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Neuropharmacology. 2020 Feb;163:107853. doi: 10.1016/j.neuropharm.2019.107853. Epub 2019 Nov 14.

Mild hypothermia protects synaptic transmission from experimental ischemia through reduction in the function of nucleoside transporters in the mouse hippocampus.

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Department of Pharmacology, Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan.
Department of Pharmacology, Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan. Electronic address:


Ischemia, a severe metabolic stress, increases adenosine levels and causes the suppression of synaptic transmission through adenosine A1 receptors. Although temperature also regulates extracellular adenosine levels, the effect of temperature on ischemia-induced activation of adenosine receptors is not yet fully understood. Here we examined the role of adenosine A1 receptors in mild hypothermia-mediated neuroprotection during the acute phase of ischemia. Severe ischemia-induced neurosynaptic impairment was reproduced by oxygen-glucose deprivation at normothermia (36 °C) and assessed with extracellular recordings or whole-cell patch clamp recordings in acute hippocampal slices in mice. Mild hypothermia (32 °C) induced the protection of synaptic transmission by activating adenosine A1 receptors. Stricter hypothermia (28 °C) caused additional neuroprotective effects by extending the onset time to anoxic depolarization; however, this effect was not associated with adenosine A1 receptors. The response of exogenous adenosine-induced inhibition of hippocampal synaptic transmission was increased by lowering the temperature to 32 °C or 28 °C. Hypothermia also reduced the function of dipryidamole-sensitive nucleoside transporters. These findings suggest that an increased response of adenosine A1 receptors, caused by a reduction in the function of nucleoside transporters, is one mechanism by which therapeutic hypothermia (usually used within the mild range) mediates neurosynaptic protection in the acute phase of stroke.


Acute hippocampal slices; Adenosine A(1) receptors; Field recordings; Patch clamp; Therapeutic hypothermia

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