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Updated: Sep 8, 2025
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice
Hashan S M Jayarathne1, Lucas K Debarba1, Jacob J Jaboro1
1Department of Biological Sciences, IBio (Integrative Biosciences Center), Wayne State University, Detroit, Michigan, USA.
Abstract:
The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana-treated male and female mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, we demonstrate the sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.
Insights
Canagliflozin (Cana) improved brain insulin sensitivity and reduced neuroinflammation in aged male mice, offering potential neuroprotective effects. This diabetes drug showed sex-specific benefits, impacting cognitive function and activity in males more than females.
Area of Science:
- Neuroscience
- Endocrinology
- Gerontology
Background:
- Aging brains exhibit increased neuroinflammation and insulin resistance, linked to cognitive decline and neurodegeneration.
- The anti-diabetic drug Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, previously showed lifespan extension in male mice.
- Aged male mice exhibit more pronounced neuroimmune responses compared to aged females.
Purpose of the Study:
- To investigate the sex-specific effects of Canagliflozin on neuroinflammation and insulin sensitivity in the aging brain.
- To determine if Cana treatment can mitigate age-associated changes in the hypothalamus and hippocampus.
- To explore the correlation between molecular changes in microglia and behavioral improvements.
Main Methods:
- Treatment of 30-month-old male and female mice with Canagliflozin.
- Assessment of central insulin sensitivity in the hypothalamus and hippocampus.
- Analysis of hypothalamic and hippocampal gliosis (microgliosis and astrogliosis).
- Measurement of inflammatory cytokine production by microglia.
- Evaluation of S6 kinase phosphorylation in microglia.
- Behavioral testing of exploratory and locomotor activity.
Main Results:
- Canagliflozin treatment significantly improved central insulin sensitivity in the hypothalamus and hippocampus of aged male mice.
- Both male and female mice showed reduced hypothalamic gliosis and inflammatory cytokine production after Cana treatment.
- In the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in females.
- Reduced microgliosis in males was partially correlated with decreased S6 kinase phosphorylation in microglia.
- Canagliflozin improved exploratory and locomotor activity in aged male mice, but not in females.
Conclusions:
- Canagliflozin demonstrates sex-specific neuroprotective effects in the aging brain, primarily in males.
- The drug improves insulin responsiveness and reduces neuroinflammation, particularly in the male hypothalamus and hippocampus.
- These findings suggest Canagliflozin as a potential therapeutic agent for age-related cognitive impairment and neurodegenerative diseases, with a notable sex-specific efficacy.
