Targeting the Brain: Neuroprotection and Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, M.D., FAHA, FAAN

Disclosures

Pharmacotherapy. 2010;30(7):62S-69S. 

In This Article

Prehospital Treatment Delivery

Enrolling patients in the field in acute neuroprotective trials is a highly promising approach to the challenge of testing neuroprotective agents in hyperacute time epochs. In the analogous setting of acute myocardial ischemia, randomized clinical trials have shown that paramedic prehospital diagnosis and initiation of defibrillation and thrombolytic therapy reduce time to start of treatment and improve clinical outcome. Prehospital therapy has been proven beneficial for other acute neurologic conditions. In status epilepticus, the Prehospital Treatment of Status Epilepticus trial showed that paramedic initiation of anticonvulsants in the field is safe, reliable, and yields better clinical outcomes than standard in-hospital therapy.[6] In cardiac arrest and global cerebral ischemia, the Melbourne hypothermia trial showed benefit of neuroprotective temperature reduction initiated in ambulances before hospital arrival.[7]

In focal ischemic stroke, National Institutes of Health (NIH) studies have been investigating magnesium sulfate as a potential field neuroprotective agent. In a variety of human organ systems, magnesium plays a regulatory role in cellular energy metabolism, vascular tone, and cell membrane ion transport. Magnesium sulfate has been used as a dietary supplement and intravenous therapeutic agent in clinical medicine for many decades, with a well-established safety record. Laboratory studies have identified multiple neuronal and vascular effects of magnesium that likely contribute to the potent neuroprotective effects observed in stroke models.[8] In a wide variety of in vitro systems and animal models, magnesium has been shown to inhibit presynaptic release of excitatory neurotransmitters, noncompetitively block the N-methyl-D-aspartate (NMDA) receptor, presynaptically potentiate adenosine, block voltage-gated calcium channels, suppress cortical spreading depression and anoxic depolarizations, relax vascular smooth muscle resulting in vasodilation of large and small vascular beds and increased cerebral blood flow, antagonize endothelin-1 and other vasoconstrictors, and replete an underlying and/or ischemia-induced magnesium-deficient state. Moreover, in multiple randomized clinical trials, magnesium sulfate has shown signals of benefit for averting brain ischemic injury, including in cardiac arrest,[9] preterm birth,[10] cardiac bypass surgery,[11] and aneurysmal subarachnoid hemorrhage.[12] In an old-fashioned, late-treatment–start trial in focal stroke, magnesium sulfate demonstrated a neutral effect, but among patients treated within the first 3 hours of onset, point estimates suggested potential benefit.[13] Because it is long off patent protection, magnesium sulfate is inexpensive and can be tested using innovative clinical trial methodology unconstrained by conservative corporate-sponsored development programs.

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