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Neuroinflammation and Epilepsy
Epilepsy can be both a primary pathology and a secondary effect of many neurological conditions. Many papers show that neuroinflammation is a product of epilepsy, and that in pathological conditions characterized by neuroinflammation, there is a higher probability to develop epilepsy.
Several factors can activate neuroinflammation, such as infection, traumatic brain injury, toxic metabolites, autoimmune diseases, aging, air pollution, passive smoke or spinal cord injury, and stimulate the production of cytokines and chemokines, which also act as a support for cell growth and survival. They include at least 40 types of interleukins (IL), first thought to be expressed only by leukocytes, but later found to be produced by different cell types. Continuous microglia activation causes the recruitment of peripheral immune cells, such as macrophages and B and T lymphocytes, which are responsible for the innate and adaptive immune response. Another cellular component activated during neuroinflammation is represented by astrocytes; they are strictly linked to the BBB structure and can be responsive to signals released by injured neurons or activated microglia.
In the latter case, it can be a consequence of traumatic brain injuries and brain tumors; then, it can be related to an infectious, metabolic, immune or unknown etiology, as summarized in the last ILAE classification of the epilepsies. Undoubtedly, the presence of certain chronic inflammatory diseases facilitates epilepsy or other neurological manifestations. Indeed, in most autoimmune diseases, there is a five-fold increased risk of epilepsy in children and a four-fold increased risk in non-elderly adults (aged < 65). Even though the impaired regulation of the inflammatory response in injured neuronal tissue is a critical factor to the development of epilepsy, it is still unclear howthisunbalanced regulation of inflammation contributes to epilepsy.
In epileptic rodent models, a key role is played by IL-1β, its receptor (IL-1R), and the antagonist of its receptor (IL-1Ra) Moreover, various hyperacetylated molecules, such as “high-mobility box 1 group protein” (HMGB), a chromatin component released during necrosis, are capable to amplify TLRs activation , and are involved in ictogenesis in models of chronic epilepsy and in humans. It interacts with the extracellular matrix and participates in remodeling AMPA receptors, regulating circuit excitability. Another novel mechanism reinforcing neuroinflammation is supported by the renin-angiotensin system (RAS), which reinforces immune system activation; blocking this pathway prevents neurobehavioral effects of neuroinflammation, induced by lipopolysaccharide (LPS) treatment.
Considering this background, the goal of our review is to show some of the known aspects of the mechanistic relationship between neuroinflammation and epilepsy, mainly focusing on certain paradigmatic diseases as focal cortical dysplasia, PCDH19 epilepsy, glioblastoma multiforme (GBM), maternal immune activation, multiple sclerosis, autism spectrum disorders (ASD) associated with epilepsy, and SARS-COV-2. Following this, we finally explore several therapies that are currently being employed in epileptic patients, targeting neuroinflammation.
2. An Overview on Therapies Affecting Neuroinflammation with Possible Outcome in Epilepsy
2.1. Inhibition of Immune Response
– Corticosteroids and especially adrenocorticotropic hormone (ACTH) have been used in various forms of childhood epilepsy, as in the case of PCDH19 female epilepsy;
– Antagonists of Toll-like receptor have been efficaciously used in convulsive epilepsy, as in the case of resveratrol, an anti-inflammatory stilbenoid. The application of resveratrol reduced the frequency of spontaneous seizures in KA-treated rats. This effect was associated with a reduction in neuronal cell loss and an inhibition of mossy fiber sprouting in the hippocampus;
– Inhibition of the prostaglandin E2-PGE2- receptor subtype is neuroprotective in a pilocarpine model of SE;
– Immunosuppressants, such as cyclosporine A, FK-506 (also known as tacrolimus), and rapamycin inhibiting T-lymphocyte activation, can stop seizures. Indeed, daily systemic injection of cyclosporine A or FK-506 during electrical amygdala kindling prevented the acquisition of severe chronic seizures in rats. However, long-term protection from crisis failed after drug withdrawal, showing limited anticonvulsant capacities. Moreover, these data are quite controversial, since other authors showed opposite effects;
– Immunoglobulins (IVIg) have been first employed in intractable epilepsy, starting from the empirical observation of its beneficial effect on seizures. Indeed, immune system dysfunction could trigger, maintain or, unexpectedly, sustain intractable seizures;
– In status epilepticus, minocycline represents a promising candidate for the anti-inflammatory treatment of epilepsy. Despite often being referred to as an inhibitor of microglial activation, minocycline also affects—either directly or indirectly—other cell types, such as neurons, astrocytes, and oligodendrocytes. A similar drug, Minozac, blocks the production of pro-inflammatory cytokines and prevents the cognitive degenerative phenotype associated in a mouse ‘two-hit’ model of epilepsy . Interestingly, an IL-1β inhibitor, VX-765, being used in psoriasis therapy, completed phase 2 clinical trials in 60 people with treatment-resistant partial-onset epilepsy.
2.2. Antibody Antagonists
According to the results in animal models, the use of probiotics, prebiotics (as probiotic nutrients) and dietary manipulations, such as a ketogenic diet, could be promising to regulate homeostasis in brain excitability. However, standardized studies with controlled administration of probiotics need to be done to better investigate this issue. For example, a recent clinical trial reported a beneficial effect of probiotics in a pilot study, with a reduction in seizures to a 50% level in about 30% of the subjects, and a general amelioration of life quality.
2.5. Inhibitors of Voltage-Gated Potassium Channels Kv1.3
The entry is from 10.3390/ijms22136981