Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage

Microcirculatory dysfunction may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Using a prechiasmatic injection model, this study investigated ultrastructural changes in microvessels in brain parenchyma to determine the nature of the microthromboemboli, the involvement of nitric oxide (NO) and P-selectin in their formation, and relationship to brain injury after SAH. Brains were examined by electron microscopy (EM) and immunohistochemistry. EM demonstrated that mice with SAH had significantly more arterioles filled with lesions consistent with microthrombi (in cortex, 20±5 for SAH, 8±4 saline-injected and 2.4±0.2 for sham). SAH animals also had more constriction of arterioles. The concentration of NO was lower in mice with SAH (44±9 for sham, 46±20 for saline-injected and 24±11 for SAH). The number of microthrombi correlated with the number of apoptotic neuronal cells (R =0.80 in cortex). Cell membrane P-selectin increased in the endothelium of arterioles in mice with SAH (11.4±0.7 for SAH, 6.8±0.9 for sham and 6.1±0.9 for saline-injected controls). This correlated with decreased NO in the brain. In conclusion, SAH causes microthrombosis and constriction of arterioles, which correlates with neuronal cell death. Increased P-selectin and decreased NO suggest a mechanism for microthrombosis and arteriolar constriction. © 2012 IBRO.

Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage

Microcirculatory dysfunction may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Using a prechiasmatic injection model, this study investigated ultrastructural changes in microvessels in brain parenchyma to determine the nature of the microthromboemboli, the involvement of nitric oxide (NO) and P-selectin in their formation, and relationship to brain injury after SAH. Brains were examined by electron microscopy (EM) and immunohistochemistry. EM demonstrated that mice with SAH had significantly more arterioles filled with lesions consistent with microthrombi (in cortex, 20±5 for SAH, 8±4 saline-injected and 2.4±0.2 for sham). SAH animals also had more constriction of arterioles. The concentration of NO was lower in mice with SAH (44±9 for sham, 46±20 for saline-injected and 24±11 for SAH). The number of microthrombi correlated with the number of apoptotic neuronal cells (R =0.80 in cortex). Cell membrane P-selectin increased in the endothelium of arterioles in mice with SAH (11.4±0.7 for SAH, 6.8±0.9 for sham and 6.1±0.9 for saline-injected controls). This correlated with decreased NO in the brain. In conclusion, SAH causes microthrombosis and constriction of arterioles, which correlates with neuronal cell death. Increased P-selectin and decreased NO suggest a mechanism for microthrombosis and arteriolar constriction. © 2012 IBRO.

Bilirubin and its oxidation products damage brain white matter

Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compounds have an effect on the structure and function of white matter in vivo. In all, 0.5 mmol/L bilirubin treatment significantly damaged both the function and the structure of myelinated axons but not the unmyelinated axons in brain slices. Toxicity of bilirubin in vitro was prevented by dimethyl sulfoxide. Bilirubin oxidation products (BOXes) may be responsible for the toxicity of bilirubin. In in vivo experiments, unmyelinated axons were found more susceptible to damage from bilirubin injection. These results suggest that unmyelinated axons may have a major role in white-matter damage in vivo. Since bilirubin and BOXes appear in a delayed manner after ICH, preventing their toxic effects may be worth investigating therapeutically. Dimethyl sulfoxide or its structurally related derivatives may have a potential therapeutic value at antagonizing axonal damage after hemorrhagic stroke