History Of Neuroprotection: Trials And Tribulations

Neuroprotection is a strategy of interference, antagonism, and slowing down the sequence of molecular pathophysiological processes eventually resulting in irreversible cerebral ischemia. Over the past two decades, neuroprotection in ischemic stroke has emerged as a central topic of intense experimental animal studies and clinical trials in humans. Although rigorous animal studies have provided the proof of principle that neuroprotection is achievable, the novel agents and mechanisms investigated in human clinical trials have consistently failed to demonstrate a significant beneficial effect. Here we survey key neuroprotective trials and consider the strengths and shortcomings of these studies. Agents and mechanisms considered include calcium channel blockers, glutamate antagonists, GABA agonists, antioxidants and free radical scavengers, nitric oxide signal-transduction, modulation of inflammation, hemodilution, hypothermia, albumin therapy, and magnesium therapy. These human trials of neuroprotection therapies have been disappointing, unlike successful acute stroke approaches using reperfusion therapies such as thrombolytics or clot-retrieving devices. We highlight how improved clinical trial design and translational strategies and lessons learned from these negative trials will guide future directions including better clinical trial design and patient selection, multiple agent-combination therapies, and pre-hospital intervention.