The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success

A review

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Ischemic stroke remains a leading cause of morbidity and death for which few therapeutic options are available. The development of neuroprotective agents, a once promising field of investigation, has failed to translate from bench to bedside successfully. This work reviews the ischemic cascade, agents targeting steps within the cascade, and potential reasons for lack of translation. Additional therapeutic targets are highlighted and areas requiring further investigation are discussed. It is clear that alternative targets need to be pursued, such as the role glia play in neurological injury and recovery, particularly the interactions between neurons, astrocytes, microglia, and the vasculature. Similarly, the biphasic nature of many signaling molecules such as matrix metalloproteinases and high-mobility group box 1 protein must be further investigated to elucidate periods of detrimental versus beneficial activity.

Abbreviations used in this paper:AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ATP = adenosine 5'-triphosphate; ATPase = adenosine triphosphatase; GABAA = γ-aminobutyric acid-A; MMP = matrix metalloproteinase; MPTP = 1-methyl-4-phenyl-2,5,6-tetrahydropyridine; NADPH = nicotinamide adenine dinucleotide phosphate (reduced form); NMDA = N-methyl-d-aspartate; ROS = reactive oxygen species; SAINT = Stroke Acute Ischemic NXY Treatment; STAIR = Stroke Therapy Academic-Industry Roundtable; tPA = tissue plasminogen activator; VENUS = Very Early Nimodipine Use in Stroke; 5-HT = 5-hydroxytryptamine.

Article Information

Address correspondence to: Charles L. Rosen, M.D., Department of Neurosurgery, West Virginia University School of Medicine, One Medical Center Drive, PO Box 9183 Health Sciences Center, Morgantown, West Virginia 26506-9183. email:

Please include this information when citing this paper: published online January 18, 2012; DOI: 10.3171/2012.11.JNS12408.

© AANS, except where prohibited by US copyright law.



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    A diagrammatic representation of the ischemic injury cascade from the onset of ischemia to cell death.

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    A representation of targets pursued for preventing neuronal excitotoxicity, often attributed to excessive glutamate release. These targets include the following: 1) NMDA receptor antagonists; 2) AMPA receptor antagonists; 3) kappa opiate receptor antagonists; 4) GABAA receptor agonists; 5) 5-HT1A receptor agonist; and 6) potassium channel openers.

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    Schematic showing that ischemia results in increased intracellular calcium levels through not only the NMDA and AMPA receptors but also through a slow Ca++ channel. Increased cytosolic calcium results in activation of endonucleases and phospholipases as well as proteases. The MPTP allows calcium to enter the mitochondria, which causes production of ROS and further damage. Calcium in the mitochondria also causes swelling and eventual rupture, releasing cytochrome c, long known to play a role in apoptosis.

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    Inflammation has been identified as a promising avenue of therapeutic development. Multiple aspects can be inhibited, including release of inflammatory mediators from microglia, preventing adhesion, and blocking migration of inflammatory cells outside of the vasculature and into the parenchyma. ICAM-1 = intercellular adhesion molecule–1.

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    The concept of neuroprotection is perhaps misguided; the neurocentric approach has failed to produce effective therapeutic agents. Cerebroprotection is needed, and for that the entire neurovascular unit must be considered. Also, supporting glia play a crucial role in health and disease, necessitating inclusion in therapeutic development.



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