Effect of lacosamide on neuroinflammation-mediated seizures comorbid with depression in C57BL/6 mice- Role of kynurenine pathway

Abstract

Comorbid conditions in persons with epilepsy (PWE) are very common with depression being highly prevalent. Lacosamide (LCM) is used to treat patients with seizures, but the underlying pathways associating the seizures and comorbid depression are still unknown. Kynurenine pathway (KP) has a major role in seizures, inflammation as well as depression, considering which we evaluated the effect of LCM on kynurenine levels in murine model of neuroinflammation-mediated seizures. We then evaluated the effects on the depressive symptoms associated with seizures. Lipopolysaccharide (LPS) primed pilocarpine (PILO) is an established model for neuro-inflammation-mediated seizures. The anti-seizure and anti-depressive effects of 21 days of LCM administration were studied in this model. After 24 h of seizure termination, behavioral parameters viz. forced swimming test and sucrose preference test were performed to study its antidepressant effect. Biochemical estimations of levels of kynurenine, inflammatory cytokines, and oxidative markers were also evaluated. Lacosamide significantly reduced hippocampal kynurenine levels in LPS and LPS + PILO groups but did not show significant reduction in the PILO alone group. Levels of inflammatory cytokines and oxidative stress markers were also reduced significantly. Lacosamide has shown positive effects against neuroinflammation-mediated model of seizures comorbid with depression by reducing hippocampal kynurenine levels. No reduction in the PILO group is suggestive of the principal contribution of its anti-inflammatory and antioxidant activity in its anti-seizure potential in this model via KP.

Keywords: Comorbid model; Depression; Kynurenine pathway; Lacosamide; Neuro-inflammation; Seizures.