Abstracts

Rationale: Post-status epilepticus (SE) temporal lobe epilepsy (TLE) in rats is accompanied by endocrine, biochemical and behavioral hallmarks of depression (Mazarati et al., Brain, 2008;131;2071-2083; Mazarati et al., Neurobiol. Dis, 2009; In press), and as such represents a model of comorbidity between TLE and depression. The upregulation of an inflammatory cytokine interleukin-1β (IL-1β)and its receptor in the hippocampus is an established hallmark of TLE. At the same time, the activation of hippocampal IL-1β may lead to depression via the dysregulation of hypothalamo-pituitary-adrenocortical axis, and subsequent deficit of raphe-hippocampal serotonergic transmission. Such connections between TLE and IL-1β signaling on the one hand and between IL-1β and depression on the other hand suggest that blocking of effects IL-1β in the hippocampus may be beneficial in TLE-associated depression. We examined how protracted blockade of IL-1 receptor in the hippocampus of post-SE rats affects endocrine, behavioral and biochemical hallmarks of concurrent depression. Methods: TLE was induced in adult male Wistar rats by LiCl and pilocarpine SE. Four-six weeks after SE, the establishment of depression was verified by radioimmunoassay of plasma corticosterone (CORT) under baseline conditions and in response to dexamethasone/corticotropin releasing hormone (DEX/CRH) test, and by behavioral assays - the taste preference saccharin consumption test (to study anhedonia) and forced swim test (FST, to study the state of despair). Afterwards, animals underwent 10 days-long continuous bilateral infusion into the hippocampus with human recombinant IL-1 receptor antagonist (hrIL-1Ra, 0.1 mg/hippocampus), using subcutaneously implanted ALZET osmotic pumps connected to intrahippocampal cannulas. At the end of treatment, rats underwent endocrine and behavioral tests, as well as fast cyclic voltammetry to examine the release of serotonin in the raphe-hippocampal pathway. Results: In agreement with earlier studies, post-SE animals developed hallmarks of depression: endocrine - elevated plasma CORT level and positive DEX/CRH test; behavioral - loss of taste preference towards saccharin (anhedonia) and increased immobility time in the FST (despair); biochemical - compromised serotonergic transmission in the raphe-hippocampal pathway. Treatment with hrIL-1Ra lowered plasma CORT level; mitigated positive DEX/CRH test; reduced immobility time in the FST; increased saccharin intake; increased serotonin release in the hippocampus (p<0.05 vs. vehicle-treated post-SE rats). However, neither of the examined indices returned to normal values, as observed in vehicle-treated non-epileptic controls. Administration of hrIL-1Ra in naïve animals did not modify any of endocrine, behavioral, or biochemical parameters. Conclusions: Hippocampal IL-1β signaling may contribute to (although does not constitute a sole cause of) depression in TLE. Il-1β antagonists may be beneficial in the adjunctive therapy of epilepsy-associated depression. Supported by the NIH grant MH079933. hrIL-1Ra was a gift from Amgen (Thousand Oaks, CA).