Suppression of seizure-induced increased expression of JAK/STAT Signaling in Kindling model of epileptogenesis using Isoxylitones [E/Z]

Abstract

Epilepsy is a chronic neurologic disorder result from electrical disturbances that lead to abnormal discharge of neurons within the CNS. This discharge produced unprovoked and recurrent seizures which alter the normal brain functions. These functional alterations often give rise to behavioral abnormalities, with devastating effect on the patients and their families. To date, major advancement has been done in the treatment of epilepsy, but still, epilepsy is a great challenge in the medicine field which pays attention towards the invention of new and more potential AEDs. Regardless of latest advancement in the epilepsy, an about one third population is unresponsive. So, the proposed underlying mechanism of transfer of normal brain to epileptic is still unanswered and this highlight to identify new targets of drug treatement. For it , we established the seizure threshold, and used exogenous antiepileptogenic mediator i.e., isoxylitones [E/Z] to evaluate if this can control the over expressed JAK-STAT pathway in the model of epileptogenesis and finally discuss the attempts to halt the process of epileptogenesis by regulating the JAK-STAT pathway. From ancient time to present, there is a strong history of usage of plants and their extracts in the treatment of different neurological disorders. Delphinium denudatum is a medicinal plant of Himalayas and Kashmir, locally called Jadwar. This plant is claimed by many local practitioners to be used in seizure treatment. The novel antiepileptic compound ISO[E/Z] was initially isolated from the same plant and later it was synthesized. Previous studies in our lab already reported that ISO[E/Z] have potent antiepileptic effect. It is able to reduce the seizures in kindling model of epileptogenesis. This inhibition of seizure was further confirmed by modulation of BDNF, cfos and through blockage of sodium channel. In current study, we explored the effect of ISO[E/Z] at the molecular and cellular level by targeting JAK-STAT pathway, that is involved in the epileptogenesis process. The ISO[E/Z] was re-synthesized by our collaborator’s team, X therefore in order to validate and standardize the fresh supply of ISO[E/Z], we re-tested the compound both in acute and chronic seizure model. This step was carried out in order to keep compliance with previous findings. For present study, we choose JAK-1, JAK-3, STAT-2 and STAT-5a isoforms of JAK-STAT pathway due to their importance and involvement in the process of epileptogenesis. We found over expression of mRNA and protein of the above mentioned biomarkers in both cortex and hippocampus of untreated PTZ-kindled group. However, the treatment of ISO[E/Z] was able to reduced the JAK-1, JAK-3, STAT-2 and STAT5a expression. These findings suggest that ISO[E/Z] can halt the epileptogenesis progression by interrupting the underlying functional changes at molecular level. Moreover, our findings also validate our previous studies on isoxylitones with a promising compliance. In the light of all these observations, it can be said that isoxylitones in future would be a potential AED in the treatment of refractory epilepsy. At this stage, promising data support the further development of ISO[E/Z] as an inhibitor of JAK-STAT pathway and this strategy is expected to be valuable to modify or prevent the epilepsy. We think, for an adequate control, it is necessary to used a combination of drugs that hit the multiple targets which are the main players underlying epileptogenesis.