Major depressive disorder (MDD) is considered a major
cause of
suicide worldwide. As previous studies revealed that neuroinflammation
is a significant factor in the etiology of MDD, this study proposed
to unravel the possible antidepressant effect of Empagliflozin (EMPA)
through targeting miRNA-134 (miR-134)/brain-derived neurotrophic factor
(BDNF) and liver kinase B1 (LKB1)/adenosine 5′-monophosphate-activated
protein kinase (AMPK)/silent information regulator 1 (SIRT1) axes
in ovariectomized (OVX) female rats. Rats were assigned randomly to
four groups: Sham operation (SO), OVX, OVX + EMPA (10 mg/kg/day, p.o.),
and OVX + EMPA + Dorsomorphin (DORSO) (25 μg/day/rat, i.v.).
Drugs were administered for 28 days after 2 weeks of surgery. EMPA
debilitated OVX-induced depressive-like behavior by mitigating the
immobility time in the tail suspension test and forced swimming test.
Moreover, EMPA curtailed OVX-induced alterations of serum estradiol,
hippocampal serotonin, miR-134 expression, as well as BDNF. EMPA also
dwindled OVX-induced changes of hippocampal p-LKB1/LKB1, p-AMPK/AMPK,
SIRT1, and inflammatory markers (nuclear factor-kappa-B, interleukin-1
beta, interleukin-6, and tumor necrosis factor alpha). Additionally,
the EMPA-treated group exhibited marked improvement in different brain
regions’ histopathology. However, DORSO coadministration reversed
most of EMPA’s beneficial effects. The current study displayed
the modulatory role of EMPA on miR-134/BDNF and LKB1/AMPK/SIRT1 axes,
thus offering a partial explanation of its antidepressant efficacy
and proposing EMPA as a novel therapeutic avenue for MDD.