We are studying cerebral injury during the first 48 hours after subarachnoid hemorrhage (SAH).
SAH occurs when an intracranial aneurysm ruptures and releases blood into the subarachnoid space. SAH strikes up to 30,000 North Americans each year, and it accounts for 5-10% of all stroke cases. Epidemiological, population, and community based studies demonstrate that approximately 50% of patients die within 30 days of aneurysmal SAH, and two thirds of the deaths occur within 48 hours. Hence, early diagnosis and treatment are critical for potential reduction of the mortality rate.
Cerebral injury after SAH is ischemic in nature and occurs in two phases; early ischemia and injury at the time of the initial hemorrhage (≤48 hours), and delayed vasospasm and ischemia that develops 72 hours -7 days after SAH. Early ischemic brain injury after SAH accompanies reduced cerebral blood flow (CBF) and is the most important contributor to poor outcome after SAH. However, the mechanisms underlying early ischemic injury after SAH are poorly understood.
We have developed an animal (rat) model of SAH that simulates human SAH: immediate rise in intracranial pressure and fall in CBF at SAH induction, followed by cerebral ischemia. We are using this model to study cerebral injury during the first 48 hours after SAH with the focus on elucidating underlying mechanisms and identifying preventive therapeutic strategies.
One of our laboratory projects investigates alteration in Nitric Oxide/ nitric oxide synthase (NO/NOS) pathway after SAH. This pathway plays an important role in maintaining basal cerebral blood flow. NO is a vasodilator that is synthesized and released upon demand. Endothelial Nitric Oxide synthase (eNOS), found on the vascular endothelium represents one of the major sources of vascular NO. We have found that cerebral NO levels are decreased acutely after SAH. This decrease differentiates cerebral injury after SAH from other forms of ischemic stroke in which an increase in NO levels is found. A decrease in cerebral NO level would lead to unopposed constriction and contribute to ischemia after SAH. Indeed, we have found that if cerebral NO level is restored early after SAH (such as via an NO donor), CBF recovers and development of cerebral ischemia is prevented. We are now developing the therapeutic window during which administration of NO would be beneficial to the ischemic brain after SAH.
The mechanism underlying decreased cerebral NO is also of great interest as it helps design a more direct therapy to prevent cerebral injury via altered NO levels. Early reduction of vascular eNOS could be a central mechanism in pathophysiological cascade of SAH; interventions which preserve eNOS or restore vascular NO could attenuate cerebral injury. We are now investigating the mechanisms underlying decrease in eNOS after SAH.
Another equally important project investigates contribution of cerebral microvessels (≤100μm) that are below the resolution of conventional angiography in development of ischemia after SAH. In humans, although early cerebral ischemia occurs, cerebral angiography shows little evidence of acute arterial spasm. Using the rat SAH model, we have discovered structural alterations that are sufficient to affect vessel function: perfusion and BBB function in microvessels. These include platelet aggregation in vascular lumen, degradation of collagen IV; the major protein of basal lamina, activation of vascular collagenases such as MMP-9 and loss of endothelial barrier protein (EBA, marker of blood brain barrier integrity in the rat). Platelet aggregates lodged in microvessels can cause structural changes by obstructing the lumen mechanically, and by releasing the vasoactive contents of their dense granules (serotonin, ADP, PDGF etc.) encouraging vasoconstriction. Moreover, platelets are a rich source of MMP-9 and can contribute to collagen IV degradation by releasing MMP-P during activation/aggregation process. We are now investigating the role of platelet aggregation in vascular alterations after SAH.
More recently we have adapted our rat endovascular model to the mouse. We are excited about this significant achievement as it allows us the use of transgenic technology. We are looking forward to using the mouse SAH model to gain new insights towards the genes and their products involved in cerebral injury after SAH.
A thorough understanding of the nature and the mechanisms of injury is prerequisite for developing therapy. The overall goal of our research is to determine mechanisms of early brain injury after SAH to develop therapy. We are studying a number of mechanisms. It is very likely that the ultimate treatment designed will address more then one mechanism of injury.