Opposing actions of hippocampus TNFα receptors on limbic seizure susceptibility

Abstract

Resected epileptic tissues exhibit elements of chronic neuroinflammation that include elevated TNFα and increased TNFα receptor activation, but the seizure related consequences of chronic TNFα expression remain unknown. Twenty four hours after acute limbic seizures the rat hippocampus exhibited a rapid upregulation of TNFR1, but a simultaneous downregulation of TNFR2. These limbic seizures also evoked significant increases in measures of neuroinflammation and caused significant neuronal cell death in both the hilus and CA3 of the hippocampus. In order to mimic a state of chronic TNFα exposure, adeno-associated viral vectors were packaged with a TNF receptor 1 (TNFR1) specific agonist, human TNFα, or a TNF receptor 1/2 agonist, rat TNFα. Subsequently, chronic hippocampal overexpression of either TNFR ligand caused microglial activation and blood-brain barrier compromise, a pattern similar to limbic seizure-induced neuroinflammation. However, no evidence was found for neuronal cell death or spontaneous seizure activity. Thus, chronic, in vivo TNFα expression and the subsequent neuroinflammation alone did not cause cell death or elicit seizure activity. In contrast, chronic hippocampal activation of TNFR1 alone significantly increased limbic seizure sensitivity in both amygdala kainic acid and electrical amygdala kindling models, while chronic activation of both TNFR1 and TNFR2 significantly attenuated the amygdala kindling rate. With regard to endogenous TNFα, chronic hippocampal expression of a TNFα decoy receptor significantly reduced seizure-induced cell death in the hippocampus, but did not alter seizure susceptibility. These findings suggest that blockade of endogenous TNFα could attenuate seizure related neuropathology, while selective activation of TNFR2 could exert beneficial therapeutic effects on in vivo seizure sensitivity.

Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus

“…In addition to its well-established pro-inflammatory activities, the immunosuppressive role of TNF-α has recently been appreciated in many inflammatory conditions (Masli and Turpie, 2009). TNF-α can also mediate both pro- and anti-seizure effects through its receptors TNFR1 and TNFR2, respectively (Balosso et al, 2013; Weinberg et al, 2013). A major source of TNF-α and TGF-β1 in the CNS is astrocytes and microglia although other cell types might also contribute.…”

Infections, inflammation and epilepsy

“…Over 20 years ago, transgenic mice overexpressing IL-6 driven by the glial fibrillary acidic protein (GFAP) promoter were found to develop spontaneous seizures [27]. There is also evidence that TNF-R1 mediates the proconvulsive effects of TNF-α in mice exposed to chemoconvulsants [9, 10, 144]. …”

Immunity and Inflammation in Epilepsy

“…Pharmacologic antagonism of specific proinflammatory pathways activated in glia and neurons has been attempted in animals with acute or chronic seizures: the data showed a reduction of 50% -70% of seizure recurrence by targeting IL-1R1/TLR4 signaling or TNF-a/p55 receptors demonstrating a significant anti-ictogenic effect of such treatments (Vezzani et al 2011c;Balosso et al 2013;Iori et al 2013;Weinberg et al 2013). Pharmacological blockade of individual proinflammatory pathways after an epileptogenic injury and before epilepsy develops induced disease-modifying effects (e.g., neuroprotection, decreased frequency and severity of chronic seizures, reduced comorbidities) in animal models, although not preventing the onset of the disease (Vezzani et al 2013a,b;Rojas et al 2014).…”