Resatorvid as a promising neuroprotective agent in pentylenetetrazol-kindling rat model: Suppressing neuroinflammation and enhancing cognitive and motor functions

Toll-like receptor 4 (TLR4) plays a key role in promoting seizure susceptibility, neuronal damage, and network dysfunction in epilepsy through its downstream inflammatory pathways. However, the therapeutic potential of resatorvid, a TLR4 inhibitor remains underexplored. This study investigated the neuroprotective effects of resatorvid (0.25 mg/kg) in a pentylenetetrazole (PTZ)-induced kindling model in rats. Seizures were induced by PTZ (35 mg/kg, every other day, i.p), and once full kindling was established, animals received either resatorvid or the standard antiepileptic drug carbamazepine for 14 days.

Resatorvid significantly reduced seizure severity, duration, and latency, mirroring the effects of carbamazepine. Using the Morris water maze and open field tests demonstrated improvements in locomotor activity, spatial memory, and cognitive performance. These behavioral gains correlated with hippocampal histopathological improvements, including reduced neuronal damage in the CA1 and CA3 regions as observed via H&E staining.

At the molecular level, resatorvid treatment downregulated hippocampal protein expression of high mobility group box 1 (HMGB1), TLR4, and its downstream inflammatory signal, phosphorylated-nuclear factor kappa (NF-κ)B p65, and proinflammatory cytokines interleukin (IL)-1β and IL-8, while restoring that of the inhibitory kappa (Iκ)B. In addition, resatorvid reduced glial activation, as evidenced by decreased expression of the astrocytic marker GFAP and microglial marker Iba1 in the cytoplasm. These findings suggest that resatorvid exerts a multimodal neuroprotective effect by attenuating neuroinflammation and glial reactivity, preserving hippocampal structure, and improving cognitive and motor functions. Altogether, the results highlight resatorvid as a promising therapeutic candidate for epilepsy, warranting further exploration in preclinical and clinical settings.