Effects of GABA_B receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

Abstract

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.

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

“…Although this article focused on investigational treatments for which clinical data are available, or likely to be available in the short term, preclinical research in this area is also very active. Drug candidates being investigated preclinically include, among others, novel GABA A receptor agonists and allosteric modulators [14,33,111], compounds targeting GABA B receptors [116,117], a highly potent inhibitor of GABA transaminase [118], a new class of selective NKCC1 inhibitors [82] and novel GABA-targeting viral vectors [119]. At the other extreme of the development spectrum, clinical studies are ongoing to assess novel applications of already marketed GABA-targeting ASMs.…”

Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease

“…The GABA-B receptor, which can be proposed as a potential treatment target for Alzheimer's disease (AD), inhibited oxidative stress damage in the neurons of AD model rats by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway [15] (Figure 1). BHF177, a positive allosteric modulator of the GABA-B receptor, can activate GABA-B receptors to induce the expression of insulin receptor substrate 1 (IRS-1), PI3K, and anti-apoptotic factors (including Bcl-2 and mTOR); inhibit apoptotic factors, including BCL2 Associated X (Bax), which is known as an apoptosis regulator by releasing cytochrom C in the inner membrane of mitochondria, in hippocampal tissues; and protect against refractory epilepsy (RE) via IRS-1/PI3K [16]. Studying diverse mechanisms involving GABA, especially in the context of neurotransmitters, offers an entry point for understanding the metabolite-mediated signaling cascade in the brain.…”