The present study was conducted to determine the effects of the γ-
aminobutyric acid B (GABAB ) receptor positive allosteric modulator
BHF177 on
refractory epilepsy (RE). An RE rat model was initially established via treatment with
lithium-
pilocarpine. The RE rats were then treated with
BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of
BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that
BHF177 treatment diminished
P-glycoprotein (P-gp) expression in the hippocampal tissues of RE rats. Next, we found that
BHF177 activated GABAB receptor, resulting in upregulated expression of
insulin receptor substrate 1 (IRS-1) and PI3K, as well as antiapoptotic factors (Bcl-2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved
caspase-3 in the hippocampal tissues. Further, activation of GABAB receptors by
BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced
VCAM-1,
ICAM-1, and
tumor necrosis factor-α levels. Next, we treated primary cultured rat hippocampal neurons with
BHF177 and the IRS-1 selective inhibitor NT157.
BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABAB and
insulin-like growth factor-1 receptors. Collectively, our findings indicate that the
BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE.