The effect of granulocyte colony-stimulating factor administration on carbon monoxide neurotoxicity in rats

Granulocyte colony-stimulating factor (G-CSF) is considered to be a novel neuroprotective agent. Beneficial effects have been demonstrated by administrating G-CSF in different experimental stroke models. In this study, we evaluated the efficacy of G-CSF therapy on carbon monoxide (CO) neurotoxicity in rats exposed to acute CO poisoning. Immediately after exposure to 3,000 ppm of CO for 60 minutes, 50, 100, and 150 µg/kg of G-CSF or normal saline were administered to rats. Rats were sacrificed after 24 hours for serum marker analysis or 1 week for histopathological examination. Brain sections were stained with hematoxylin and eosin to assess leukocyte infiltration and hippocampal injury and with Luxol fast blue to assess demyelination. S100β and glial fibrillary acidic protein (GFAP) serum levels were evaluated by commercial enzyme-linked immunosorbent assay kits. According to histopathological findings, G-CSF administration significantly restricted white-matter demyelination (150 µg/kg) (P = 0.006). Also, serum levels of S100β in G-CSF-treated groups (100 and 150 µg/kg) decreased significantly (P < 0.01and P < 0.05, respectively). In all does, G-CSF significantly reduced serum levels of GFAP (P < 0.01 for 50 µg/kg and P < 0.001 for other doses). Administration of G-CSF after CO poisoning attenuates brain cell damage through remyelination. G-CSF also decreases levels of related biomarkers, such as S100β and GFAP.     

Induction of heme oxygenase-1 with hemin attenuates hippocampal injury in rats after acute carbon monoxide poisoning

Carbon monoxide (CO) poisoning is a major cause of brain injury and mortality; delayed neurological syndrome (DNS) is encountered in survivors of acute CO exposure. The toxic effects of CO have been attributed to oxidative stress induced by hypoxia. Heme oxygenase-1 (HO-1) is the inducible heme oxygenase isoform, and its induction acts as an important cellular defense mechanism against oxidative stress, cellular injury and disease. In this study, we examined the functional roles of HO-1 induction in a rat model of CO-exposured hippocampal injury. We report that acute CO exposure produces severe hippocampal injury in rats. However, hemin pretreatment reduced both the CO-induced rise in hippocampal water content and levels of neuronal damage in the hippocampus; survival rates at 24 h were significantly improved. Upregulation of HO-1 by hemin pretreatment resulted in a significant decrease in hippocampal levels of malondialdehyde (MDA), a marker of oxidative stress; levels of pro-apoptotic caspase-3 were also reduced. In contrast, inhibition of HO activity by administration of tin protoporphyrin IX (SnPP, a specific inhibitor of HO) abolished the neuroprotective effects of HO-1 induction. These data suggested that the upregulation of endogenous HO-1 expression therefore plays a pivotal protective role in CO neurotoxicity. Though the precise mechanisms underlying hemin-mediated HO-1 induction and neuroprotection are not known, these may involve the anti-oxidant and anti-apoptotic effects of HO-1 enzyme activity.     

铁离子沉积在急性CO中毒迟发性脑病白质脱髓鞘中的作用

摘要：目的　研究铁离子沉积在急性一氧化碳（CO）中毒迟发性脑病（DEACMP）大鼠脑白质脱髓鞘中的作用。方法　将经Morris水迷宫实验筛选后的SD大鼠随机分成空气对照组（AC组）、CO中毒组（CO组）、去铁胺（DFO）+CO中毒组（DC组）,各组内再分为1、3、7、14、21 d亚组。CO组和DC组采用腹腔注射CO气体法制备DEACMP模型,DC组大鼠于造模前1 h腹腔注射去铁胺100 mg/kg,造模后每天注射1次,AC组和CO组腹腔注射等量生理盐水。采用Morris水迷宫、HE染色观察大鼠染毒前后行为学改变和神经元细胞病理变化;普鲁士蓝染色检测铁离子表达;Western blot检测铁蛋白（Fn）、髓鞘碱性蛋白（MBP）的表达;免疫组化染色检测2',3'-环核苷酸磷酸二酯酶（CNPase）表达;免疫荧光染色检测MBP蛋白表达。结果　染毒14 d后,CO组、DC组逃避潜伏期较AC组延长,DC组逃避潜伏期较CO组缩短,CO组穿越平台次数较AC组及DC组明显减少（P＜0.05）。CO组于染毒14 d细胞变性、坏死明显;DC组细胞变性、坏死介于AC、CO组之间。CO组铁离子表达于14 d达峰值（P＜0.05）,与CO组比较,DC组铁离子、Fn表达减少,染毒3 d后DC组MBP表达增加,14 d和21 d时CNPase表达增多（P＜0.05）。DC组较CO组髓鞘排列较密集,MBP表达增加。结论　急性CO中毒后,过量沉积的铁离子可能通过减少CNPase和MBP的表达,损伤少突胶质细胞,导致大鼠脑白质进行性脱髓鞘,从而发生迟发性认知功能障碍。     

急性一氧化碳中毒迟发性脑病的临床表现与脑电图改变(附31例报告)

目的 分析急性一氧化碳中毒迟发性脑病的临床表现与脑电图（EEG）异常改变,为判定和指导治疗提供依据。方法 4对31例急性一氧化碳中毒迟发性脑病的临床与EEG资料,进行回顾性分析。结果 31例患者多数于急性一氧化碳中毒昏迷清醒后不久出现迟发性脑病特有的神经精神症状与体征,全部病例EEG均表现为异常,其中轻度异常10例,中度异常13例,重度异常8例,且与临床表现大致对应。结论 EEG检查对急性一氧化碳中毒迟发性脑病的预防、指导临床治疗、判定预后、降低迟发性脑病的发生率等方面具有重要意义。     

Low dose of carbon monoxide intraperitoneal injection provides potent protection against GalN/LPS‐induced acute liver injury in mice

Carbon monoxide (CO) is an important effector‐signaling molecule involved in various pathophysiological processes. Here we investigated the protective effects of exogenous CO in a murine model of acute liver damage induced by d ‐galactosamine (GalN) and lipopolysaccharide (LPS). Exogenous CO gas was administered to mice via intraperitoneal injection (first at a dose of 15 ml kg^?1 and then, 6 h later, 8 ml kg^?1), which caused a significant elevation of blood carboxyhemoglobin levels of up to 12–14% for more than 12 h. GalN/LPS were given to induce acute liver damage in mice 30 min prior to CO exposure. This showed that GalN/LPS induced severe liver injury in mice, whereas CO injection remarkably improved the survival rate of mice and led to attenuated hepatocellular damage. CO exhibited anti‐oxidative capabilities by inhibiting hepatic malondialdehyde contents and restoring superoxide dismutase and glutathione, as well as by reducing inducible NOS/NO production. The anti‐apoptotic and anti‐inflammatory effects of CO were substantial, characterized by a notable inhibition of hepatocyte apoptosis and a reduction of pro‐inflammatory cytokines in mice. Our findings thus supported the hypothesis that exogenous CO provides protective effects against acute liver damage in mice, mainly dependent on its anti‐oxidative, anti‐inflammatory and anti‐apoptotic properties. Copyright © 2012 John Wiley & Sons, Ltd.     

Regional variations of vasomotion to G‐protein coupled receptor agonists following heat stress in rats

Objectives This study was designed to compare vascular contractile and relaxing responses to G‐protein coupled receptor agonists among the different regions of arteries following heat stress in rats. Methods Heat exposure was performed by increasing the internal temperature of the rats to 42°C for 15 min. After heat stress for 48 h, a myograph system was used to monitor the contractile responses in rat renal, femoral and mesenteric arteries to agonists of endothelin type B (ET_B) receptor, endothelin type A (ET_A) receptor, serotonin receptor and α‐adrenoceptor, respectively. In addition, calcitonin gene‐related peptide (CGRP)‐induced vasodilation was studied. Key findings The results showed that heat stress induced decreased contractions mediated by α‐adrenoceptors and serotonin receptors (at lower concentration), while it increased contraction mediated by endothelin ET_B receptors and enhanced relaxation mediated by CGRP receptors in the renal artery. Heat stress increased contractions mediated by endothelin ET_B receptors, endothelin ET_A receptors and α‐adrenoceptors in the femoral artery. In the mesenteric artery, heat stress increased contractions mediated by endothelin ET_B and serotonin receptors and relaxation mediated by CGRP receptors. Conclusions The vasomotor responses to the G‐protein coupled receptor agonists with altered vascular contractions and relaxations were different in rat renal, femoral and mesenteric arteries after heat stress. This might have contributed to the redistribution of blood flow and aids understanding of the preconditioning phenomenon.     

[carbonyl‐11C]Benzyl acetate: Automated radiosynthesis via Pd‐mediated [11C]carbon monoxide chemistry and PET measurement of brain uptake in monkey

[carbonyl‐¹¹C]Benzyl acetate ([¹¹C]1) has been proposed as a potential agent for imaging glial metabolism of acetate to glutamate and glutamine with positron emission tomography. [¹¹C]1 was synthesized from [¹¹C]carbon monoxide, iodomethane and benzyl alcohol via palladium‐mediated chemistry. The radiosynthesis was automated with a modified Synthia platform controlled with in‐house developed Labview software. Under production conditions, [¹¹C]1 was obtained in 10% (n=6) decay‐corrected radiochemical yield from [¹¹C]carbon monoxide in >96% radiochemical purity and with an average specific radioactivity of 2415 mCi/µmol. The total radiosynthesis time was about 45 min. Peak uptake of radioactivity in monkey brain (SUV=3.1) was relatively high and may be amenable to measuring uptake and metabolism of acetate in glial cells of the brain. Published in 2010 by John Wiley & Sons, Ltd.     

Dynamic changes of heme oxygenase-1 and carbon monoxide production in acute liver injury induced by carbon tetrachloride in rats

Heme oxygenase-1, a stress-responsive enzyme that catabolizes hemes into carbon monoxide, biliverdin, and iron, has been shown to play a pivotal role in many physiological and pathological situations. Here we investigated changes in HO-1 enzyme activity and protein expression, and its end product carbon monoxide concentrations in the liver of rats after CCl(4) treatment. We found that CCl(4) administration not only induced severe liver damage in rats, as demonstrated by dramatic elevation of ALT, AST levels and severe histopathological changes, but also resulted in a prominent up-regulation of HO-1 enzyme activity. Western blot and immunohistochemical analysis confirmed that expression of HO-1 protein was also increased significantly in a time-dependent manner following CCl(4) treatment, and localized mainly in liver cells around the central vein. In addition, CO concentrations in the liver of CCl(4)-treated rats were elevated remarkably in the same time-dependent way as HO-1 induction in contrast to the control rats. These data indicated that HO-1/CO pathway was greatly up regulated in the liver of rats after CCl(4) treatment, which might play an important protective role in the pathophysiological mechanism underlying CCl(4)-induced hepatotoxicity. It therefore suggested that more relevant studies should be carried out in the future to clarify the detailed mechanisms.     

A high‐fat diet and multiple administration of carbon tetrachloride induces liver injury and pathological features associated with non‐alcoholic steatohepatitis in mice

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