Pathophysiology of blood-brain barrier, brain edema and cell injury following hyperthermia : New role of heat shock protein, nitric oxide and carbon monoxide : an experimental study in rat using light and electron microscopy
Abstract: This thesis deals with the molecular mechanisms of hyperthermia induced brain damage in rats. The results clearly establish that hyperthermia caused by 4 h heat stress at 38° C is associated with a breakdown of the blood-brain barrier (BBB) permeability which seems to be instrumental in causing brain edema and cell injury. Using immunohistochemistry, the results presented in this thesis demonstrate for the first time that hyperthermia induces profound alteration in the molecular machinery of the CNS resulting in altered expression ofseveral proteins namely glial fibrillary acidic protein (GFAP), vimentin, myelin basic protein (MBP), heat shock protein (HSP) 72 kD and enzymes e.g., nitric oxide synthase (NOS) and heme oxygenase (HO). Immunoelectron microscopic observations confirm the findings at light microscopy and further show that altered expression of these proteins and enzymes are mainly located within the damaged regions of the CNS. Ultrastructural studies demonstrate breakdown of the BBB permeability using lanthanum in brain regions exhibiting ischemia,edema and damage to the nerve cells, glial cells and myelin. The salient new findings of this thesis is that the brain damage caused by heat stress is mediated by several neurochemicals such as serotonin, prostaglandins, opioids, histamine and catecholamines. Pharmacological receptor blockade of serotonin, prostaglandins, opioids and histamine attenuated BBB permeability and was also able to reduce brain edema, cell injury and expression of the above proteins and enzymes in the CNS following heat exposure. These observations strongly indicate that cellular stress and disturbances in the fluidmicroenvironment of the brain play a detrimental role in expression of these molecules. In conclusion, this thesis has advanced our knowledge on the pathophysiology of cell injury using heat stress as a new model. The works presented in this thesis strongly advocate that (i) the breakdown of the BBB plays a major role in cell injury, (ii) the basic mechanisms of cell injury occurring in various neuronal diseases appears to be similar in nature, and (ii) no single chemical compound or factor is solely responsible for brain injury in heat stress. Finally, heat stress seems to be useful as a new model to study brain injury and to evaluate theneuroprotective effects of the compounds which may have therapeutic potentials to attenuate cell injury in traumatic, ischemic, hypoxic conditions as well as in other neurodegenerative diseases.
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