Inflammation and oxidative stress are two important processes known to occur concurrently in epilepsy. Neuroinflammation is a well-recognized mediator of acquired epilepsy and a highly investigated target for therapeutic intervention. Glutathione depletion occurs following insults that cause epilepsy and its repletion can modify seizures and cognitive impairment. Recent work in our laboratory has shown that elevation of glutathione can inhibit neuroflammation. The long term goal of this proposal is to elevate brain glutathione levels in models of acquired epilepsy by a novel mechanism i.e. direct posttranslational activation of its rate-limiting synthetic enzyme, ?- glutamyl cysteine ligase. The goal of this proposal is to test the hypothesis that increased de novo synthesis of glutathione decreases neuroinflammation, seizures and/or cognitive dysfunction.
Aim. 1 will test select compounds for their ability to increase glutathione, inhibit neuroinflammation and neuronal excitability in vitro.
Aim 2 will determine if compounds capable of elevating glutathione inhibit seizures, epilepsy and/or cognitive dysfunction. These studies can identify a novel mechanism of reducing neuroinflammation in acquired epilepsy and suggest redox-based compounds for the treatment of epilepsy and associated comorbidities.
Neuroinflammation is a critical therapeutic target for acquired epilepsy; novel ways to reduce it with fewer adverse effects are much needed. The proposal explores a novel mechanism of elevating brain glutathione to decrease neuroinflammation, epilepsy and cognitive dysfunction. The studies can provide a novel redox based mechanism to decrease neuroinflammation in epilepsy.
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