reduced apoptosis, attenuated oxidative stress and mitochondrial damage in the brain.
- Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear translocation, increased HO-1 expression, and decreased tau phosphorylation.
Conclusions:
- Isoorientin demonstrates significant neuroprotective effects in a preclinical model of TDACD.
- ISO exerts its benefits by mitigating oxidative stress through the GSK3β/Nrf2 pathway.
- ISO represents a promising therapeutic candidate for managing cognitive dysfunction associated with type 2 diabetes.
