Hypothermia increases adenosine monophosphate and xanthosine monophosphate levels in the mouse hippocampus, preventing their reduction by global cerebral ischemia.

Global cerebral ischemia (GCI) caused by clinical conditions such as cardiac arrest leads to delayed neuronal death in the hippocampus, resulting in physical and mental disability. However, the mechanism of delayed neuronal death following GCI remains unclear. To elucidate the mechanism, we performed a metabolome analysis using a mouse model in which hypothermia (HT) during GCI, which was induced by the transient occlusion of the bilateral common carotid arteries, markedly suppressed the development of delayed neuronal death in the hippocampus after reperfusion. Fifteen metabolites whose levels were significantly changed by GCI and 12 metabolites whose levels were significantly changed by HT were identified. Furthermore, the metabolites common for both changes were narrowed down to two, adenosine monophosphate (AMP) and xanthosine monophosphate (XMP). The levels of both AMP and XMP were found to be decreased by GCI, but increased by HT, thereby preventing their decrease. In contrast, the levels of adenosine, inosine, hypoxanthine, xanthine, and guanosine, the downstream metabolites of AMP and XMP, were increased by GCI, but were not affected by HT. Our results may provide a clue to understanding the mechanism by which HT during GCI suppresses the development of delayed neuronal death in the hippocampus.

Triiodothyronine Aggravates Global Cerebral Ischemia-Reperfusion Injury in Mice.

Thyroid hormones (THs) have been suggested to play an important role in both physiological and pathological events in the central nervous system. Hypothyroidism, which is characterized by low levels of serum THs, has been associated with aggravation of ischemic neuronal injuries in stroke patients. We hypothesized that administration of T3, the main active form of THs, may attenuate the ischemic neuronal injuries. In mice, global cerebral ischemia (GCI), which is induced by transient occlusion of the bilateral common carotid artery, causes neuronal injuries by inducing neuronal death and activating inflammatory responses after reperfusion in the hippocampus. In this study, we examined the effect of T3 administration on DNA fragmentation induced by neuronal death and the activation of inflammatory cells such as astrocytes and microglia in the hippocampus following GCI. The content of nucleosomes generated by DNA fragmentation in the hippocampus was increased by GCI and further increased by T3 administration. The protein expression levels of glial fibrillary acidic protein (GFAP), an astrocytic marker, and Ionized calcium binding adaptor protein 1 (Iba1), a microglial marker, in the hippocampus were also increased by GCI and further increased by T3 administration. The levels of T3 in both the serum and hippocampus were elevated by T3 administration. Our results indicate that T3 administration aggravates GCI-reperfusion injury in mice. There may be an increased risk of aggravation of ischemic stroke by the excessive elevation of T3 levels during the drug treatment of hypothyroidism.