Evaluation of phosphoinositide 3 kinase mammalian target of rapamycin and their dual inhibition in experimental epilepsy

Abstract

The evidences from various studies show the association of peripheral and neuronal newlineinflammation with complex pathophysiology of status epilepticus (SE). In this view, the newlinepresent work attempted to develop a model of neuronal inflammation mediated SE by newlinecombining both epileptic and inflammatory components of the disease and also to mimic SE newlineco-morbid with systemic inflammation by peripheral administration of the lipopolysaccharide newline(LPS) 2 hours prior to the pilocarpine induction in C57BL/6 mice. We evaluated the anti newlineconvulsant and neuroprotective effects of 7-day prophylactic treatment with three newlineconventional anti-epileptic drugs (Sodium valproate, SVP 300 mg/kg p.o.; Carbamazepine newlineCBZ 100 mg/kg p.o.; Levetiracetam; LEV 200 mg/kg p.o.) of widespread clinical use. Morris newlinewater maze and Rota rod tests were carried out 24-hours post-exposure to evaluate the newlineneurobehavioral co-morbidities associated with neuroinflammation-mediated status newlineepilepticus. Upon priming with LPS, the loss of protection against pilocarpine-induced newlineseizures was observed by SVP and CBZ, however, LEV showed protection by delaying the newlineseizures. Dramatic elevation in the seizure severity and neuronal loss demonstrated the newlinepossible pro-convulsant effect of LPS in the pilocarpine model. Also, the decreased cytokine newlinelevels by the AEDs showed their association with NF-and#954;B, IL-1and#946;, IL-6, TNF-and#945; and TGF-b newlinepathways in PILO model. However, loss of protective activities of SVP and CBZ and only a newlinepartial efficacy of LEV in LPS+PILO model is suggestive of the possibility of involvement newlineof some other neuroinflammatory-pathway involved in the same. Over-activation of newlinephosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, newlinewe speculate PI3K/Akt/mTOR pathway as promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in newline.........