Background: Ischemic stroke is a devastating neurological deficit that accounts for 87% of all stroke cases in the US. Post ischemic stroke, oxidative stress leads to a production of reactive oxygen species, which cause considerable tissue damage. Inflammation plays an important role in ischemic stroke brain injury by activating resident cells and producing proinflammatory mediators. The scavenger receptor CD163, and the acute-phase plasma glycoprotein Haptoglobin (Hp) alleviate post ischemic damage resulting from toxic oxidative reactions and inflammation. This is the first investigation into the roles of CD163 and Hp in ischemic stroke, specifically in tMCAO.
Methods: Transient focal cerebral ischemia was induced by MCAO in wildtype (WT), CD163 knockout (CD163-/-), haptoglobin knockout (Hp-/-), and haptoglobin-CD163 double knockout mice (Hp-/-xCD163-/-) using the intraluminal filament protocol. Focal neurological deficit was observed post-surgery daily at 24, 48 and 72h through neurological deficit scoring (NDS). Mice were tested in an open field chamber for basic locomotion and circling behaviors activity in a pretest before surgery and at 24, 48, and 72h post-stroke. Lesion volume and hemispheric enlargement were assessed in a blinded manner using cresyl violet staining. Data is expressed as mean ± SEM and all statistical analysis was performed in JMP Pro 12.
Results: The Hp-/- and Hp-/-xCD163-/- had better functional and anatomical outcomes. Regression analysis of open field shows better recovery for Hp-/- and Hp-/-xCD163-/-. Hp-/- had 45.2% smaller lesion volume (p=0.0049) and 66.1% reduced hemispheric enlargement (p=0.0174) compared to WT. The Hp-/-xCD163-/- mice had 55.0% smaller lesion volume (0.0210) and 64.5% reduced hemispheric enlargement (p=0.0037) compared to CD163-/- mice.
Conclusion: These results suggest that there is a significant decrease in neuronal damage post ischemia following the genetic deletion of Hp suggesting a unique role of the haptoglobin-CD163 pathway in stroke.