Kamel, Ahmed SFarrag, Sama MMansour, Heba MNassar, Noha NSaad, Muhammed A2023-04-282023-04-282023-04https://doi.org/10.1080/14728222.2023.2206955http://repository.msa.edu.eg/xmlui/handle/123456789/5563Background Although, disturbances in cellular energy demarcate the neuronal hyperexcitability in essential tremor (ET), nevertheless, no available data relates energy sensors and GABAergic neurotransmission in ET. Noteworthy, reports have asserted dapagliflozin’s (DAPA) role in enhancing autophagic sensors in other disorders. Herein, this study aimed to investigate DAPA’s impact on the GABAB receptor subunit (GABAB R2), notwithstanding the GABA A involvement, in an ET model. Methods ET was induced by a single dose of harmaline (30 mg/kg; i.p.) while DAPA (1mg/kg/day; p.o.) was given for 5 days before ET induction. The autophagic sensors were examined by injecting a single dose of dorsomorphin (DORSO) AMPK inhibitor (0.2 mg/kg; i.p.) on the 5th day before ET induction. Results DAPA decreased HAR-induced tremor score and alleviated motor disabilities observed in the open field, rotarod, wire grip strength, and gait kinematics confirmed by reduced electrical activity in electroencephalogram. In the cerebella, DAPA curbed HAR-evoked inflammatory cytokines, apoptotic markers, and glutamate while restoring the disturbed GABA, BDNF, LKB1, p-AMPK, and GABAB R2 levels. DAPA’s effect was mostly obliterated by DORSO. Conclusion DAPA offers a potential neuroprotective effect in ET by augmenting the neuronal inhibitory machinery via suppressing the inflammatory and excitotoxicity systems thru LKB1/p-AMPK/GABAB R2 signaling.en-USDapagliflozinEssential tremorGlutamateHarmalineLKB1/p-AMPK/GABAB R2Articlehttps://doi.org/10.1080/14728222.2023.2206955