Yue Fu

Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: contribution of TNF-α-induced protein 6

Aim:To investigate the effects of mesenchymal stem cells (MSCs) transplantation on rat global cerebral ischemia and the underlying mechanisms.Methods:Adult male SD rats underwent asphxial cardiac arrest to induce global cerebral ischemia, then received intravenous injection of 5×106 cultured MSCs of SD rats at 2 h after resuscitation. In another group of cardiac arrest rats, tumor necrosis factor-α-induced protein 6 (TSG-6, 6 μg) was injected into the right lateral ventricle. Functional outcome was assessed at 1, 3, and 7 d after resuscitation. Donor MSCs in the brains were detected at 3 d after resuscitation. The level of serum S-100B and proinflammatory cytokines in cerebral cortex were assayed using ELISA. The expression of TSG-6 and proinflammatory cytokines in cerebral cortex was assayed using RT-PCR. Western blot was performed to determine the levels of TSG-6 and neutrophil elastase in cerebral cortex.Results:MSCs transplantation significantly reduced serum S-100B level, and improved neurological function after global cerebral ischemia compared to the PBS-treated group. The MSCs injected migrated into the ischemic brains, and were observed mainly in the cerebral cortex. Furthermore, MSCs transplantation significantly increased the expression of TSG-6, and reduced the expression of neutrophil elastase and proinflammatory cytokines in the cerebral cortex. Intracerebroventricular injection of TSG-6 reproduced the beneficial effects of MSCs transplantation in rats with global cerebral ischemia.Conclusion:MSCs transplantation improves functional recovery and reduces inflammatory responses in rats with global cerebral ischemia, maybe via upregulation of TSG-6 expression.

Impaired Cerebral Mitochondrial Oxidative Phosphorylation Function in a Rat Model of Ventricular Fibrillation and Cardiopulmonary Resuscitation

Postcardiac arrest brain injury significantly contributes to mortality and morbidity in patients suffering from cardiac arrest (CA). Evidence that shows that mitochondrial dysfunction appears to be a key factor in tissue damage after ischemia/reperfusion is accumulating. However, limited data are available regarding the cerebral mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) and its relationship to the alterations of high-energy phosphate. Here, we sought to identify alterations of mitochondrial morphology and oxidative phosphorylation function as well as high-energy phosphates during CA and CPR in a rat model of ventricular fibrillation (VF). We found that impairment of mitochondrial respiration and partial depletion of adenosine triphosphate (ATP) and phosphocreatine (PCr) developed in the cerebral cortex and hippocampus following a prolonged cardiac arrest. Optimal CPR might ameliorate the deranged phosphorus metabolism and preserve mitochondrial function. No obvious ultrastructural abnormalities of mitochondria have been found during CA. We conclude that CA causes cerebral mitochondrial dysfunction along with decay of high-energy phosphates, which would be mitigated with CPR. This study may broaden our understanding of the pathogenic processes underlying global cerebral ischemic injury and provide a potential therapeutic strategy that aimed at preserving cerebral mitochondrial function during CA.

Protective effect of mild hypothermia on oxygen-glucose deprivation injury in rat hippocampal neurons after hypoxia

The present study aimed to establish an oxygen‑glucose deprivation (OGD) model of ischemic and hypoxic cerebral neurons to investigate the protective effect of mild hypothermia on neuronal OGD and its mechanisms. OGD injury was significantly mitigated in cells with 24 h of mild hypothermia compared with cells without mild hypothermia; cell morphology improved, the lactic acid dehydrogenase (LDH) release rate was decreased, cytoactivity was increased and the neuronal apoptotic rate was decreased. By contrast, no significant improvement in injury was observed after 6 h of mild hypothermia. This suggests that mild hypothermia treatment following OGD is effective only when implemented for 24 h. Additionally, the caspase-3 activity of neurons increased following OGD, which was positively associated with the neuronal apoptotic rate. However, the caspase-3 activity after 24 h of mild hypothermia was reduced. Simultaneously, the neuronal apoptotic rate was decreased, suggesting that mild hypothermia may inhibit neuronal apoptosis by reducing caspase-3 activity. Therefore, reducing caspase-3 activity potentially constitutes one of the protective mechanisms of mild hypothermia in neuronal OGD.

Ultrastructural evidence of mitochondrial abnormalities in postresuscitation myocardial dysfunction

OBJECTIVES Though there is evidence to implicate that the mitochondrion may play an important role in the development of postresuscitation myocardial dysfunction, limited data are available regarding the ultrastructural alterations of the mitochondria, mitochondrial energy-producing ability, and their relationship to postresuscitation myocardial dysfunction. This study was designed to determine whether mitochondrial abnormalities contribute to the development of postresuscitation myocardial dysfunction. METHODS Fifteen anesthetized male Sprague-Dawley rats were randomized to: (1) global myocardial ischemia/reperfusion, in which 8 min of ventricular fibrillation was induced and successful defibrillation was achieved after 6 min of cardiopulmonary resuscitation (CPR); (2) global myocardial ischemia, in which ventricular fibrillation and CPR were performed without defibrillation attempt; and (3) sham control. RESULTS Myocardial function was significantly impaired after resuscitation. Mitochondria were massively swollen in global ischemic hearts and mildly swollen in the resuscitated hearts. Concomitantly, ATP levels abruptly declined during global ischemia and partially recovered after resuscitation. Furthermore, mitochondrial abnormalities were supported by the incapability of utilizing energy substrates manifested by the accumulations of intramyocellular lipid droplets and glycogen deposits. CONCLUSIONS In this model of cardiac arrest and CPR, the presence of ultrastructural mitochondrial abnormalities, further evidenced by the incapability of utilizing energy substrates and impairment of energy-production, might, in part, contribute to the development of postresuscitation myocardial dysfunction.