Restoring neuroprotection through a new preclinical paradigm: translational success for NA-1 in stroke therapy

Cerebrovascular disease remains one of the leading causes of death and disability throughout the world, and with an aging population, prevalence rates are expected to rise dramatically over the coming years¹. It is thus imperative that we develop effective treatment strategies to meet this challenge. Presently, the only established method of pharmacological stroke intervention is early reperfusion by way of thrombolytic agents, yet the narrow therapeutic window and high risk of complications associated with these drugs disqualify most patients from receiving them. This has led researchers to pursue neuroprotective strategies aimed at amplifying the capacity of neural tissue to tolerate ischemia, independent of blood flow restoration. However, all previous attempts to improve clinical outcomes through neuroprotection have been unsuccessful, and many have suggested abandoning the concept entirely². After decades of failure, Michael Tymianski's group may have provided evidence and a translational paradigm capable of reestablishing neuroprotection as a viable avenue for stroke treatment³.

The role of glutamate in excitotoxic cell damage following ischemia, particularly through its interaction with the N-methyl-D-aspartate receptor (NMDAR), has been well documented. For this reason, stroke research has focused mainly on achieving neuroprotection through the use of NMDAR antagonists. Many of these therapeutic agents generated encouraging experimental results in animal models, but each failed to demonstrate positive effects in humans during clinical trials⁴. Moreover, antagonists produced numerous psychological side-effects, and some even had deleterious consequences in terms of patient outcome. Glutamate is the primary neurotransmitter in the brain, thus appropriate NMDAR activity is required for normal physiological, behavioral and cognitive functioning, as well as for promoting pro-survival pathways. The reliance of the brain on NMDA signaling accounts for the myriad of problems associated with completely blocking the channels and its overall ineffectiveness as a treatment for stroke.

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