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The stark rise of depression rates influenced by life stressors, economic threats, pandemic era, and resistance to classical treatments, has made the disorder rather challenging. Adult hippocampal neurogenesis and plasticity are particularly sensitive to the dynamic interplay between autophagy and inflammation. In fact, the intricate balance between the two processes contributes to neuronal homeostasis and survival.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objectives<\/jats:title>\n                <jats:p>Having demonstrated promising potentials in AMPK activation, a major metabolic sensor and autophagy regulator, empagliflozin (Empa) was investigated for possible antidepressant properties in the reserpine rat model of depression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>While the reserpine protocol elicited behavioral, biochemical, and histopathological changes relevant to depression, Empa outstandingly hindered these pathological perturbations. Importantly, hippocampal autophagic response markedly declined with reserpine which disrupted the AMPK\/mTOR\/Beclin1\/LC3B machinery and, conversely, neuro-inflammation prevailed under the influence of the NLRP3 inflammasome together with oxidative\/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKC\u03b6\/NF-\u03baB\/BDNF\/CREB signal restriction. Empa restored hippocampal monoamines and autophagy\/inflammation balance, driven by AMPK activation. By promoting the atypical PKC\u03b6 phosphorylation (Thr403) which subsequently phosphorylates NF-\u03baB at Ser311, AMPK successfully reinforced BDNF\/CREB signal and hippocampal neuroplasticity. The latter finding was supported by hippocampal CA3 toluidine blue staining to reveal intact neurons.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The current study highlights an interesting role for Empa as a regulator of autophagic and inflammatory responses in the pathology of depression. The study also pinpoints an unusual contribution for NF-\u03baB in neurotrophins secretion <jats:italic>via<\/jats:italic> AMPK\/PKC\u03b6\/NF-\u03baB\/BDNF\/CREB signal transduction. Accordingly, Empa can have special benefits in diabetic patients with depressive symptoms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Limitations<\/jats:title>\n                <jats:p>The influence of <jats:italic>p<\/jats:italic>-NF-\u03baB (Ser311) on NLRP3 inflammasome assembly and activation has not been investigated, which can represent an interesting point for further research.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00213-024-06663-0","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T06:40:19Z","timestamp":1724049619000},"page":"2565-2584","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Empagliflozin-activated AMPK elicits neuroprotective properties in reserpine-induced depression via regulating dynamics of hippocampal autophagy\/inflammation and PKC\u03b6-mediated neurogenesis"],"prefix":"10.1007","volume":"241","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3377-6502","authenticated-orcid":false,"given":"Radwa N.","family":"Muhammad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed A.","family":"Albahairy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai A.","family":"Abd El Fattah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weam W.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"6663_CR1","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1007\/s12272-020-01237-y","volume":"43","author":"RG Abdel-latif","year":"2020","unstructured":"Abdel-latif RG, Rifaai RA, Amin EF (2020) Empagliflozin alleviates neuronal apoptosis induced by cerebral ischemia\/reperfusion injury through HIF-1\u03b1\/VEGF signaling pathway. 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