The pathophysiology of ischemic brain injury

Brain tissue ischemia and hypoxia may be due to a variety of mechanisms to activate the Erzhi brain edema and neuronal injury, and the resulting patient permanent disability and even death. Cerebral ischemia and hypoxia, microcirculation and cerebral ischemia after free radicals, arachidonic acid metabolites, excitatory amino acids and free fatty acids increased, resulting in severe vasogenic and cell-derived brain edema. Cerebral blood flow, vascular endothelial hypoxic injury and permeability increased destruction of blood-brain barrier function, resulting in secondary brain edema occurs when blood flow recanalization. The cerebral edema cerebral perfusion pressure changes and the enormous changes of the extracellular environment and further increase the brain tissue ischemia and hypoxia, and secondary apoptosis and inflammatory responses, forming a vicious cycle until the cell death.

In the middle cerebral artery occlusion and reperfusion (MCAO melon) model, starting with the glutamate-dependent, excitotoxic nerve damage. Hours is followed by cell death stage of infarct development to peripheral areas and the cerebral cortex when neuronal injury and apoptosis and inflammatory responses. Ischemia-induced neuronal damage response includes the following three mechanisms: ischemia-induced expression of IL-1pmRNA; ischemia-induced neuronal apoptosis; ischemia-induced glial reaction. Exacerbate neuronal death caused by the mechanism of apoptosis in the early stages of cell death caused by inflammation. Interleukin-1 (inierlukin a 1, IL-1) is the inflammation of early cytokines, is considered to be important factors controlling neuronal apoptosis induced by ischemic brain injury. One result of ischemia-mediated inflammatory response is the activation and infiltration of mononuclear cells, the cerebral cortex of macrophages / microglia infiltration and activation is a characteristic reaction of ischemic stroke-induced inflammation. Can be found in a large number of macrophages / microglia in the infarcted cerebral hemisphere contralateral but not MCAO rat brain cortex around the infarct area after 24h of glial fibrillary acidic protein (gelatinousfiberac remember Protein GEAp) immune response was significantly enhanced, suggesting the presence of astrocytes.


The introduction of NRG and MCAO / R

Neuregulin (Neuregulln, NRG) is a family of polypeptides encoded by four genes on the developing nervous system has a variety of important regulatory role. Brain tissue after ischemia and hypoxia due to the activation of a variety of mechanisms may cause brain edema and neuronal damage. Cerebral ischemia and hypoxia, microcirculation and cerebral ischemia after free radicals, arachidonic acid metabolites, excitatory amino acids and free fatty acids increased, resulting in severe vasogenic and cell-derived brain edema. Reduce cerebral blood flow, increased hypoxic injury and permeability of the vascular endothelial blood-brain barrier function damage, blood flow through the secondary brain edema. Brain edema and further aggravate ischemia and hypoxia of brain tissue, forming a vicious cycle. In the rat permanent MCAO model of ischemic penumbra zone cells can be observed NRG EthB its receptor tyrosine kinase receptor to induce the expression of positive. Xu Zhen peak experiments show that NRG anti-inflammatory substances in the body outside the central nervous system can inhibit brain ischemia-reperfusion injury-induced neuronal apoptosis, glial response and inflammation, induced expression of the neurotrophic factor have neuroprotective effects.

Artery occlusion and reperfusion (MCAO / R) model has been widely used in acute focal cerebral infarction studied in rat and rabbit brain. In this study, attempts to model NRG through carotid artery in mice with focal cerebral ischemia and reperfusion, by observing the neurobehavioral score, brain water content, changes in the scope of the ischemic penumbra, as well as immunofluorescence staining of nerve cells apoptosis, immunohistochemistry chemical detection of nerve cells AQP 4 expression, study neuroprotective NRG in ischemic brain injury and its mechanism of action, and to further explore the potential value of its clinical application. In particular, its anti-inflammatory, anti-apoptotic role of cerebral edema and reperfusion injury, it is possible to extend the time window of thrombolytic therapy, and increase safety and improve the prognosis of the treatment.

Neuregulin on focal cerebral ischemia and reperfusion injury in rats and mechanisms

The study of nervous somatomedin IB (NRG IB) on cerebral ischemia reperfusion neurobehavioral function, infarct volume, brain water content, neuronal apoptosis and aquaporin 4 (aquaPorin a 4 and AQP4) expression, and to explore the neural regulation of the protective mechanism on Cerebral Ischemia reperfusion Injury. Method of application of the suture method to establish the arterial occlusion and reperfusion (a reperfusion middlecerebralarteryoeelusion mouse brain MCAO melon) model, the intervention by the internal carotid artery injection of NRG-IB (as well stay kg) the Bederson method to evaluate the animal’s neurobehavioral function, chlorine of triphenyl tetrazolium wow (tetrazoliumehloride, TI’C) staining of the volume of cerebral infarction, the water content of wet and dry weight determination of brain tissue, immunofluorescence staining was used to detect neuronal apoptosis, immunohistochemical staining of nerve cells AQP 4 expression . Results after cerebral ischemia and reperfusion injury, the animals were shown to the neurobehavioral dysfunction, ischemic hemisphere cerebral infarction lesions, accompanied by increased water content in brain tissue, nerve cells AQP 4 enhanced expression and neuronal apoptosis. NRG an IB treatment after ischemia 24h animals neurobehavioral dysfunction is significantly lighter than the control group, the decrease in the number of apoptotic nerve cells, significantly reduced infarct volume, p <0.05; brain water content and AQP-4 expression and control was no significant difference (P> 0.05). Ischemia and reperfusion 22h, 46h and 70h group, the five indicators compared with the corresponding control groups were significant differences (p <0.05). Changes in brain water content and AQP-4 expression was positively correlated (p <0.05). Conclusion neuregulin may be by blocking ischemia-induced apoptosis gene activation pathway, down AQP-4 expression in order to reduce cerebral edema and reduce the infarct volume, thereby reducing the degree of cerebral ischemia and reperfusion injury and neurological deficit symptoms, protect brain tissue and their functions.