Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis

Inflammation is the most common feature of many chronic diseases and complications, while playing critical roles in carcinogenesis. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response element (ARE). The Keap1 (Kelch-like ECH-associated protein)/Nrf2 (NF-E2 p45-related factor 2)/ARE signaling pathway mainly regulates anti-inflammatory gene expression and inhibits the progression of inflammation. Therefore, the identification of new Nrf2-dependent anti-inflammatory phytochemicals has become a key point in drug discovery. In this review, we discuss the members of the Keap1/Nrf2/ARE signal pathway and its downstream genes, the effects of this pathway on animal models of inflammatory diseases, and crosstalk with the NF-κB pathway. In addition we also discuss about the regulation of NLRP3 inflammasome by Nrf2. Besides this, we summarize the current scenario of the development of anti-inflammatory phytochemicals and others that mediate the Nrf2/ARE signaling pathway.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.

Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.