Could be relevant for seizures [25].Author Manuscript Author Manuscript Author Manuscript
May perhaps be relevant for seizures [25].Author Manuscript Author Manuscript Author Manuscript Author ManuscriptTNF-alpha, p55 and p75 receptorsEmerging proof has demonstrated that, along with its effects on cell survival, TNFalpha has neuromodulatory properties by advertising fast changes in neuronal excitability [46]. In analogy with IL-1beta and HMGB1, TNF-alpha affects seizure susceptibility in animal models as shown by pharmacological interventions that either mimic cytokine’s action or block either TNFR1 (p55) or TNFR2 (p75) receptor signaling [29,38,47]. Generally, TNFR1 has been reported to mediate the ictogenic effects of TNF-alpha, whereas TNFR2 mediates the neuroprotective actions of this cytokine. Interestingly, a progressive reduction of TNFR2 using a concomitant raise of TNFR1 in forebrain IL-4 Protein Purity & Documentation neurons was reported in animal models of seizures [47], thus shifting the balance towards the excitotoxic effects of this cytokine. TNF-alpha can induce neuronal channelopathies considering the fact that it affects both the assembly as well as the synaptic clustering of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as well as the membrane expression of GABA-A receptors. In specific, TNFalpha by activating intracellular kinases induces the expression of extrasynaptic GLUR2lacking, hence Ca2+ permeable, AMPA receptors, a mechanism involved in excitotoxicity and synaptic scaling [480]. TNF-alpha promotes the induction of neuronal NMDA-NR1 receptors [51] along with the endocytosis of GABA-A receptors, hence decreasing inhibitory strength and reinforcing excitability [49]. Activation of protein kinases, for instance PI3K and PKC, mediates TNF-alpha as well as IL-1beta modifications within the function of both receptor- and voltage-gated ion channels in neurons [5]. TNF-alpha also can induce glutamate release from microglia [52] and astrocytes [53]. In microglia, TNF-alpha evokes glutamate release by escalating the glutaminase convertion of glutamine to glutamate which can be released via connexin 36 hemi-channels [52]. The astrocytic TNF-alpha evoked release requires COX-2/PGE2 synthesis, thereby resulting in improved intracellular Ca2+ mobilization [53].Long-term modification in neuronal excitabilityIn addition for the fast effects on neuronal excitability above described, that are mediated by post-translational modifications in neuronal channels, a transient raise in IL-1beta and TNF-alpha in microglial cell resident in seizure susceptible brain locations, can induce longlasting and profound synaptic modifications in brain. This benefits in a chronic decrease in seizure threshold, also evoking behavioral comorbidities for instance anxiety, depression, and cognitive dysfunction [21,22,54]. Neuronal cell loss is enhanced in seizing rats if they are pre-exposedCurr Opin Pharmacol. Author manuscript; offered in PMC 2017 February 01.Iori et al.IL-12 Protein medchemexpress Pageto LPS 24 h before the convulsive challenge [55], and seizure threshold is decreased in adult rats which have been exposed to LPS for the duration of the first two post-natal weeks [22]. Inside the frame of long-term consequences on neuronal function, there is rising evidence that injury-induced brain inflammation contributes to the development and extension of brain tissue that generates spontaneous seizures (i.e. epileptogenesis) in animal models of symptomatic epilepsies [56].Author Manuscript Author Manuscript Author Manuscript Author ManuscriptConclusionsActivation of innate immunity and inflammation have been demonstrated in epilepsy.