The Role of the Complement Cascade in Ischemia/Reperfusion Injury: Implications for Neuroprotection

Abstract

Background: The complement cascade plays a deleterious role in multiple models of ischemia/reperfusion (I/R) injury, including stroke. Investigation of the complement cascade may provide a critical approach to identifying neuroprotective strategies that can be effective at clinically relevant time points in cerebral ischemia. This review of the literature describes the deleterious effects of complement activation in systemic I/R models and previous attempts at therapeutic complement inhibition, with a focus on the potential role of complement inhibition in ischemic neuroprotection. Translation of these concepts into ischemic stroke models and exploration of related neuroprotective strategies are also reviewed. Summary of Review: We performed a MEDLINE search to identify any studies published between 1966 and 2001 dealing with complement activation in the setting of I/R injury. We also searched for studies demonstrating up-regulation of any complement components within the central nervous system during inflammation and/or ischemia. Conclusions: The temporal and mechanistic overlap of the complement cascade with other biochemical events occurring in cerebral I/R injury is quite complex and is only beginning to be understood. However, there is compelling evidence that complement is quite active in the setting of acute stroke, suggesting that anticomplement strategies should be further investigated through genetic analysis, nonhuman primate models, and clinical investigations.

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…However, many of them can be synthesized locally in the brain as well (Barnum 1995;Gasque et al 1995;Morgan and Gasque 1996;Nataf et al 1999). The abnormality of the complement system has been reported in brain injury and neurodegenerative disease (D'Ambrosio et al 2001;Gasque 2004), including AD. In the brain of AD patient, it has been observed that the expression of C1q, C3b, C4d and C5b-9 is elevated, and the MAC colocalizes with senile plaques and tangle-positive neurons (Blalock et al 2004;Fonseca et al 2004;Katsel et al 2009;Shen et al 2001).…”

Complement C5 in Experimental Autoimmune Encephalomyelitis (EAE) Facilitates Remyelination and Prevents Gliosis

“…[1][2][3][4][5] Deposition of complement-activation products has been shown in Alzheimer's disease, 6,7 ischemia/reperfusion injury, 8 Huntington's and Prion disease, 9,10 and multiple sclerosis (MS). [11][12][13][14][15] In the immune-mediated inflammatory demyelinating disease, multiple sclerosis, and its animal model, experimental autoimmune encephalomyelitis (EAE), myelin, and oligodendrocytes are primary targets of damage.…”

Complement Receptors in Inflammation

“…However, the precise roles of various proinflammatory mediators, including cytokines, chemokines and immune cells, are still largely unknown. Increasing evidence suggests that the activation of the complement cascade contributes to pathological inflammatory events in brain (upregulation of adhesion molecules, immune cell activation, chemotaxis, expression of IL-8 and MCP-1 by endothelial cells) (D'Ambrosio et al, 2001), resulting in ischemic insult, neurodegeneration and stroke development. Following brain I/R injury ROS, RNS as well as oxygen free radicals are generated by activated brain cells and infiltrating immune cells, which stimulate stroke-associated brain injury (Elsner et al, 1994, McColl et al, 2009).…”

“…Ischemic stroke enhances interaction between endothelial cells, brain cells, and immune cells that may aggravate the injury process (Urra et al, 2009). All these strokeassociated brain pathologies are function of C3a-C3aR and C5a-C5aR interactions (D'Ambrosio et al, 2001). Strong C3a and C5a activation is observed in patients with acute ischemic stroke, which correlates with disease severity (Szeplaki et al, 2009).…”