Abstract TP129: Increased Levels Of Matrix Metalloproteinases-induced BBB Dysfunction May Be Responsible For Increased Post-sich Hematoma Growth In Nicotine-exposed Rats.

Abstract

Spontaneous intracerebral hemorrhage (sICH) is the deadliest type of stroke, accounting for as high as 28% of all strokes. Tobacco use is one of the major risk factors of sICH, and it also worsens outcomes following sICH. In our earlier study, we observed that nicotine exposure increases TNFα levels in brain vessels, impairs BBB integrity, and increases post-sICH hematoma volume in a TNFα-dependent manner compared to saline-exposed controls. Earlier studies have demonstrated interactions between MMPs and TNFα. Increased levels of matrix metalloproteinases (MMPs) have been found in sICH patients and nicotine-exposed individuals. MMPs are involved in BBB breakdown, edema formation, hematoma expansion, and neuronal loss that follow hematoma development after sICH. In the present study, we tested the hypothesis that nicotine exposure-induced increase in TNFα is responsible for increased post-sICH hematoma volume in a MMP-dependent manner. To test our hypothesis, young male and female rats were exposed to chronic nicotine treatment for 2-3 weeks using osmotic pumps containing either saline or nicotine (4.5 mg/kg/day). Levels of MMPs (2, 3, 9, and 12) and GAPDH were evaluated in brain homogenates using Western blot. Nicotine-treated female rats showed a 37% (100±7 vs. 137±10, p<0.05), 144% (100±18 vs. 244±16, p<0.01), 29% (100±7 vs. 129±9, p<0.05), 22% (100±6 vs. 122±6, p<0.05), and 24% (100±6 vs. 124±7, p<0.05) increase in levels of pro and cleaved forms of MMP-3, cleaved form of MMP-9, pro and cleaved forms of MMP-12, respectively, compared to saline-treated female rats. We are in the process of evaluating levels of MMPs in male samples. Considering the role of MMP-9 in BBB integrity, using both TNFα and MMP-9 inhibitors, we are also in the process of evaluating if TNFα increases post-sICH hematoma growth in nicotine-exposed rats via increased levels of MMP-9. The results so far imply that increased TNFα levels in nicotine-exposed rats may be responsible for increased post-sICH hematoma growth in a MMP-dependent manner. Support: James Esther King Biomedical Research Grant 9JK08 and PK is a recipient of the Lois Pope Neuroscience Summer Research Fellowship.