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

A review

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  • 1 Department of Neurosurgery and
  • 2 The Center for Neuroscience, School of Medicine; and
  • 3 Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia
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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.

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Contributor Notes

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: crosen@hsc.wvu.edu.

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

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