Current Pharmaceutical Design, 2008, 14, 3549-3564 3549 1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Inflammation as Therapeutic Objective in Stroke Joaquín Jordán 1, * , Tomás Segura 2 , David Brea 3 , Maria F. Galindo 4 and José Castillo 3 1 Grupo de Neurofarmacología. Departamento de Ciencias Médicas. Facultad de Medicina. Universidad Castilla-La Mancha. Centro Regional de Investigaciones Biomédicas. Spain; 2 Servicio de Neurología. Complejo Hospitalario Uni- versitario de Albacete. Albacete. Spain; 3 Department of Neurology, Clinical Neuroscience Research Laboratory, Hospi- tal Clínico Universitario de Santiago de Compostela, University of Santiago de Compostela. Spain and 4 Unidad de Neu- ropsicofarmacología Translacional. Complejo Hospitalario Universitario de Albacete. Albacete. Spain Abstract: Ischemic stroke is the most frequent cause of persistent neurologic disability in modern Western societies. Al- beit it is still not clear whether inflammation is merely an epiphenomenon or rather has a disease-promoting function, ac- cumulating evidence implicates inflammation in many forms of acute neurodegenerative disorders including ischemia. The immune cell influx during a neuropathological event is thought to be elicited by glial cells, especially microglia. This article reviews the cellular and molecular pathways involved in stroke-induced inflammatory response in the CNS. We fo- cused on how CNS innate immune cells including microglia and macrophages play integral roles in receiving and propa- gating inflammatory signals, and how activated microglia secrete a wide range of factors. We present the relevance of the expression of adhesion molecules after ischemia including selectin, immunoglobulin superfamily, integrins, and the role of inflammatory mediators such as cytokines, chemokines and matrix metalloproteinases. Further, we explore the role of transcription factors in inflammation, and the function of immunomodulation and innate and adaptive immunity in brain ischemia, focusing on immunosupression therapies for acute stroke. Although several approaches for anti-inflammatory treatment have proven effective in animal models, clinical trials of immune system modulation therapy after stroke have not yet proved successful. There is still much to be done in order to translate interesting findings into therapies, but un- doubtedly studying the cellular and molecular pathways may not only improve our understanding of inflammatory mechanism but also serve as a basis for designing effective therapies. 1. INTRODUCTION Stroke is the second leading cause of death and the bur- den of disease in high income countries [1]. Stroke occurs due to a loss of blood supply to part of the brain, initiating the ischemic cascade. As oxygen or glucose becomes de- pleted in ischemic brain tissue, the production of high energy phosphate compounds such as adenosine triphosphate (ATP) fails leading to failure of energy dependent processes (such as ion pumping) necessary for tissue cell survival. This sets off a series of interrelated events that result in cellular injury and death by necrosis. Dead cells by necrosis produce the release of all cytoplasmatic content into the extracellular space activating the corresponding inflammatory response. The central nervous system (CNS) has for long been re- garded as an immune privileged organ, with the blood–brain barrier (BBB) tightly regulating the influx of immune cells and mediators from the vascular compartment to the brain parenchyma [2]. Inflammation is generally a beneficial re- sponse of an organism to infection but, when prolonged or inappropriate, it can be detrimental. Neuronal loss in acute (e.g. stroke and head injury) and chronic [e.g. multiple scle- rosis and Alzheimer's disease] CNS diseases has been asso- ciated with inflammatory processes systemically and in the *Address correspondence to this author at the Grupo de Neurofarmacologia, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha. Centro Regional de Investigaciones Biomédicas, Avda Almansa, 14, 02006-Albacete, Spain; Tel: 34-967599200; Fax: 34-967- 599327; E-mail: Joaquin.jordan@uclm.es brain. Brain inflammation is characterized by activation of microglia and astrocytes, expression of key inflammatory mediators, but limited invasion of circulating immune cells. Inflammation induces rapid expression of key inflammatory mediators -cytokines, chemokines and prostaglandins- which in turn up-regulate adhesion molecules, increase permeabil- ity of the BBB, facilitating invasion of peripheral immune cells, induce release of potentially toxic molecules and com- promise brain cells. Because the BBB is disrupted after stroke, the immune system comes into contact with CNS antigens, in both the brain and periphery [3]. In recent years, major advances in the study of the role of the immune system and inflammation in brain ischemia have been done. There are many evidences that inflammation and immune response play an important role in the outcome of ischemic stroke patients, and they have been associated to larger brain damage. However, on the other hand, these mechanisms might be necessary for the resolution of dead cells and the initiation of repairing mechanisms. In this work we review the inflammatory response to brain ischemia, the role of innate immunity, and the potential role of endogenous anti-inflammation and immune-modulation processes. 2. CELLULAR INFLAMMATORY RESPONSE The CNS innate immune cells including microglia and macrophages play integral roles in receiving and propagating inflammatory signals. Microglia are a highly responsive population of cells with a well established role in regulating the immune surveillance of the nervous system [4,5]. Found