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

Patients with diabetes mellitus can experience hyperglycemia, which affects brain function and produces cognitive impairment or neurodegeneration. Neuroinflammation is an important cause of cognitive dysfunction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic agents that reportedly possess anti-inflammatory properties and may produce beneficial cognitive effects. We hypothesized that SGLT2 inhibitors alleviate hyperglycemia-related inflammation in brain immune cells. Cultured BV-2 microglia were exposed to high glucose (HG) in the absence or presence of SGLT2 inhibitors including canagliflozin (Cana), dapagliflozin (Dapa), empagliflozin (Empa), and ertugliflozin (Ertu). Afterward, we evaluated the cytotoxic and inflammatory responses by specific biochemical assays. Treatments with non-toxic Cana or Dapa, but not Empa or Ertu, inhibited proliferation without cell death. Only Cana rescued BV-2 microglia from HG-induced cytotoxicity, including apoptosis or autophagic degradation. None of SGLT2 inhibitors affected the HG-stimulated induction of stress proteins HO-1 and HSP70. Also, compared to the other three SGLT2 inhibitors, Cana was better at inhibiting HG-induced oxidative/inflammatory stress, as evidenced by its ability to repress proinflammatory factors (e.g., oxygen free radicals, iNOS, NLRP3, IL-1β, and TNF-α) other than COX-2. Cana's action to alleviate HG insults was mediated not by altering SGLT2 protein expression, but by reducing HG-stimulated signaling activities of NFκB, JNK, p38, and PI3K/Akt pathways. Particularly, Cana imitated the effects of NFκB inhibitor on HG-induced iNOS and COX-2. Of the four SGLT2 inhibitors, Cana provided BV-2 microglia with the best protection against HG-induced inflammatory toxicity. Thus, Cana may help to reduce innate neuroimmune damage caused by hyperglycemia.