Bone-marrow-derived human MSCs (mesenchymal stem cells) support repair when administered to animals with TBI (traumatic brain injury) in large part through secreted trophic factors. We directly tested the ability of the culture medium (or secretome) collected from human MSCs under normoxic or hypoxic conditions to protect neurons in a rat model of TBI. Concentrated conditioned medium from cultured human MSCs or control medium was infused through the tail vein of rats subjected to TBI. We have demonstrated that MSCs cultured in hypoxia were superior to those cultured in normoxia in inducing expression of both HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) in the cultured medium. We showed further that rats treated with the secretome from both normoxic- and hypoxic-preconditioned MSCs performed significantly better than the controls in both motor and cognitive functional test. Subsequent post-mortem evaluation of brain damage at the 4-day time point confirmed that both normoxic- and hypoxic-preconditioned MSC secretome-treated rats had significantly greater numbers of newly forming neurons, but significantly less than the controls in brain damaged volume and apoptosis. The TBI rats treated with hypoxic-preconditioned MSC secretome performed significantly better in both motor and cognitive function tests and neurogenesis, and had significantly less brain damage than the TBI rats treated with the normoxic-preconditioned MSC secretome. Collectively, these findings suggest that MSCs secrete bioactive factors, including HGF and VEGF, that stimulate neurogenesis and improve outcomes of TBI in a rat model. Hypoxic preconditioning enhances the secretion of these bioactive factors from the MSCs and the therapeutic potential of the cultured MSC secretome in experimental TBI.
In urethane‐anaesthetized rats, we assessed the protective effects of glucocorticoids against heatstroke‐induced arterial hypotension and ischaemic neuronal damage. Heatstroke was induced by exposing the animals to an ambient temperature of 42°C. The time at which both the mean arterial pressure (MAP) and local cerebral blood flow (CBF) in the striatum decreased from their peak levels was taken as the onset of heatstroke. Control rats were exposed to a temperature of 24°C. The values of MAP and CBF after heatstroke onset were all significantly lower than those in control rats. However, the neuronal damage score in the striatum and serum levels of interleukin‐1β (IL‐1β) were greater. Systemic pretreatment or treatment with an exogenous glucocorticoid, dexamethasone (4 mg or 6 mg kg−1, i.v.), reduced the heatstroke‐induced arterial hypotension, serum IL‐1β levels, cerebral ischaemia and neuronal damage, and resulted in prolongation of the time to death (TTD; the interval between the onset of heat stress and cardiac arrest). Following bilateral adrenalectomy, MAP, CBF and TTD values were found to be significantly lower in the adrenalectomized (ADX) rats than in the sham‐ADX rats after heat exposure. These changes were attenuated by dexamethasone. The data support the argument that glucocorticoids reduce the plasma IL‐1β concentration and may provide the neuroprotective effects observed in rat heatstroke.
Background and Purpose-Heatstroke is associated with cerebral ischemia as well as increased levels of interleukin-1, dopamine, and glutamate in the brain. These factors are known to increase free radical production. This study attempted to ascertain whether an excessive accumulation of cytotoxic free radicals in the brain and oxidative stress can occur during heatstroke. Methods-Urethane-anesthetized rats underwent instrumentation for the measurement of mean arterial pressure, cerebral blood flow, neuronal damage score, and colonic temperature. Rats were exposed to heat stress (ambient temperature, 42°C) until mean arterial pressure and cerebral blood flow began to decrease from their peak levels, which was arbitrarily defined as the onset of heatstroke. Controlled rats were exposed to 24°C. Concentrations of dihydroxybenzoic acid, lipid peroxidation, rate of O 2 · Ϫ generation, superoxide dismutase, and catalase activity of the brain or other vital organs were assessed during heatstroke. Results-The values of mean arterial pressure and cerebral blood flow after heatstroke onset were all significantly lower than those in control rats. However, the values of colonic temperature, dihydroxybenzoic acid levels in the striatum, and neuronal damage score were greater. The extent of lipid peroxidation in the brain and the rate of O 2 · Ϫ generation in the brain, liver, and heart were all greater in rats after heatstroke onset. In contrast, the values of total superoxide dismutase in the brain, liver, and heart and the catalase activity in the brain were lower. Conclusions-Taken
BackgroundMesenchymal stem cell (MSC) transplantation has been reported to improve neurological function following neural injury. Many physiological and molecular mechanisms involving MSC therapy‐related neuroprotection have been identified.MethodsA review is presented of articles that pertain to MSC therapy and diverse brain injuries including stroke, neural trauma, and heat stroke, which were identified using an electronic search (e.g., PubMed), emphasize mechanisms of MSC therapy‐related neuroprotection. We aim to discuss neuroprotective mechanisms that underlie the beneficial effects of MSCs in treating stroke, neural trauma, and heatstroke.Results MSC therapy is promising as a means of augmenting brain repair. Cell incorporation into the injured tissue is not a prerequisite for the beneficial effects exerted by MSCs. Paracrine signaling is believed to be the most important mediator of MSC therapy in brain injury. The multiple mechanisms of action of MSCs include enhanced angiogenesis and neurogenesis, immunomodulation, and anti‐inflammatory effects. Microglia are the first source of the inflammatory cascade during brain injury. Cytokines, including tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6, are significantly produced by microglia in the brain after experimental brain injury. The proinflammatory M1 phenotype of microglia is associated with tissue destruction, whereas the anti‐inflammatory M2 phenotype of microglia facilitates repair and regeneration. MSC therapy may improve outcomes of ischemic stroke, neural trauma, and heatstroke by inhibiting the activity of M1 phenotype of microglia but augmenting the activity of M2 phenotype of microglia.ConclusionThis review offers a testable platform for targeting microglial‐mediated cytokines in clinical trials based upon the rational design of MSC therapy in the future. MSCs that are derived from the placenta provide a great choice for stem cell therapy. Although targeting the microglial activation is an important approach to reduce the burden of the injury, it is not the only one. This review focuses on this specific aspect.
Experiments were carried out to ascertain whether the levels of brain monoamines and cytokines are involved in the heatstroke-induced cerebral ischemia and neuronal damage. Heatstroke was induced by exposing anesthetized rats to a high ambient temperature of 42 degrees C; the moment at which the mean arterial pressure began to decrease from its peak level was taken as the onset of heatstroke. It was found that, during the heatstroke-induced cerebral ischemia and neuronal damage, the extracellular concentration of either dopamine, serotonin or norepinephrine were increased in the hypothalamus, the corpus striatum and other brain regions. In addition, the concentration of interleukin-1 (IL-1), IL-6 and tumor necrosis factor in both the plasma and brain was also increased during heatstroke-induced cerebral ischemia and neuronal damage. Heatstroke-induced cerebral ischemia and neuronal damage were attenuated by depletion of brain dopamine or serotonin produced by intracerebral injection of 6-hydroxydopamine or 5,7-dihydroxytryptamine, respectively. Accordingly, the survival of these heatstroke rats was increased after brain dopamine or serotonin depletion. Furthermore, heatstroke-induced cerebral ischemia, neuronal damage and monoamine accumulation were attenuated by blockade of IL-1 receptor produced by treatment with an IL-1 receptor antagonist. The survival of the heatstroke rats was also increased after induction of heat shock protein. The results suggest that marked accumulation of either dopamine, serotonin or IL-1 in brain is important for the occurrence of heatstroke-induced cerebral ischemia and neuronal damage in rats. The survival of these heatstroke rats can be increased by inhibition of IL-1 receptors or monoamine system in brain as well as by induction of heat shock protein.
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