Abstract WMP32: Immunomodulation and Neuroprotection by Progesterone in Infections following Ischemic Brain Injury in Middle-Aged Rats
Infection is one of the major complications during the acute phase following stroke, accounting for in-hospital deaths and worsening outcomes. We investigated the effect of delayed systemic inflammation on stroke outcomes and neuroprotection by progesterone (P4). Middle-aged rats underwent transient middle cerebral artery occlusion (MCAO) and received P4 (8 or 16 mg/kg) or vehicle until day 7 post-MCAO. Beginning 24h post-MCAO systemic inflammation was induced by 3 doses of lipopolysaccharide (LPS; 50 mg/kg, i.p.) to model post-stroke infections. We evaluated serum brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, brain infarctions, and conducted behavioral testing at multiple time points. Data were analyzed using repeated measures (RM)-ANOVA followed by LSD and Tukey’s tests. RM-ANOVA revealed a significant group effect (F(4,25)=153.60; P<0.001) for IL-1β, IL-6 (F(4,25) = 179.56; P<0.001), and TNFα (F(4,25) = 58.94; P<0.001). Vehicle-alone showed a significant increase in all cytokine levels at different times following stroke which were further elevated after LPS injections in the vehicle+LPS group. P4 at both doses produced a significant decline (P<0.05) in cytokine levels compared to vehicle and vehicle+LPS. BDNF levels showed a significant group effect (F(4,25) = 24.838; P<0.001) and greater (P<0.05) decrease in the vehicle+LPS group compared to vehicle-alone at 3 and 7 days post-injury. P4 significantly (P<0.001) restored BDNF levels post-injury. At 3, 5 and 7 days, a significant group effect was observed in rotarod (F(4, 26) = 33.059, P<0.001), grip strength (F(4, 26) = 42.263, P<0.001), sensory neglect (F(4, 26) = 150.712, P<0.001), and locomotor activity (F(4,25) = 63.423, P<0.001). The vehicle group had significant (P<0.05) deficits in all tests, and performance was worse in the vehicle+LPS group. P4 produced significant (P<0.05) improvement in the animals’ performance on all tests. Systemic inflammation did not show an additive effect on infarct volume but P4 at both doses showed significant infarct reduction. Ourb data suggest that post-stroke infection exacerbates stroke outcomes and P4 exerts neuroprotective/modulatory effects through its anti-inflammatory and BDNF regulatory action.
- © 2012 by American Heart Association, Inc.