Abstracts

Rationale: Accumulating evidence from experimental models and human studies suggests that IL-1ߠshows neurotoxic or proconvulsant effects, whereas an interleukin-1 receptor antagonist (IL-1RA) prevents the production of IL-1ߠin the brain, resulting in neuroprotective or powerful anticonvulsant effects. Although the efficacy of adrenocorticotropic hormone (ACTH) for the elimination of West syndrome (WS) has been recognized, the underlying mechanisms of action remain unknown. We previously reported elevated serum IL-1RA levels subsequent to the resolution of clinical symptoms in WS patients, with levels higher in patients treated with ACTH than in those treated with antiepileptic drugs (Yamanaka et al. J Neurol Sci. 2010). We speculated that IL-1RA or cytokines might play a role in mediating the anticonvulsant effects of ACTH. The aim of this study was to evaluate various cytokine responses to ACTH in patients with WS to explore the mechanism of its actions. Methods: Five Japanese patients with WS (3 cryptogenic, 2 symptomatic) were enrolled. The diagnosis of WS was made based on observations of typical tonic spasms and hypsarrhythmia. The age of onset was 5 -15 months old. Informed consent was received from the parents to use serum samples for clinical investigation. Serum samples were obtained prior to and at 30,120, and 720 minutes after the injection of ACTH (0.0125 mg/kg). Using the Bio-Plex multiplex cytokine assay, we measured the following 27 cytokines:IL-2, -4, -5, -6, -7, -8, -9, -10, -12, -13, -15 -17, IL-1߬ IL-1RA, Eotaxin, FGF-basic, G-CSF, GM-CSF, IFN-?, IP-10, MCP-1, MIP-1a, MIP-1b, PDGF-bb, RANTES, TNFa, and VEGF. We divided the subjects into two groups, the early group and the delayed group, who received the injection of ACTH on days 1-4 and days 10-28, respectively. The changes in response to ACTH over time were analyzed within each group. Results: In the early group, all patients showed higher serum levels of IL-5, IL-9, IL-17, PDGF-bb, FGF-basic, IFN-?, IP-10, MCP-1, MIP-1a, and MIP-1b prior to ACTH administration than at the 720-minute time point. IL-9, PDGF-bb, and MCP-1 levels were also higher prior to treatment than at 120 minutes post-injection. In the delayed group, all patients showed higher serum MCP-1 levels prior to injection than at the 720-minute time point. No definite tendency was observed in any of the other cytokines. Conclusions: In this study, we found that ACTH decreased the sera levels of specific cytokines, including IL-17, which has been implicated in the pathophysiology of epilepsy. The alterations in these cytokines may be associated with the underlying mechanisms of ACTH's anticonvulsant effects. Further studies with a larger patient group are needed to assess whether immunological processes are associated with the pathophysiology of WS. Funding: This study was supported by the Supporting Positive Activities for Female Researchers of Tokyo Medical University, Japan.