Conditioning medicine最新文献

Hypoxic Ischemic Encephalopathy (HIE) is the result of severe anoxic brain injury during the neonatal period and causes life-long morbidity and premature mortality. Currently, therapeutic hypothermia immediately after birth is the standard of care for clinically relevant HIE. However, therapeutic hypothermia alone does not provide complete neuroprotection and there is an urgent need for adjunctive therapies. Ischemic conditioning is an adaptive process of endogenous protection in which small doses of sub-lethal ischemia can provide a protection against a lethal ischemic event. Remote Ischemic Post-conditioning (RIPC), a form of ischemic conditioning, is highly translatable for HIE diagnosed immediately after birth as the conditioned ischemic stimulus is applied at the limb after the lethal ischemic episode. A number of studies in neonatal rats have demonstrated that RIPC is effective at reducing injury in focal cerebral ischemia models and improves neurological outcomes. In this review, we focus on the available data on HIE and its current treatment, models in HIE studies, ischemic conditioning/RIPC and its mechanism. We discuss in particular the effect of RIPC on neonatal brain with HIE. We postulate that combining RIPC with standard therapeutic hypothermia can be an attractive therapeutic approach for HIE.

Ischemic and traumatic injuries to CNS remain leading causes of death and disability worldwide, despite decades of research into risk factors, therapies, and preventative measures. Recent studies showed that CNS injuries significantly alter the cerebral microRNAome that impact the secondary brain damage as well as plasticity and recovery. Many microRNA based therapies are currently in various clinical trials for different pathologic conditions indicating their therapeutic potential. In the present review, we discuss the role of miR-21 in acute CNS injuries which is currently thought to be a potent neuroprotective microRNA. We emphasize on the potential of miR-21 in promoting cell and tissue survival and preventing inflammation and apoptosis. We also discussed the role of miR-21 in conditioning the brain to promote ischemic tolerance. Finally, we discussed some of the challenges and difficulties to develop miR-21 as a neuroprotective therapy in humans.

Ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia. While our group has previously shown IPC to induce neuroprotection through various pathways, the role of astrocytes in supporting IPC-induced neuroprotection has not been extensively studied. Astrocyte-derived lactate has gained attention as a potential soluble mediator through which astrocytes could impart ischemic tolerance to neurons. Therefore, the goal of this study was to determine if i) IPC-treatment of astrocytes alone could transfer ischemic tolerance to neurons; ii) if IPC-treatment of astrocytes increases lactate production; and if iii) exogenous lactate administration to neurons could induce neuroprotection against lethal ischemia in vitro. For this purpose, a co-culture system was used and modified from a previous method. This system allows astrocytes and neurons to be separated by a physical barrier, while allowing secreted substances from either cell type to interact with each other. Oxygen-glucose deprivation was used as a model of cerebral ischemia and IPC in cultured rodent astrocytes and neurons. Neurons incubated with IPC-treated astrocytes were significantly protected against lethal ischemic injury compared to neurons incubated with sham-treated astrocytes. In addition, IPC-treatment of astrocytes significantly increased lactate secretion into the extracellular media. Finally, exogenous lactate administration can significantly attenuate cell death in neuronal cultures following exposure to lethal OGD. Our results suggest that IPC-treatment of astrocytes alone can transfer ischemic tolerance to neurons. In addition, the ability of IPC to increase lactate production in astrocytes suggest that lactate could represent a neuroprotective agent to protect neurons against lethal ischemic injury.

Stroke is the third leading cause of death and the leading cause of long-term disability, with very few effective treatments and limited progress in the effort to search for novel therapeutic approaches. The phenomenon that a sublethal ischemic insult induces protection against a subsequent severe ischemia, termed ischemic preconditioning (IPC), represents an endogenous protective approach against ischemic brain injury, and may direct a breakthrough to future therapeutic strategies. It is broadly accepted that new protein synthesis is required for IPC-mediated long-term neuroprotection; however, their relative regulatory mechanisms are poorly understood. In the present review, we summarize genomic-based studies on alterations in gene expression and protein synthesis, particularly categorizing potential pathways regulated by IPC. We also review the role of epigenetics, an inheritable genetic regulatory mechanism without changes in DNA sequence, in IPC-mediated neuroprotection.

Stroke is one of leading causes of mortality and morbidity in the world with limited availability of therapeutic intervention. Exercise has been shown to improve stroke functional outcome in different preclinical and clinical setup. Exercise preconditioning induced neuroprotection in preclinical stroke models is believed to be mediated through its ability to restore brain vasculature and blood brain barrier integrity, promote neurogenesis, and help fight against neuroinflammation and excitotoxicity. In this short review, we will summarize the molecular mechanisms of exercise preconditioning described in preclinical stroke studies. We will also discuss the neuroprotective effects of pre-ischemic exercise.