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Epilepsy is a common neurological disorder often unresponsive to pharmacological treatment. Seizures initiate brain inflammation in glia and promote blood brain barrier (BBB)damage. Erythropoietin(EPO)has been suggested a promising therapeutic and prophylactic for epilepsies based on its neuroprotective, antiapoptotic, and antiinflammatory potency. Exogenously given EPO traverses BBB through EPO receptors. Our previous study showed that pretreatment with recombinant human EPO (rhEPO) suppresses epileptic seizures and prevents BBB damage, but the mechanisms are still unclear. The present study investigated a possible role of EPO pretreatment in reducing inflammatory events, in pentylenetetrazole (PTZ)-induced generalized epilepsy model. Adult male Sprague-Dawley rats were used (seven animal/each group). PTZ (80mg/kg i.p) was given to induce generalized seizures. rhEPO (3000 IU/kg i.p) applied 24 h before PTZ administration. The control group was given saline, the EPO control group was given the same dose of EPO. After injection of PTZ, seizures were observed for two hours and scored as seizure stage, latency. Under general anesthesia(thiopental sodium, 50mg/kg) blood samples were taken from heart and immediately the brain removed. NSE, S100Band imflammation biomarkers were performed with ELISA tests. The serum levels of neuron specific enolase(NSE) and S100B(astrocytic protein) as peripheral markers of neuronal and BBB damage, respectively and levels of proinflammatory cytokines, interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α),interleukin(IL-6) as indicator of brain inflammation were measured in brain tissue. Data represented as mean ± SEM and were compared among groups by using oneway ANOVA. PTZ induced seizures significantly (p<0.001) increased proinflammatory cytokines (IL1 β:1,584±0.187pg/ml vs 0.434±0.434pg/ml control, TNFα :0.488±0.083 pg/ml vs 0.120±0.015pg/ml control, IL-6:0.610±0.043 pg/ml vs0.509±0.042 pg/ml control). Likewise, the serum levels of S100B and NSE significantly (p<0.001 )were increased ( S100B: 0.89±pg/ml vs 0.32±0.05pg/ml control, NSE: 0.83± 0.087pg/ml vs 0.051 ± 0.011 pg/ml control). EPO pretreatment significantly(p<0.001) reduced seizure stage. Serum markers of BBB and neuron damage and all cytokines fell to control levels (IL1β:0.593±0.065pg/ml vs 1.584±0.187pg/ml PTZ group, TNFα: 0.177±0.007pg/ml vs 0.488±0.083 pg/ml PTZ group, IL-6: 0.339±0.017pg/ml vs 0.610±0.043 pg/ml PTZ group). Likewise, S100B and NSE fell to control levels (S100B: 0.33±0.041 pg/ml vs 0.89±0.03 pg/ml PTZ group, NSE: 0.2±0.075pg/ml vs 0.83± 0.087pg/ml PTZ group ). We suggest that the anticonvulsive effect of EPO is result of BBB protection due to its antiinflammatory activity. [ABSTRACT FROM AUTHOR]