Lessons from nature: signalling cascades associated with vertebrate brain anoxic survival

New Findings What is the topic of this review? Although the mammalian brain is exquisitely sensitive to hypoxia, some turtles survive complete anoxia by decreasing metabolic demand to match reduced energy supply. These animal models may help to elucidate neuroprotective mechanisms and reveal novel therapeutic targets for diseases of oxygen deprivation. What advances does it highlight? The mitogen‐activated protein kinases (MAPKs) are part of the suite of adaptive responses to anoxia that are modulated by adenosine, a ‘retaliatory metabolite’ released in early anoxia. In anoxic turtle neurons, upregulation of pro‐survival Akt and extracellular signal‐regulated kinase 1/2 and suppression of the p38MAPK and JNK pathways promote cell survival, as does the anoxic‐ and post‐anoxic upregulation of the antioxidant methionine sulfoxide reductase. Mammalian neurons undergo rapid degeneration when oxygen supply is curtailed. Neuroprotective pathways are induced during hypoxia/ischaemia, but their analysis is complicated by concurrent pathological events. Survival mechanisms can be investigated in anoxia‐tolerant freshwater turtle species, which survive oxygen deprivation and post‐anoxic reoxygenation by entrance into a state of reversible hypometabolism. Many energy‐demanding processes are suppressed, including ion flux and neurotransmitter release, whereas cellular protective mechanisms, including certain mitogen‐activated protein kinases (MAPKs), are upregulated. This superfamily of serine/threonine kinases plays a significant role in vital cellular processes, including cell proliferation, differentiation, stress adaptation and apoptosis in response to external stimuli. Here, we report that neuronal survival relies on robust co‐ordination between the major signalling cascades, with upregulation of the pro‐survival Akt and extracellular signal‐regulated kinase 1/2 and suppression of the p38MAPK and JNK pathways. Other protective responses, including the upregulation of heat shock proteins and antioxidants, allow the turtle brain to abrogate potential oxidative stress upon reoxygenation.