We congratulate Hui-Bih Yuan et al.  1for demonstrating the feasibility of inducing acute preconditioning with mild hypothermia and the adenosine receptors triggering this phenomenon. However, is it truly independent from hypoxia/anoxia, and are two phenomena indeed sharing the same final pathway? Before we can categorically state that hypothermia per se  is the triggering factor, we must rule in or out the role that bioenergetics might play in activating adenosine triphosphate–sensitive potassium and adenosine receptors. Having the perfusate oxygenated may not be enough to prove that oxygen was used aerobically to synthesize ∼P creatine phosphate by the slice. As pointed out by the authors, although in vitro  preparations are suited for mechanistic studies, results cannot be extrapolated to in vivo  conditions; the “protected” time of 20 min of oxygen–glucose deprivation could be far shorter in in vivo  conditions. Under these conditions, the anoxia-sensitive blood–brain barrier is broken, and reperfusion is followed by diapedesis, with its consequent deleterious effects of leukocytes on the ischemic neurons. Early (4 h) conventional light microscopy may not discern subtle changes in creatine phosphate or even adenosine triphosphate depletion already jeopardizing viability in a system devoid of leukocytes. It would have been informative if (1) the effluent lactic acid,2glutamate or nitric oxide,3,4lactic dehydrogenase or creatine phosphokinase or (2) the slice creatine phosphate and adenosine triphosphate contents5had been determined before and during preconditioning to assess the role bioenergetics might have had in activating those receptors.

Nevertheless, we credit the authors for further identifying molecular mechanisms involved in neuronal injury and their inhibition by harmless mild hypothermic preconditioning. The fact that in their study the acute hypothermic preconditioning effects lasted for 3–4 h is in accord with the period reported by Benveniste et al.  3in which taurine concentrations were increased after ischemia.

The protective mechanisms of taurine, a β amino acid universally present in mammalian tissues, have been attributed to the marked cell membrane effects, nonspecific in nature, acting ubiquitously in the entire body, with the magnitude of such effects depending on the tissue concentration.6,7Taurine is released dose dependently by adenosine in the nonischemic rabbit hippocampus8or during ischemia as part of the naturally protective array of mechanisms triggered by the activation of adenosine triphosphate–sensitive potassium and adenosine receptors in the early stages of ischemia.3,6,7These triggered mechanisms are more or less effective, depending on the subsequent ischemia times, but all aimed at providing protection through different molecular pathways.

We postulate that the mechanistic role the also innocuous taurine may have in preconditioning has been relegated to oblivion but actually might have a role greater than just acute protection. Indeed, taurine used in conjunction with hypothermia potentiated the protective effects of the latter.9Intravenously administered taurine protected the spinal cord of all rabbits ventilated under eucapnic conditions from 60 min of ischemia at 30.6°C, whereas hypothermia at 29.9°C without taurine uniformly failed, and hypothermia at 29.4°C was required to consistently protect from 60 min of ischemia. These facts also underline the importance of intraischemic temperature and suggest that the beneficial effects of the authors’ advocated mild hypothermic preischemic preconditioning are time limited.

We wholeheartedly support the authors’ contention of using mild hypothermia to minimize neurologic injury. However, would not it be easier if the same innocuous protection could be readily obtained without having to induce time-consuming hypothermia, or with a lesser degree of hypothermia than that used by the authors, by intravenously administering taurine that would induce hypothermia secondarily? Time constraints might be impractical in the clinical setting.

* Kyoto University, Kyoto City, Japan. tkmiyamo@f3.dion.ne.jp

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