Brain Injury review

This article by G Hsiao and colleagues from Taipai takes a look at the antioxidant properties of PMC and its effects upon cerebral artery ischemia.

2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC) is the most potent analogue of alpha-tocopherol for anti-oxidation. It is more hydrophilic than other alpha-tocopherol derivatives and has potent free radical-scavenging activity. In the present study, PMC significantly attenuated middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. Administration of PMC at 20mg/kg, showed marked reductions in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1alpha, active caspase-3, iNOS, and nitrotyrosine expressions in ischemic regions.

These expressions were markedly inhibited by treatment with PMC (20mg/kg). In addition, PMC (4-12muM) inhibited respiratory bursts in human neutrophils stimulated by fMLP (800nM) and PMA (320nM). Furthermore, PMC (6, 12, and 60muM) also significantly inhibited neutrophil migration stimulated by leukotriene B(4) (160nM). An electron spin resonance (ESR) method was conducted on the scavenging activity of PMC on the free radicals formed. PMC (12muM) greatly reduced the ESR signal intensities of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, we demonstrate a potent neuroprotective effect of PMC on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by inhibition of free radical formation, followed by inhibition of HIF-1alpha activation, apoptosis formation (active caspase-3), neutrophil activation, and inflammatory responses (i.e., iNOS and nitrotyrosine expressions), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, PMC treatment may represent a novel approach to lowering the risk or improving function in ischemia-reperfusion brain injury-related disorders.

The full article, which is published in the journal biochemical pharmacology is availble under the pubmed identifier 17157269

by Davis and Patel

PURPOSE OF REVIEW: Brain ischemia is responsible for significant morbidity and mortality associated with cardiovascular surgery, and is the end result of multiple disease states, including cardiac arrest, stroke, and traumatic brain injury. Despite significant resources dedicated to developing neuroprotective strategies, little progress has been made in this regard. Neuronal ischemic preconditioning is an endogenous neuroprotective strategy that provides sustained and robust ischemic tolerance. Identification of the mechanisms responsible for mediating the preconditioning response may offer novel therapeutic targets and further our understanding of the natural adaptations to brain injury. RECENT FINDINGS: Recent research efforts have elucidated many intracellular signaling pathways that ultimately lead to ischemic tolerance after a preconditioning stimulus. Most of these are associated with glutamate receptor signal transduction, the intracellular kinases, and several transcription regulators. Microarray analysis has identified several gene families that warrant further investigation to identify novel candidates for neuroprotective therapies. These include genes involved in synaptic architecture and signal propagation, cell cycle and transcription regulators, and mediators of apoptosis such as the heat shock proteins and anti-apoptotic mitochondrial proteins. SUMMARY: Neuronal ischemic preconditioning is an endogenous mechanism that leads to robust neuroprotection from ischemia. Identification of the upstream pathways that initiate preconditioning and candidate genes that mediate this phenomenon may offer novel therapeutic targets, with applicability to a variety of disease states and perioperative complications.

from pubmed 17021495

This article is from H. Wu and friends at the Jingling hospital within Nanjing University in China. it is published in the European Journal of cardio-throrac surgury.

Objective: Based on the findings that erythropoietin has been proved to be a multiple functional cytokine to attenuate ischemia-reperfusion (I/R) injury in various organs such as brain, heart, and kidney in animals, this experiment was designed to evaluate the effect of pretreatment with recombined human erythropoietin on I/R-induced lung injury. Methods: Left lungs of rats underwent 90min of ischemia and then were reperfused for up to 2h. Animals were randomly divided into three experimental groups as sham group, I/R group, and recombined human erythropoietin +I/R group (a single dose of recombined human erythropoietin was injected intraperitoneally 3000U/kg 24h prior to operation). Lung injury was evaluated according to semi-quantitive analysis of microscopic changes, tissue polymorphonuclear neutrophils (PMNs) accumulation (myeloperoxidase (MPO) activity), and pulmonary microvascular permeability (Evan’s blue dying method). Peripheral arterial and venous blood samples were obtained for blood-gas analysis after 5min occlusion of right lung hilus at the end of reperfusion. The serum concentration of tumor necrosis factor (TNF)-alpha was also measured by the method of enzyme-linked immunosorbent assay.

Results: Histological injury scoring revealed significantly lessened lung alveolus edema and neutrophils infiltration in the recombined human erythropoietin pretreated group compared with I/R group (p<0.05). The recombined human erythropoietin pretreated animals exhibited markedly decreased lung microvascular permeability (p<0.05) and myeloperoxidase activity (p<0.05). Blood-gas analysis demonstrated that the pretreated animals had significantly ameliorated pulmonary oxygenation function (p<0.05). The serum concentration of tumor necrosis factor-alpha in recombined human erythropoietin pretreated group was markedly decreased compared with that of I/R group (p<0.05).

Conclusions: Pretreatment with recombined human erythropoietin appears to attenuate I/R-induced lung injury. This function is partly related with the capacity that recombined human erythropoietin inhibits the accumulation of polymorphonuclear neutrophils in lung tissue and decreases the systematic expression of tumor necrosis factor-alpha.

The pubmed ID is 16675226