Neuroprotective effects of sulfasalazine in experimental model of seizures and epilepsy

Overexpression of Sxc-, a cystine/glutamate antiporter is implicated in several neurological disorders including epilepsy. Physiologically, it regulates the hippocampal synaptic glutamate pool, influencing the neuronal excitability. Sulfasalazine (SAS) recently garnered interest owing to its system xc- (Sxc-) inhibitory potential. Therefore, the current study investigated the effects of SAS in two distinct models, (i) maximal electroshock (MES) induced acute seizure model and (ii) Pentylenetetrazol (PTZ) induced kindling model of chronic epilepsy and associated cognitive impairment. Initially, rats treated with different doses of SAS (25- 200 mg/kg, i.p.) for 7 days were subjected to MES and observed for seizures. SAS 50 mg/kg improved the extension-to-flexion ratio (E/F ratio) in MES induced seizures and exhibited neuroprotection, whereas the higher doses failed. In another experiment, mice were treated with PTZ (35 mg/kg) on alternate days for 24 days to induce kindling. SAS (50 or 100 mg/kg, i.p.) or vehicle was administered daily, 30 min prior to each PTZ injection. Seizures were monitored for 30 min following PTZ injection. Chronic PTZ administration led to progressively increased seizure severity, culminating in generalized tonic-clonic seizures in mice. SAS 100 mg/kg treatment reduced stage 4 and 5 seizure scores and improved spatial retention memory in mice. SAS also significantly attenuated the gene expression of inflammatory cytokines, TNF-α, IL-1β, and IL-6, and mitigated neuronal damage induced by epileptic kindling. Altogether, results suggest that SAS exhibits anti-epileptic effects, reduces neuroinflammation, and alleviates cognitive dysfunction in the PTZ kindling model of epilepsy in mice.