Post-ischemic inflammation: molecular mechanisms and therapeutic implications

Abstract

Ischemic stroke is characterized by the disruption of cerebral blood flow (CBF). This reduction of CBF results in energy failure and secondary biochemical disturbances, eliciting a robust in situ inflammatory response. Post-ischemic inflammation is a dynamic process involving a complicated set of interactions among various inflammatory cells and molecules. The resident inflammatory brain cells, microglia, are especially activated in response to ischemic insults, many of which are regulated by nuclear transcription factor, kappa B (NF-kappaB). As a result, several inflammatory genes are expressed, leading to local generation of various cytokines, which in turn promulgate inflammatory signals. Meanwhile, endothelial cells lining the local cerebral blood vessels are stimulated to produce adhesion molecules, causing the migration of peripheral circulating leukocytes into the compromised brain tissue, an event that amplifies inflammatory signaling cascades. Post-ischemic inflammation appears to serve multiple purposes, depending on its timing and magnitude, as well as the topographic distribution of various inflammatory molecules. Data from experimental manipulations of some inflammatory molecules are yielding insight into therapeutic strategies for ischemic stroke. This review focuses on some recent advances regarding the regulation of inflammatory signaling pathways, the detrimental effects of post-ischemic inflammation and the potential molecular targets for ischemic stroke therapy.

Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury

“…Seventeen inflammatory genes showed uniformly increased expression in DHT-treated versus castrated brain at 6 h reperfusion, including proinflammatory cytokines (e.g., IL-1a, IL-1b, IL-6, and TNF), chemokines (e.g., MIP1a, MIP1b, CXCL1, CXCL2, and CCL2), and adhesion molecules such as intercellular adhesion molecule. Many of these gene products are known to contribute to ischemic cell death (Zheng and Yenari, 2004). For example, pharmacological inhibition or genetic deletion of IL-1 and TNF is neuroprotective in focal ischemia models (Reiton et al, 1996;Loddick and Rothwell, 1996;Ohtaki et al, 2003), and high peak plasma IL-6 levels after clinical stroke correlate with poor outcomes (Smith et al, 2004).…”

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

“…In particular, the degree of leukocyte infiltration following focal stroke correlates with the severity of neuronal injury and neurological deficits in animals Clark et al, 1994;del Zoppo et al, 1991) and humans (Akopov et al, 1996). Moreover, in focal ischemia models, anti-leukocyte interventions decrease cerebral edema (Strachan et al, 1992), improve cerebral blood flow (Grogaard et al, 1989;Connolly et al, 1996;Ishikawa et al, 2004), and reduce infarct size (Connolly et al, 1996;Chopp et al, 1994;Beech et al, 2001;Xu et al, 2004;Zheng et al, 2004). Finally, adhesion molecule knockout mice consistently exhibit smaller lesion volumes following focal stroke than their wild-type counterparts (Prestigiacomo et al, 1999;Soriano et al, 1996).…”

Microglial Activation in Stroke: Therapeutic Targets

“…Microglial activation is the initial step in the CNS inflammatory response; depending on the stimulus, this step may be followed by infiltration of circulating monocytes, neutrophils, and T-cells, and by reactive astrocytosis. 10 Microglial activation is not, however, a univalent state, and the morphological and gene expression changes associated with microglial activation vary enormously with the nature, strength, and duration of the stimulus. 11 Moreover, evidence suggests that microglia populations in the brain are heterogeneous, and that these populations may respond differently to similar stimuli.…”