Systemic inflammation as a therapeutic target in acute ischemic stroke

Abstract

Acute systemic inflammatory reaction superimposed on chronic low-grade inflammation accompanies acute ischemic stroke. Elevated blood levels of systemic inflammatory markers such as IL-6 or C-reactive protein are associated with an unfavorable functional outcome and increased mortality after stroke. Animal studies have demonstrated a causal relationship between systemic inflammation and ischemic brain damage. The mechanisms linking systemic inflammation with poor outcome include increased neutrophil infiltration of cerebral cortex, disruption of the blood–brain barrier, impaired tissue reperfusion, increased platelet activation and microvascular coagulation and complement-dependent brain injury. Non-selective (e.g., by statins) or selective (e.g., by inhibition of IL-6) attenuation of systemic inflammation, enhancement of systemic anti-inflammatory response (e.g., by infusion of IL-1 receptor antagonist), prevention of infections that exacerbate systemic inflammation or inhibition of neuronal pathways triggering inflammatory reaction are potential therapeutic targets in stroke patients. This review discusses the relationship between systemic inflammation, cerebral ischemia and prognosis in the context of therapeutic strategies.

Keywords:

• cerebral ischemia
• cytokines
• inflammation
• outcome
• stroke

Financial & competing interests disclosure

This study was supported by the grant from National Science Center (DEC-2013/09/B/NZ4/01572). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Acute-phase reaction and chronic low-grade inflammation accompany acute ischemic stroke.

• Elevated blood levels of IL-6 and C-reactive are associated with unfavorable functional outcome and increased mortality after stroke.

• The causal relationship between systemic inflammation and ischemic brain damage was demonstrated in animal models of cerebral ischemia.

• The mechanisms linking systemic inflammation with poor outcome include increased neutrophil infiltration of cerebral cortex, persistent disruption of blood–brain barrier, impaired tissue reperfusion, increased platelet activation and microvascular coagulation and complement-dependent brain injury.

• The potential therapeutic targets include non-selective (e.g., by statins) or selective (e.g., by inhibition of IL-6 activity) attenuation of systemic inflammation, enhancement of systemic anti-inflammatory response (e.g., by infusion of IL-1 receptor antagonist), prevention of infections that exacerbate systemic inflammation or inhibition of neuronal pathways triggering inflammatory reaction.

Notes

^†Variable effect.