The Role of Cytokines in the Neuropathology of Stroke and Neurotrauma

Abstract

Accumulating evidence during the last decade has shown that the CNS can mount a well-defined inflammatory reaction to a variety of insults including trauma, ischemia, transplantation, viral infections as well as neurodegeneration. Many aspects of this centrally derived inflammatory response parallel to some extent the nature of such a reaction in the periphery. Through the recent application of molecular genetic techniques including PCR, utilization of cDNA probes in conjuncture with the availability of highly specific antibodies, new concepts are rapidly emerging as to the molecular mechanisms associated with the development of brain injury. In particular, the importance of cytokines, especially TNFα and IL-1β, is emphasized in the propagation and maintenance of a CNS inflammatory response. This review summarizes evidence in support of a case for ischemia and trauma eliciting an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils early after the onset of brain injury and subsequently monocyte infiltration) and mediators (cytokines, chemokines and adhesion molecules). It is clear that de novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of the inflammatory response and its contribution to brain injury are now becoming better understood. Evidence has emerged in support of the role of cytokines in driving the inflammatory response and that this process is causally related to the degree of brain injury. Evidence reviewed includes: (1) the capacity of specific cytokines to exacerbate brain damage; (2) the capacity of specific cytokine blockade to reduce ischemic brain damage; (3) depletion of circulating neutrophils reduces ischemic brain injury, and (4) antagonists of the endothelial-leukocyte adhesion interactions (e.g. anti-ICAM-1) reduce ischemic brain injury. Targeting the cytokines that drive the brain inflammatory response to injury provides opportunities to intervene with novel therapeutics in stroke and neurotrauma.

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

“…Since ECs are also capable of activating a number of inflammatory factors, including inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX), phospholipase A2 (PLA2), cyclooxygenase-2 (COX2), as well as NF-kB, 76 it is possible that these inflammatory factors may generate "cell swelling mediators", including arachidonic acid, RONS, prostaglandins and CKs, 76 that may ultimately result in astrocyte swelling/brain edema in acute HE. In support of this view, we recently reported that cultured ECs treated with ammonia showed evidence of ONS [77][78][79][80] and the activation of NF-kB.…”

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

“…The inflammatory response in the CNS may have various consequences on outcome, depending upon the degree of inflammatory response and when it occurs (Blight, 1985;Benveniste, 1992). Both acute and chronic inflammatory processes have been shown to influence outcome in various experimental models of cerebral ischemia and trauma (Arvin et al, 1996;Clark et al, 1994;del Zoppo et al, 2000;Fan et al, 1995;Fan et al, 1996;Feuerstein et al, 1998;Kochanek and Hallenbeck, 1992). While acute inflammatory events may participate in secondary injury processes, more delayed inflammatory events may be reparative (Bethea and Dietrich, 2002;Kerschensteiner et al, 1999).…”

“…These changes are mediated through the altered expression of released and cell surface signaling molecules (Feuerstein et al, 1998). Altered adhesion molecule expression promotes cellular interactions that are critical for inflammatory and thrombotic processes.…”

Role of Histamine and Its Receptors in Cerebral Ischemia

“…71,72 Accompanying these morphological changes is a range of physiological changes, including secretion of a variety of cytokines. 73,74 At the late phase of focal cerebral ischemia, astrogliosis results in glial scar formation, which obstructs axonal regeneration, and finally impedes neurological recovery. 75 So, mechanisms to limit glial scar formation are the focus of much research.…”