SGLT2 Inhibitor Canagliflozin Alleviates High Glucose-Induced Inflammatory Toxicity in BV-2 Microglia

Area of Science:

• Neuroscience
• Immunology
• Endocrinology

Background:

• Hyperglycemia in diabetes mellitus can lead to cognitive impairment and neurodegeneration, often driven by neuroinflammation.
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs with reported anti-inflammatory effects and potential cognitive benefits.

Purpose of the Study:

• To investigate the hypothesis that SGLT2 inhibitors alleviate hyperglycemia-related inflammation in brain immune cells (microglia).
• To compare the protective effects of four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) against high glucose-induced toxicity in BV-2 microglia.

Main Methods:

• Cultured BV-2 microglia were exposed to high glucose (HG) with or without SGLT2 inhibitors.
• Cytotoxic and inflammatory responses were assessed using biochemical assays.
• The involvement of signaling pathways (NFκB, JNK, p38, PI3K/Akt) was evaluated.

Main Results:

• Canagliflozin (Cana) and dapagliflozin (Dapa) showed non-toxic proliferation inhibition; only Cana rescued microglia from HG-induced cytotoxicity (apoptosis, autophagy).
• Cana demonstrated superior inhibition of HG-induced oxidative/inflammatory stress, reducing reactive oxygen species, iNOS, NLRP3, IL-1β, and TNF-α, but not COX-2.
• Cana's protective effects were mediated by reducing HG-stimulated NFκB, JNK, p38, and PI3K/Akt signaling, mimicking NFκB inhibitor effects.

Conclusions:

• Canagliflozin offers the most significant protection to BV-2 microglia against hyperglycemia-induced inflammatory toxicity among the tested SGLT2 inhibitors.
• Canagliflozin may mitigate neuroimmune damage associated with hyperglycemia in diabetic patients, potentially benefiting cognitive health.