Sodium-dependent
glucose co-transporter-2 (
SGLT2) inhibitor empagliflozin (EMP), is the new class of oral
hypoglycemic agent approved as a treatment for
Type 2 diabetes.
SGLT2 inhibitors may induce ketogenesis through inhibiting the renal reabsorption of
glucose. In recent years, positive effects of
ketogenic diets on
neurodegenerative diseases such as
Parkinson's disease (PD) have been reported by improving autophagy. We aimed to evaluate the effects of EMP treatment as a
SGLT2 inhibitor that can mimic the effects of
ketogenic diet, in
rotenone induced PD model in zebrafish focusing on ketogenesis, autophagy, and molecular pathways related with PD progression including oxidative stress and
inflammation. Adult zebrafish were exposed to
rotenone and EMP for 30 days. Y-Maze task and locomotor analysis were performed.
Neurotransmitter levels were determined by liquid chromatography tandem- mass spectrometry (LC-MS/MS). Lipid peroxidation (LPO),
nitric oxide (No),
alkaline phosphatase,
superoxide dismutase,
glutathione,
glutathione S-transferase (GST),
sialic acid,
acetylcholinesterase, and the expressions of autophagy, ketogenesis and PD-related genes were determined. Immunohistochemical staining was performed for the microglial marker
L-plastin (Lcp1) and
tyrosine hydroxylase (Th). EMP treatment improved
DOPAC/DA ratio, Y-Maze task, locomotor activity, expressions of Th and Lcp-1, autophagy and
inflammation related (mTor, atg5, tnfα,
sirt1,
il6, tnfα); PD-related (lrrk2, park2, park7, pink1), and
ketone metabolism-related genes (slc16a1b, pparag, and pparab), and
oxidant-damage in brain in the
rotenone group as evidenced by decreased LPO, No, and improved
antioxidant molecules. Our results showed benefical effects of EMP as a
SGLT2 inhibitor in
neurotoxin-induced PD model in zebrafish. We believe our study, will shed light on the mechanism of the effects of
SGLT2 inhibitors, ketogenesis and autopahgy in PD.