Role of selected aspects of inflammation in age-dependent seizure susceptibility and neuronal injury in rats

Rizzi, Massimo (2007). Role of selected aspects of inflammation in age-dependent seizure susceptibility and neuronal injury in rats. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fa7f

Abstract

Besides systemic infection, proinflammatory signals in the CNS are also recruited by epileptic activity. Chronic stimulation of proinflammatory signals by seizures, or a persistent proinflammatory situation in brain may contribute to the establishment of a pathological substrate (i.e. neurodegeneration, neuronal hyperexcitability, blood-brain barrier damage, etc) playing a role in epileptogenesis and in the acute manifestation or reinforcement of seizures. Interestingly, in humans and in experimental models of epilepsy, seizure susceptibility and associated neuronal damage are age-dependent. Therefore, we wondered whether a hypothetical age-dependent relationship between proinflammatory molecules and seizure-susceptibility and related neurodegeneration there might exist and to what extent. A first group of experiments investigated the hypothesis that activation of glia and subsequent production of proinflammatory molecules such as interleukin-1(3 (IL-1(3) and tumor necrosis factor-a (TNF-a), as well as the naturally occurring anti-inflammatory molecule interleukin-1 receptor antagonist (IL-1Ra), are age-dependently involved in seizure-induced neuronal damage. A second group of experiments investigated whether a pre-existing LPS-induced inflammatory state in the CNS may enhance the predisposition of rat pups to develop seizures. We concluded that the induction of proinflammatory cytokines, per se, cannot be regarded as a general mechanism which underlies the appearance of neurodegeneration. In addition, there were no clear indications emerging from our data concerning the role of proinflammatory cytokines in modulating seizure-susceptibility in rat pups. Nonetheless, we showed that prostaglandin E₂ (PGE2) production and the activation of the Hypothalamic-Pituitary-Adrenal axis play a relevant role in the modulation of seizure-susceptibility in rat pups. Interestingly, our experiments seem to support the hypothesis that production of proinflammatory molecules such as IL-1 (3 and TNF-a in rat pups might be down-regulated upon elevation of parenchymal PGE₂ levels.