LPM682000012, a Synthetic Neuroactive Steroid That Ameliorates Epileptic Seizures by Downregulating the Serpina3n/NF-κB Signaling Pathway

Epilepsy is characterized by abnormal neuronal firing in the brain. Several therapeutic strategies exist for epilepsy; however, several patients remain poorly treated. Therefore, the development of effective treatments remains a high priority in the field. Neuroactive steroids can potentiate extra-synaptic and synaptic GABA_A receptors, thereby providing therapeutic benefits relative to benzodiazepines. This research study investigated the therapeutic effectiveness and underlying mechanisms of LPM682000012, a new synthetic neuroactive steroid-positive allosteric modulator (PAM) of GABA_A receptors employed for treating epilepsy. Acute and chronic rat epilepsy models were established to identify the anti-seizure potency of LPM682000012. The dose-dependent sedative effects of LPM682000012 and Ganaxolone in normal rats were evaluated, which revealed that they both dose-dependently alleviated acute epileptic seizure in the pentylenetetrazol (PTZ)-mediated seizure model. Furthermore, LPM682000012 indicated an enhanced safety profile than Ganaxolone. Moreover, LPM682000012 also indicated therapeutic effects in the kainic acid (KA)-induced chronic spontaneous seizure model. Morphologically, LPM682000012 decreased neuronal loss in the hippocampal CA1 and CA3 regions and increased dendritic spine density in the CA1 region. In addition, mechanical analyses, including transcriptomics, Western blot, and proteomics analyses, revealed that the <i>Serpina3n</i>/NF-κB signaling pathway was up-regulated in epileptic rat hippocampal tissue, and LPM682000012 treatment reversed these changes. In summary, this report demonstrated that the novel neurosteroid GABA_A PAM LPM682000012 activated the synaptic and extra-synaptic GABA_A receptors and alleviated KA-induced neuronal loss and synaptic remodeling, potentially by down-regulating the <i>Serpina3n</i>/NF-κB signaling pathways. The results provide evidence that LPM682000012 is a potential anti-seizure pharmacotherapy candidate for epilepsy and warrants further research.