Susceptibility to intracerebral hemorrhage-induced brain injury segregates with low aerobic capacity in rats.

Although low exercise capacity is a risk factor for stroke, the exact mechanisms that underlie this connection are not known. As a model system for exploring the association between aerobic capacity and disease risks we applied two-way artificial selection over numerous generations in rats to produce low capacity runners (LCR) and high capacity runners (HCR). Here we compared intracerebral hemorrhage (ICH)-induced brain injury in both genders of these rat lines. HCR and LCR rats had 100μl blood injected into the right caudate and were killed at days 1, 3, 7 and 28 for brain water content determination, immunohistochemistry, histology, Western blot, and behavioral tests. Compared to male HCRs, male LCRs had more severe ICH-induced brain injury including worse brain edema, necroptosis, brain atrophy, and neurological deficits, but not increased numbers of Fluoro-Jade C positive cells or elevated cleaved caspase-3 levels. This was associated with greater microglial activation, and heme oxygenase-1 and protease activated receptor (PAR)-1 upregulation. In females, edema was also greater in LCRs than in HCRs, although it was less severe in females than in males for both LCRs and HCRs. Thus, ICH-induced brain injury was more severe in LCRs, a model of low exercise capacity, than in HCRs. Increased activation of microglia and PAR-1 may participate mechanistically in increased ICH-susceptibility. Females were protected against ICH-induced brain edema formation in both HCRs and LCRs.