Abstract TMP97: Progesterone Attenuates Acute Seizure and Brain Infarction by Modulating Pro-Inflammatory Cytokines in a Mouse Model of Neonatal Stroke
Neonatal stroke is among the top ten causes of childhood death and causes long-term permanent disability and neurological deficits in survivors. In most cases, recurrent clonic seizure is the only clinical manifestation which worsens the stroke outcomes. A treatment or pediatric stroke is essential, but no candidate intervention is supported by substantiated data. We tested the hypothesis that progesterone (P4) treatment would be beneficial in a neonatal model of stroke. P12 CD1 mice (mixed gender) underwent permanent unilateral right common carotid ligation (pUCCL) or sham surgery (n=10/group). Pups which showed seizure activity during the 1h post-pUCCL were randomly assigned to receive P4 (8 mg/kg) or vehicle injections at 1, 3 and every 24h post-pUCCL for 6 days. We assessed acute behavioral seizures (during the first 4h post-pUCCL), serum pro-inflammatory cytokines (IL-1β, IL-6, TNFα at 6, 24 and 48h) and brain infarction (at day 7 by CV-staining). Cytokine data were analyzed by repeated measures one-way ANOVA followed by LSD and Tukey’s tests for independent comparisons. For seizure and infarct data, a two-tailed unpaired t-test was employed. We observed acute seizures during the first 4h post-pUCCL in the vehicle group (90.8±11.77). P4 treatment significantly (P<0.05) reduced seizure occurrence (58.4±8.97) by 35% compared to vehicle. Repeated measures ANOVA revealed a significant group effect in IL-1β (F(2,15)=110.706; P<0.001), IL-6 (F(2,15)=66.067; P<0.001), and TNFα (F(2,15)=146.263; P<0.001) levels. Serum IL-1β, IL-6 and TNFα were significantly higher (P<0.001) at 6 and 24h and remained elevated until 48h post-pUCCL in the vehicle group compared to sham. The P4-treated group showed a significant (P<0.01) decrease in all pro-inflammatory cytokine levels at all time points. Further, pUCCL resulted in severe hemispheric damage (16.88±1.48) as evidenced by cresyl-violet staining at 7 days post-pUCCL. P4 treatment showed a significant (P<0.05) reduction (4.93±1.1) in infarct volume (~70%) compared to vehicle. Our data demonstrate that P4 reduces acute seizures and brain infarction following neonatal stroke by modulating the inflammatory process, and warrants detailed studies of functional outcomes and mechanism of action.
- © 2012 by American Heart Association, Inc.