Hypoxia Tolerant Species: The Wisdom of Nature Translated into Targets for Stroke Therapy

Human neurons rapidly die after ischemia and current therapies for stroke management are limited to restoration of blood flow to prevent further brain damage. Thrombolytics and mechanical thrombectomy are the available reperfusion treatments, but most of the patients remain untreated. Neuroprotective therapies focused on treating the pathogenic cascade of the disease have widely failed. However, many animal species demonstrate that neurons can survive the lack of oxygen for extended periods of time. Here, we reviewed the physiological and molecular pathways inherent to tolerant species that have been described to contribute to hypoxia tolerance. Among them, Foxo3 and Eif5A were reported to mediate anoxic survival in Drosophila and Caenorhabditis elegans, respectively, and those results were confirmed in experimental models of stroke. In humans however, the multiple mechanisms involved in brain cell death after a stroke causes translation difficulties to arise making necessary a timely and coordinated control of the pathological changes. We propose here that, if we were able to plagiarize such natural hypoxia tolerance through drugs combined in a pharmacological cocktail it would open new therapeutic opportunities for stroke and likely, for other hypoxic conditions.