Phosphodiesterase-4 Inhibition: An Experimental Approach to Overcome Drug Resistance in a Rotenone-Corneal 6 Hz...

PDE4 upregulation reduces cAMP levels, leading to disrupted intracellular signaling and increased neuronal hyperexcitability. This contributes to neuroinflammation and neurodegeneration, potentially leading to cognitive decline in drug-resistant epilepsy (DRE) due to persistent seizures. Roflumilast (ROF), a selective PDE4 inhibitor that crosses the blood-brain barrier, comprises several neuroprotective properties. Therefore, this study investigates the therapeutic potential of ROF in a mitochondrial DRE model, i.e., rotenone corneal kindling (RCK). Swiss albino mice underwent for rotenone-corneal kindling for 15 days to induce DRE. Rotenone (2.5 mg/kg, i.p.) 1 h before was followed by corneal shocks (15 mA, 20 V, 6 Hz for 3 s) twice daily with a gap of 4-h. Standard anti-seizure medications (ASMs) such as pregabalin, levetiracetam, carbamazepine, phenytoin, and lamotrigine were used for resistance validation. Drug-resistant mice were then treated with roflumilast (2.5, 5, and 10 mg/kg, p.o.). Post-treatment resistance validation was done, along with cognitive behavior testing. Mice were sacrificed for neurochemical, biochemical, and histological assessments of the hippocampus and cerebral cortex. Drug resistance was confirmed as a non-significant difference in seizure scores was observed with ASMs. Roflumilast effectively treated DRE as it significantly reduced seizure severity and enhanced cognition, especially at higher doses. The restoration of key neuroactive amino acids (GABA, glutamate, tryptophan, glutamine), monoamines (dopamine, noradrenaline, serotonin, Homovanillic acid) and oxidative stress (by reducing TBARS, increasing catalase activity, and elevating glutathione levels) was well correlated with behavioral observations. Histological analysis confirmed neuroprotective effects, highlighting roflumilast's comprehensive benefits in managing DRE. Roflumilast as PDE4 inhibitor significantly manage DRE as evidenced by reducing seizure severity, improving cognitive functions and restoring neurochemical alterations. Its ability to modulate oxidative stress and provide neuroprotection in RCK mice underscores its promise as a novel adjunct treatment for DRE.