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.



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.

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