Mild hypothermia facilitates mitochondrial transfer from astrocytes to injured neurons during oxygen-glucose deprivation/reoxygenation.

Mitochondrial dysfunction is now considered an important sign of neuronal death during cerebral ischemia/reperfusion (I/R) injury. Studies have shown that the transfer of mitochondria from astrocytes to injured neurons contributes to endogenous neuroprotection after stroke. Basic and clinical studies have shown that mild hypothermia exerts a clear protective effect on neurons after cerebral ischemic injury, but the role of mild hypothermia in this endogenous neuroprotective mechanism remains unclear. Here, we established a neuronal cell oxygen-glucose deprivation (OGD)/reoxygenation (OGD/R)-induced injury model and explored the effect of mild hypothermia on the transfer of mitochondria from astrocytes to injured neurons. Astrocytes in the hypothermia group (33 °C) released more functional mitochondria into the extracellular medium than those in the normal temperature group (37 °C). Compared with cells in the normal temperature group, OGD-injured neuronal cells in the mild hypothermia group exhibited an increased intracellular ATP content, mitochondrial membrane potential (MMP) and cellular viability and a decreased death rate after the addition of astrocyte-derived conditioned medium. Based on the results of this study, mild hypothermia promotes endogenous neuroprotective effects through a mechanism related to functional mitochondria released from astrocytes into the extracellular space and transferred into injured neurons.

Mild hypothermia protects rat cortical neurons against oxygen-glucose deprivation/reoxygenation injury via the PI3K/Akt pathway.

Ischemic stroke is the most frequent cause of long-term morbidity and mortality in the elderly worldwide. Mild hypothermia (32-35°C) has been found to have a neuroprotective effect against ischemic stroke. However, the protective mechanisms remain unclear. In the present study, we explore the neuroprotective effect of mild hypothermia in neuron-astrocyte cocultures by oxygen-glucose deprivation/reoxygenation (OGD/R) as well as the underlying mechanisms. Thionin staining was performed and cell viability, extracellular glutamate concentration and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway-related proteins were detected after OGD/R. The results indicated that mild hypothermia significantly alleviated damage to Nissl bodies and increased the viability of neurons, which alleviated OGD/R-triggered neuronal injury. Furthermore, mild hypothermia significantly enhanced the phosphorylation of Akt (pAkt) and glutamate transporter-1 (GLT-1) and reduced extracellular glutamate concentration after OGD/R. When the PI3K inhibitor LY294002 was added, neuronal viability and the expression of pAkt and GLT-1 decreased, and extracellular glutamate concentration increased. The protective effect of mild hypothermia was counteracted by LY294002. There was no significant change in neuronal viability or the expression of pAkt and GLT-1 in the group treated with dihydrokainate, an inhibitor of GLT-1-function, compared with the mild hypothermia + OGD/R (HOGD) group, but extracellular glutamate concentration was increased. Consequently, mild hypothermia promoted glutamate clearance by regulating GLT-1 expression via the PI3K/Akt pathway, providing a neuroprotective effect against OGD/R injury.

Head Mild Hypothermia Exerts a Neuroprotective Role in Ischemia-Reperfusion Injury by Maintaining Glial Glutamate Transporter 1.

Stroke is the second leading cause of death worldwide; nevertheless, its pathological mechanism still remains unclear. Besides, there is an urgent need to find new effective treatment strategies for patients with stroke. Hypothermia therapy is widely used in clinical as a neuroprotective strategy practice. However, the exact mechanism is not fully understood. In this study, we examined the effects of hypothermia on glial glutamate transport-1 (GLT-1) and the extracellular glutamate concentration ([Glu]e) in cerebral ischemia-reperfusion insult rats. Our results revealed that cerebral brain ischemia-reperfusion caused the decrease of GLT-1 and Bcl-2, the increase of Bax and [Glu]e, and caused neuron loss. On the contrary, head mild hypothermia (HMH) for 2 hours alleviated the abovementioned effects and exerted neuroprotection. In the hypothermia group, pretreatment with dihydrokainate, a functional antagonist of GLT-1 by lateral ventricle injection partly reversed the abovementioned effect of HMH. Our results suggest that HMH could exert a neuroprotective role by maintaining GLT-1 and reducing the excitotoxicity of [Glu]e during ischemia-reperfusion insult in rats.