Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 169-177 169 Estrogens as Protectants of the Neurovascular Unit Against Ischemic Stroke Shao-Hua Yang, Ran Liu, Evelyn J. Perez, Xiaofei Wang and James W. Simpkins* Department of Pharmacology and Neuroscience, Health Science Center, University of North Texas, Fort Worth, TX. 76123, USA Abstract: Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke. Keywords: Estrogens, estradiol, stroke, cerebral ischemia, neuroprotection, neurons, glia, endothelial cells, tissue plasminogen activator, neurovascular unit. INTRODUCTION Two primary therapeutic approaches have been intensively studied for the treatment of acute cerebral ischemia: (i) a vascular approach that targets re-opening clotted blood vessel [3] and (ii) a cellular approach to interfere with the pathobiochemical cascade leading to ischemc damage [3]. The vascular approach is based on the fact that ischemic stroke is a cerebral vasculature event, initiated by occlusion of a cerebral artery and results in substantial brain tissue damage. Interruption of blood flow to the brain results in ischemia and deprives neurons and surrounding cells of crucial substrates. Unless the supply of these substrates can be restored, the cells in the region will ultimately die. The vascular approach focuses on limitation of cerebral ischemia by early reperfusion after cerebral ischemia. The effort to develop effective vascular therapy for acute ischemic stroke achieved several important successes during the past decade. The major successes were related to thrombolysis. Based on the results from the NINDS trial in 1995, intravenous tPA is recommended for selected patients within 3 hours of ischemic stroke [4]. The use of tPA is now the only established stroke treatment for those patients presenting within 3 hours of ischemic stroke onset. Beyond this time window, systemic tPA does not appear to be as beneficial and increases the risk of serious side effects. Few patients can reach emergency services within 3 hours after the onset of stroke, and many hospitals are not able to provide the emergency services required to treat stroke patients. Furthermore, public education is not yet adequate for stroke victims or bystanders to recognize the nature of the problem and seek emergency care. As a result, only about 1% of the potentially eligible patients receive the treatment [5]. Improvements in utilization will depend on organization of clinical service. Also, combination therapies need to be developed to promote thrombolytic safety and efficacy. Stroke ranks as the third leading cause of death and the leading cause of disability in the United States. Recent epidemiologic data suggest that the decline in both stroke incidence and mortality reached a nadir in the early 1990s and is now rising because of the aging population [1]. Stroke patients must not only survive the acute stages of infarction, but must then cope with significant mental, physical, and economic stresses associated with neurological impairment. Considering the cost in loss of life, physical and mental disability and subsequent self-esteem and productivity, the need for effective therapeutic interventions is obvious. Ischemic stroke is by far the most frequent type of stroke, accounting for 83% of all stroke cases [2]. Ischemic stroke results from an obstruction, typically a blood clot. Cerebral ischemia may be either transient followed by reperfusion, or essentially permanent. In patients, both types of focal ischemia can occur. In transient occlusion, reperfusion injury also adds to brain damage. After cerebral ischemia, perturbations in neurovascular functional integrity initiate several cascades of injury. Upstream signals such as oxidative stress and glutamate excitotoxity together with upregulation of matrix metalloproteinases (MMPs), tissue plasminogen activator (tPA) and other proteases, which degrade matrix, lead to blood brain barrier (BBB) disruption. Inflammatory products which infiltrates through the damaged BBB amplify brain tissue injury. Additionally, disruption of cell matrix homeostasis and activation of microglia can also trigger cell death pathways in both vascular and parenchymal compartments [3]. The cellular approach is based on the interference with the pathobiochemical cascade leading to ischemc damage [3]. For over a decade, monotherapy focused on a signal cell type, especial neurons, or a single pathway has dominated *Address correspondence to the author at the Department of Pharmacology & Neuroscience, 3500 Camp Bowie Bovl., University of North Texas Health Science Center, Fort Worth, TX 76107, USA; Tel: 817-725-0498; Fax: 817-735-0485; E-mail: jsimpkin@hsc.unt.edu 1568-007X/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.