The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

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Abstract

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.

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Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Shaheen E Lakhan, Annette Kirchgessner, Magdalena Hofer (2009)

Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.

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The role of inflammation in CNS injury and disease.

Sian-Marie Lucas, Nancy J Rothwell, Rosemary Gibson (2006)

For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.

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Pathobiology of ischaemic stroke: an integrated view.

C Iadecola, M Moskowitz (1999)

Brain injury following transient or permanent focal cerebral ischaemia (stroke) develops from a complex series of pathophysiological events that evolve in time and space. In this article, the relevance of excitotoxicity, peri-infarct depolarizations, inflammation and apoptosis to delayed mechanisms of damage within the peri-infarct zone or ischaemic penumbra are discussed. While focusing on potentially new avenues of treatment, the issue of why many clinical stroke trials have so far proved disappointing is addressed. This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.

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Journal

Journal ID (nlm-ta): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central

ISSN (Electronic): 1742-2094

Publication date Collection: 2010

Publication date (Electronic): 1 November 2010

Volume: 7

Page: 74

Affiliations

[1 ]Department of Pharmaceutical Chemistry and Drug Analysis, Research Group Experimental Neuropharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium

[2 ]Department of Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium

[3 ]Critical Care Department and Cerebral Resuscitation Research Group, Vrije Universiteit Brussel, Brussels, Belgium

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Publisher ID: 1742-2094-7-74

DOI: 10.1186/1742-2094-7-74

PMC ID: 2988764

PubMed ID: 21040547

SO-VID: 56d4170b-4a05-4ac4-93f4-6fcd0c9930d2

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

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Good practices in (cog-neuro) science and science communication

Most cited references 154

Inflammatory mechanisms in ischemic stroke: therapeutic approaches

The role of inflammation in CNS injury and disease.

Pathobiology of ischaemic stroke: an integrated view.

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