Canagliflozin attenuates chronic unpredictable mild stress induced neuroinflammation via modulating AMPK/mTOR autophagic signaling

Although vast progress has been made to understand the pathogenesis of depression, existing antidepressant remedies, with several adverse effects, are not fully adequate. Interestingly, new emerging theories implicating an altered HPA-axis, tryptophan metabolism, neuroinflammation and altered gut integrity were proposed to further identify novel therapeutic targets. Along these lines, canagliflozin (CAN), a novel antidiabetic medication with anti-inflammatory and neuroprotective activity may present an effective treatment for depression; nevertheless, no studies have explored its effect on depressive disorder yet. To this end, this study aimed to investigate the possible antidepressant activity of CAN in CUMS and the mechanisms underlying its action on the gut-brain inflammation axis as well as the alteration in the TRY/KYN pathway in addition to its role in modulating the autophagic signaling cascade. Interestingly, CAN successfully attenuated the CUMS-induced elevations in despair and anhedonic behaviors as well as the elevated serum CORT. Furthermore, it enhanced gut integrity via hampering the CUMS-induced colonic inflammation and amending colonic tight junction proteins. The enhanced gut integrity was further corroborated by a notable anti-inflammatory and neuroprotective activity manifested via the observed mitigation of immune cell activation in addition to IDO hippocampal protein content and promotion of the autophagy cascade. Our findings postulate the possible anti-inflammatory and neuroprotective effects of CAN and the implication of TRY/KYN and AMPK/mTOR signaling pathways in the CUMS-induced MDD. Hence, this study shed light to the promising role of CAN in the augmentation of the current antidepressant treatments.