Inflammatory Mediators and Stroke: New Opportunities for Novel Therapeutics

Abstract

Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide “neuroprotection” in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-α, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

“…Several studies have reported prominent changes in proinflammatory cytokines following stroke. [20][21][22] The proinflammatory cytokines interleukin (IL)-1, tumor necrosis factor a (TNF-a), IL-6 and IL-8 have all been shown to be involved in the initiation or amplification of the inflammatory response in patients following acute cerebral ischemia. Interestingly for our purposes, some studies on experimental models have suggested that inflammatory mediators, such as the cytokine IL-1, might contribute to the extent of cerebral ischemia through their effects on specific limbic pathways.…”

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

“…As an analogy to hippocampal neurons [10], we speculate that an ischemia-induced alteration of GluR2 expression in Deiter's neurons induced cell death. Although further investigations are required to clarify the mechanisms underlying this selective vulnerability and delayed neuronal damage, they may also be related to several other factors such as the degree of cerebral hypoperfusion after reperfusion [11], inhibition of protein synthesis [12], neutrophil infiltration following reperfusion [13], free radical production [14], dysfunction of the mitochondrial shuttle system [15] or apoptosis [16]. …”

Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia

“…Because there are multiple mechanisms involved in neuronal injury after ischemia, it is appropriate to consider using pharmacological agents that affect multiple mechanisms simultaneously or sequentially (for reviews, [4,9,22,24]). Therapeutic strategies have been designed typically to affect only one of several mechanisms in the ischemic cascade, but combinatorial therapies are likely to be more effective than monotherapy, as in the treatment of HIV/AIDS [10,14].…”