The current investigation aimed at studying the anti-epileptogenic effect of
sitagliptin. The possible effect of the drug in combination with
pregabalin in
pentylenetetrazole (PTZ)- induced
seizures was studied. In addition, the postulated mechanisms that could mediate such effect were explored namely, suppression of oxidative stress and neuro-inflammatory markers, autophagy and apoptosis. Seven days prior to PTZ (60 mg/kg, sc) injection, mice were treated with
sitagliptin (5, 15, and 60 mg/kg, twice daily, orally) or
pregabalin (30 mg/kg, once daily, orally) or their combination. At the end of the experiment, several parameters were assessed including: oxidative/nitro-oxidative stress such as
superoxide dismutase (SOD),
reduced glutathione (GSH),
glutathione peroxidase (GP-x)
catalase (CAT), and lipid peroxidation assessed as
malondialdehyde (MDA),
nitrate/
nitrite (NOx),
3-nitrotyrosine (3-NT). Seizure latency was evaluated. Neuronal damage was also assessed by performing tissue staining by
hematoxylin and
eosin, estimating hippocampus level of
glutamate,
gamma-aminobutyric acid (
GABA),
glial fibrillary acidic protein (GFAP) and
brain-derived neurotrophic factor (
BDNF). Also, markers for
inflammation, autophagy and apoptosis were measured, nuclear factor erythroid-derived 2- like 2 (Nrf2),
nuclear factor kappa-B (NF-κB),
phosphatidylethanolamine-conjugated form of
microtubule-associated protein light chain-3 (LC3-II), casapase-3, Bcl-2-like
protein 4 (BAX) and
glucagon like peptide-1 (GLP-1) activity.
Sitagliptin significantly suppressed epileptogenesis in PTZ-induced
seizures.
Sitagliptin counteracted neuronal damage and all biochemical, and histo-chemical alteration induced by PTZ. Also, a more significant protective effect was observed after combination with
pregabalin. This study is indicative for the antiepileptogenic potential of
sitagliptin with or without
pregabalin in the PTZ model of
epilepsy which is likely to be through its effect on
antioxidant, anti-apoptotic and autophagic pathways.