Chronic administration of ethyl docosahexaenoate decreases mortality and cerebral edema in ischemic gerbils

Dietary docosahexaenoic acid (DHA) intake can decrease the level of membrane arachidonic acid (AA), which is liberated during cerebral ischemia and implicated in the pathogenesis of brain damage. Therefore, in the present study, we investigated the effects of chronic ethyl docosahexaenoate (E-DHA) administration on mortality and cerebral edema induced by transient forebrain ischemia in gerbils. Male Mongolian gerbils were orally pretreated with either E-DHA (100, 150 mg/kg) or vehicle, once a day, for 4 weeks and were subjected to transient forebrain ischemia by bilateral common carotid occlusion for 30 min. The content of brain lipid AA at the termination of treatment, the survival ratio, change of regional cerebral blood flow (rCBF), brain free AA level, thromboxane B(2) (TXB(2)) production and cerebral edema formation following ischemia and reperfusion were evaluated. E-DHA (150 mg/kg) pretreatment significantly increased survival ratio, prevented post-ischemic hypoperfusion and attenuated cerebral edema after reperfusion compared with vehicle, which was well associated with the reduced levels of AA and TXB(2) in the E-DHA treated brain. These data suggest that the effects of E-DHA pretreatment on ischemic mortality and cerebral edema could be due to reduction of free AA liberation and accumulation, and its metabolite synthesis after ischemia and reperfusion by decreasing the content of membrane AA.     

Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema and brain prostaglandins in ischemic gerbils

Eicosapentaenoic acid is converted by cyclo-oxygenase to the prostacyclin, PGI3. Consequently eicosapentaenoic acid might protect the brain from the impairment in cerebral blood flow that follows temporary cerebral arterial occlusion. We studied the effect of 90% pure eicosapentaenoic acid, given intravenously, on cerebral blood flow, brain water and prostaglandins after ischemia in gerbils. Ischemia was produced by bilateral carotid occlusion for 15 min followed by reperfusion for 2 h. In experimental gerbils, 0.833 mg or 0.167 mg of eicosapentaenoic acid (Na salt) was given intravenously followed by a continuous infusion of 1 mg h-1. Control gerbils were given 0.167 mg of linoleic acid (Na salt) intravenously followed by a continuous infusion of 1 mg h-1 or a saline infusion. Regional cerebral blood flow was measured by the hydrogen clearance method and brain water by the specific gravity technique. Brain diene prostaglandins were measured by radioimmunoassay. In control gerbils cerebral blood flow decreased significantly during reperfusion and remained depressed after 2 h of reperfusion. In eicosapentaenoic acid treated gerbils blood flow decreased initially but after 2 h of reperfusion blood flow was significantly higher than in control gerbils. Brain edema and brain diene prostaglandins were not significantly different between control and experimental groups. Our study indicates that eicosapentaenoic acid, given intravenously, improves cerebral blood flow after ischemia and reperfusion. We speculate that this effect may be due to the formation of the prostacyclin, PGI3.     

Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema and brain prostaglandins in ischemic gerbils

Eicosapentaenoic acid is converted by cyclo-oxygenase to the prostacyclin, PGI₃. Consequently eicosapentaenoic acid might protect the brain from the impairment in cerebral blood flow that follows temporary cerebral artirial occlusion. We studied the effect of 90% pure eicosapentaenoic acid, given intravenously, on cerebral blood flow, brain water and prostaglandins after ischemia in gerbils. Ischemia was produced by bilateral carotid occlusion for 15 min followed by reperfusion for 2 h. In experimental gerbils, 0.833 mg or 0.167 mg of eicosapentaenoic acid (Na salt) was given intravenously followed by a continuous infusion of 1 mg h⁻¹. Control gerbils were given 0.167 mg of linoleic acid (Na salt) intravenously followed by a continuous infusion of 1 mg h⁻¹ or a saline infusion. Regional cerebral blood flow was measured by the hydrogen clearance method and brain water by the specific gravity technique. Brain diene prostaglandins were measured by radioimmunoassay. In control gerbils cerebral blood flow decreased significantly during reperfusion and remained depressed after 2 h of reperfusion. In eicosapentaenoic acid treated gerbils blood flow decreased initially but after 2 h of reperfusion blood flow was significantly higher than in control gerbils. Brain edema and brain diene prostaglandins were not significantly different between control and experimental groups.Our study indicates that eicosapentaenoic acid, given intravenously, improves cerebral blood flow after ischemia and reperfusion. We speculate that this effect may be due to the formation of the prostacyclin, PGI₃.     

The influence of proglumide, a putative CCK antagonist, on cerebral ischemia in gerbil

Studies were conducted to clarify the possible role of CCK in cerebral ischemia and to evaluate the effects of proglumide, a competitive and reversible CCK antagonist, as a potential therapeutic or prophylactic tool in the treatment of cerebral ischemia. Proglumide at the doses of 10, 50 and 150 mg/kg was administered to gerbils before unilateral carotid ligation, and its effect on stroke index score, incidence and mortality rate was observed. Our results show that proglumide injected prior to carotid ligation at the dose of 150 mg/kg significantly reduces both incidence and mortality rate and changes the distribution of the stroke index score in gerbils. There was a significant inverse relationship between the dose of proglumide and both incidence and mortality: the greater the injection dose of proglumide, the lower the incidence and mortality. These results suggest that CCK may be involved in the pathological processes of cerebral ischemia and proglumide or related compounds prove to be effective in the pharmacological prophylaxis of ischemic brain damage.     

Neuroprotective potential of group I metabotropic glutamate receptor antagonists in two ischemic models

The neuroprotective potential of mGluR1 and mGluR5 antagonists (group I), EMQMCM and MTEP, respectively was studied using the 3 min forebrain ischemia model in Mongolian gerbils and the hypoxia-ischemia model in 7-day-old rats. Hypoxia-ischemia was induced by unilateral carotid occlusion followed by 75 min exposure to hypoxia (7.3% O(2) in N(2)), forebrain ischemia in gerbils was evoked by bilateral common carotid artery occlusion. The postischemic rectal body temperature in rat pups or brain temperature of gerbils was measured. The drugs were administered i.p. three times every 2 h after the insult, each time in equal doses of 1.25, 2.5 or 5.0 mg/kg. After 2 weeks brain damage was evaluated as weight decrease of the ipsilateral hemisphere in the rat pups or damage to CA1 pyramids in the gerbil hippocampus. The results demonstrated a dose dependent neuroprotection in both ischemic models by EMQMCM, while MTEP was neuroprotective only in the gerbil model of forebrain ischemia. EMQMCM reduced postischemic hyperthermia in gerbils. Thus, the antagonists of mGluR1 and mGluR5 show differential neuroprotective ability in two models of brain ischemia. Postischemic hypothermia may be partially involved in the mechanism of neuroprotection following EMQMCM in gerbils.     

Chronic administration of ethyl docosahexaenoate reduces gerbil brain eicosanoid productions following ischemia and reperfusion

Arachidonic acid (AA) and its vasoactive metabolites have been implicated in the pathogenesis of brain damage induced by cerebral ischemia. The membrane AA concentrations can be reduced by changes in dietary fatty acid intake. The purpose of the present study was to investigate the effects of chronic ethyl docosahexaenoate (E-DHA) administration on the generation of eicosanoids of AA metabolism during the period of reperfusion after ischemia in gerbils. Weanling male gerbils were orally pretreated with either E-DHA (100, 200 mg/kg) or vehicle, once a day, for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 10 min. E-DHA (200 mg/kg) pretreatment significantly decreased the content of brain lipid AA at the termination of treatment, prevented postischemic impaired regional cerebral blood flow (rCBF) and reduced the levels of brain prostaglandin (PG) PGF(2alpha) and 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), as well as leukotriene (LT) LTB(4) and LTC(4) at 30 and 60 min of reperfusion compared with the vehicle, which was well associated with the attenuated cerebral edema in the E-DHA-treated brain after 48 h of reperfusion. These data suggest that the E-DHA (200 mg/kg) pretreatment reduces the postischemic eicosanoid productions, which may be due to its reduction of the brain lipid AA content.     

Changes in regional levels of putative neurotransmitter amino acids in brain under unilateral forebrain ischemia

The levels of the neurotransmitter amino acids glutamate, aspartate, and GABA were determined in different brain regions during ischemia and post-ischemic recirculation periods using the unilateral carotid artery occlusion model of stroke in gerbils. The levels of glutamate, aspartate and GABA in ischemic hemisphere were increased significantly by 10 min of ischemia and later declined with time. Reperfusion for 30 min following 10 min. of ischemia further enhanced the levels of glutamate and aspartate. Increase in GABA levels were found during early periods of reperfusion. Regional variations in the changes of amino acids' levels were noticed following ischemia. Hippocampus showed the highest increase in glutamate levels followed by striatum and cerebral cortex. Aspartate levels in striatum and hippocampus increased during 10 min ischemia (46% and 30%) and recirculation (70% and 79%), whereas in cerebral cortex the levels were doubled only during recirculation. Ischemia induced elevations of GABA levels were observed in cerebral cortex (68%) and in hippocampus (30%), and the levels were normalized during recirculation. No changes in GABA levels were found in striatum. It is suggested that the large increase in the levels of excitatory neurotransmitter amino acids in brain regions specially in hippocampus during ischemia and recirculation may be one of the causal factors for ischemic brain damage.     

Differential Effect of Cerebral Ischemia on Monoamine Content of Discrete Brain Regions of the Mongolian Gerbil (Meriones unguiculatus)

The effect of bilateral cerebral ischemia on noradrenaline, dopamine, and serotonin concentrations in six brain regions (i.e., the cerebral cortex, striatum, hippocampus, midbrain-diencephalon, cerebellum, and pons-medulla oblongata) was examined in the gerbil stroke model. The relative changes in regional cerebral blood flow after bilateral common carotid occlusion were also assessed using the radioactive microsphere technique. At 1 h after bilateral carotid occlusion, a significant decrease of monoamine concentration was observed in the cerebral cortex, striatum, hippocampus, and midbrain-diencephalon whereas no significant change was detected in the cerebellum and pons-medulla oblongata. The fall in NA content was most prominent in the cerebral cortex and hippocampus and percentage reductions of dopamine and serotonin were greatest in the striatum and cerebral cortex, respectively. These results suggest that the monoamine neurons in various brain regions might have different vulnerabilities to ischemic insult and show no evidence of transtentorial diaschisis.     

Mechanism of Delayed Increases in Kynurenine Pathway Metabolism in Damaged Brain Regions Following Transient Cerebral Ischemia

Abstract: Delayed increases in the levels of an endogenous N-methyl-D-aspartate receptor agonist, quinolinic acid (QUIN), have been demonstrated following transient ischemia in the gerbil and were postulated to be secondary to induction of indoleamine-2,3-dioxygenase (IDO) and other enzymes of the L-tryptophan-kynurenine pathway. In the present study, proportional increases in IDO activity and QUIN concentrations were found 4 days after 10 min of cerebral ischemia, with both responses in hippocampus > striatum > cerebral cortex > thalamus. These increases paralleled the severity of local brain injury and inflammation. IDO activity and QUIN concentrations were unchanged in the cerebellum of postischemic gerbils, which is consistent with the preservation of blood flow and resultant absence of pathology in this region. Blood QUIN and L-kynurenine concentrations were not affected by ischemia. Brain tissue QUIN levels at 4 days postischemia exceeded blood concentrations, minimizing a role for breakdown of the blood–brain barrier. Marked increases in the activity of kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase were also detected in hippocampus but not in cerebellum on day 4 of recirculation. In vivo synthesis of [¹³C₆]QUIN was demonstrated, using mass spectrometry, in hippocampus but not in cerebellum of 4-day postischemic animals 1 h after intracisternal administration of L-[¹³C₆]tryptophan. However, accumulation of QUIN was demonstrated in both cerebellum and hippocampus of control gerbils following an intracisternal injection of 3-hydroxyanthranilic acid, which verifies the availability of precursor to both regions when administered intracisternally. Notably, although IDO activity and QUIN concentrations were unchanged in the cerebellum of ischemic gerbils, both IDO activity and QUIN content were increased in cerebellum to approximately the same degree as in hippocampus, striatum, cerebral cortex, and thalamus 24 h after immune stimulation by systemic pokeweed mitogen administration, demonstrating that the cerebellum can increase IDO activity and QUIN content in response to immune activation. No changes in kynurenic acid concentrations in either hippocampus, cerebellum, or cerebrospinal fluid were observed in the postischemic gerbils compared with controls, in accordance with the unaffected activity of kynurenine aminotransferase activity. Collectively, these results support roles for IDO, kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase in accelerating the conversion of L-tryptophan and other substrates to QUIN in damaged brain regions following transient cerebral ischemia. Immunocytochemical results demonstrated the presence of macrophage infiltrates in hippocampus and other brain regions that parallel the extent of these biochemical changes. We hypothesize that increased kynurenine pathway metabolism after ischemia reflects the presence of macrophages and other reactive cell populations at sites of brain injury.     

Single, high-dose 17β-estradiol therapy has anti-apoptotic effect and induces cerebral plasticity following transient forebrain ischemia in gerbils (Short communication)

Although much is known about the protective effect of acute estrogen therapy in cerebral ischemia, relatively little is known about the importance of apoptosis and cerebral plasticity in this mechanism. In this work 10 min global cerebral ischemia was produced by transient bilateral carotid occlusion in 4-month-old ovariectomized female gerbils. In every of our experimental group (sham for ischemia group, ischemia group and ischemia + a high, single dose 17β-estradiol pre-treatment group) apoptotic (bcl-Xl, bax) and cerebral plasticity (GAP-43, synapsin-I, nestin) hippocampal genes' expression was measured four days after surgery. Expression of the anti-apoptotic bcl-Xl (p<0.01) and the cerebral plasticity marker synapsin-I and nestin (p<0.01) increased with acute estrogen pretreatment in ischemic animals. No change, however, in bax or GAP-43 expression was detected in estrogen treated animals compared to ischemic gerbils. These results suggest that acute estrogen therapy has anti-apoptotic effect and increases cerebral plasticity, which play an important role in cytoprotection or cerebroprotection.     

Chronic daily administration of ethyl docosahexaenoate protects against gerbil brain ischemic damage through reduction of arachidonic acid liberation and accumulation

Recently, we reported that dietary ethyl docosahexaenoate (Et-DHA) intake decreases the level of membrane arachidonic acid (AA), which reduces the generation of AA metabolites in ischemic gerbil brain. As an extended study, we further investigated the influence of the chronic administration of Et-DHA on free AA levels after ischemia. In addition, Na,K-ATPase activity, cation content, cerebral edema and brain damage were also evaluated. Weanling male gerbils were orally pretreated with either Et-DHA (200 mg/kg) or vehicle, once a day for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 30 min. Time-course analyses revealed that pretreatment with Et-DHA, compared with pretreatment with the vehicle, significantly decreased the brain's free AA levels during ischemia (5, 15 and 30 min) and after reperfusion (5, 10, 15 and 30 min), and attenuated the decline of Na,K-ATPase activity at examined time points. Pretreatment with Et-DHA significantly prevented an increase in Na(+) concentration and a decrease in K(+) concentration after 24 h of reperfusion, which resulted in lower cerebral water content. Reduced brain infarct volume and low animal mortality were also observed in Et-DHA-treated animals. These data suggest that the reduction of ischemia-induced AA liberation and accumulation by Et-DHA pretreatment may be attributable to (a) protection against the decline of Na,K-ATPase activity, (b) postischemic cerebral edema and brain damage and (c) animal mortality.     

Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils

Platelet-activating factor (PAF) is a potent mediator of anaphylaxis and shock. In addition, evidence for PAF participation in gastric, intestinal and heart post-ischemic phase has been recently demonstrated. Ginkgo biloba extracts improve cerebral metabolism and protect brain against hypoxic damage in various models of cerebral ischemia. Potent and specific antagonists of PAF have been found in Ginkgo biloba and termed Ginkgolides: BN 52020, BN 52021, BN 52022, BN 52024. We therefore undertook the investigation of the role of Ginkgolides in cerebral ischemia obtained by bilateral ligature of the common carotid for 10 min and 6 h of recirculation in male Mongolian adult gerbils. Given preventively (one week treatment 10 mg/kg/day orally) or at the time of clamping, BN 52021 and related Ginkgolides dose-dependently antagonize morbidity assessed by the stroke-index. Similarly the mitochondrial respiration evaluated by the respiratory control ratio is significantly improved. In both determinations, the range of activity: BN 52021 greater than, BN 52020 greater than BN 52022 greater than BN 52024 shows that the effect of Ginkgolides in cerebral ischemia are correlated with their PAF antagonistic properties. Given curatively, 1 h after declamping, BN 52021 is able to reverse the cerebral impairment trend. Kadsurenone and brotizolam, two other chemically unrelated PAF antagonists led to similar recovery. Therefore PAF appears to play an important role in the post-ischemic phase after bilateral carotid ligation in Mongolian gerbils.     

Protective effects of superoxide dismutase on acute reperfusion injury of gerbil brain

It has been postulated that oxygen-derived free radicals are produced in significant quantities upon reperfusion of ischemic brain and could cause brain edema and cell death. This study was undertaken in an attempt to examine the effect of recombinant human superoxide dismutase, a scavenger of superoxide radicals, on survival outcome and brain edema in gerbils undergoing 1-hour bilateral carotid occlusion and reperfusion. Superoxide dismutase was continuously infused over either 1 or 3 h of reperfusion. Neither low dose (100,000 U/kg bolus followed by 100,000 U/kg/h continuous infusion) nor high dose (100,000 U/kg bolus followed by 800,000 U/kg/h) recombinant human superoxide dismutase had an effect upon water and sodium content of whole brain at 1 h of reperfusion following 1 h of ischemia, but high-dose treatment effectively reduced brain water content at 3 h of reperfusion. All gerbils receiving high-dose treatment survived the 3 h of reperfusion, while 4 of the 7 gerbils in the control group died between 2 and 3 h of reperfusion (p less than 0.05). From this study, we conclude that prophylactic administration of superoxide dismutase can reduce the delayed vasogenic edema developing at 3 h of reperfusion and afford significant cerebroprotection in these models of transient global ischemia.     

The effects of Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960) on ischemia-induced changes of brain acetylcholine and monoamine levels in gerbils

The changes in acetylcholine (ACh), monoamine and monoamine metabolite levels following cerebral ischemia in Mongolian gerbils were examined. In addition, the effects of Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960), which is a spray-dried mixture of 9 herbal drugs, on these changes were also examined. The dramatic decrement of ACh levels in ischemic gerbils was significantly inhibited by p.o. administration of TJ-960 at a daily dose of 3.5 g/kg or 700 mg/kg for one month. Norepinephrine (NE) was also reduced in all ischemic brain regions, and TJ-960 also recovered the level of NE. In ischemic gerbil brains, the dopamine (DA) levels decreased and its metabolites increased in the striatum, but DA and its metabolites in the thalamus+midbrain region increased. The serotonin (5HT) level was reduced in the cerebral cortex and hippocampus. TJ-960 inhibited these monoaminergic changes in ischemic gerbils. This suggests that TJ-960 may provide anti-ischemic action and beneficial effects on various symptoms induced by ischemia.     

Cerebral Phospholipid Content and Na+, K+-ATPase Activity During Ischemia and Postischemic Reperfusion in the Mongolian Gerbil

Using bilateral carotid artery occlusion in adult gerbils we examined the effects of ischemia and ischemia/reperfusion on cerebral phospholipid content and Na+,K+-ATPase (EC 3.6.1.3) activity. In contrast to the large changes in phospholipid content and membrane-bound enzyme activity that have been observed in liver and heart tissues, we observed relatively small changes in the cerebral content of total phospholipid, phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE) following ischemic intervals of up to 240 min. Following 15 min of ischemia the cerebral content of sphingomyelin (SM) was decreased to less than 50% of control values but returned to near-normal levels with longer ischemic periods. Significant decreases in the cerebral content of phosphatidylinositol (PI) and phosphatidic acid (PA) were observed following shorter intervals of ischemia (15-45 min). Na+,K+-ATPase activity of cerebral homogenates prepared from the brains of gerbils subjected to 30-240 min of ischemia was decreased but significantly different from control activity only after 30 min of ischemia (-29%, p less than or equal to 0.05). With the exception of PS, reperfusion for 60 min following 60 min of ischemia resulted in marked increases in cerebral phospholipid content with PC, SM, PI, and PA levels exceeding and PE levels equal to preischemic values. Longer periods of reperfusion (180 min) resulted in decreases in cerebral phospholipid content toward (PC, SM, PI, and PA) or below (PE) preischemic levels. In contrast, the cerebral content of PS significantly decreased during reperfusion (-51% at 60 min, p less than or equal to 0.05) and remained below preischemic values even after 180 min of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

凝闭双侧椎动脉预处理对大鼠全脑缺血损伤的防护作用

目的：观察凝闭双侧椎动脉与夹闭双侧颈总动脉之间的不同时间间隔对Pulsinelli四血管闭塞法全脑缺血模型的影响、以及在凝闭单侧椎动脉的基础上夹闭双侧颈总动脉后的脑缺血的特点。方法：84只Wistar大鼠．随机分为以下4组：对照组、双侧椎动脉凝闭组、全脑缺血组、单侧椎动脉凝闭＋双侧颈总动脉夹闭组。全脑缺血组中,根据凝闭双侧椎动脉与夹闭双侧颈总动脉之间的时间间隔不同,又分为24h间隔、48h间隔和72h间隔3个亚组。观察大鼠脑缺血过程中的反应包括瞳孔散大、对光反射等情况,脑缺血后恢复翻正反射所需要的时间、以及动物的一般状况,并应用硫堇染色法观察海马CA1区锥体神经元迟发性死亡的情况：结果：全脑缺血72h间隔亚组的大鼠,脑缺血过程中的反应、脑缺血后的一般状况和锥体神经元迟发性死亡程度均明显重于全脑缺血24h间隔亚组及48h间隔亚组,但24h间隔亚组与48h间隔亚组之间无显著差异一单侧椎动脉凝闭＋双侧颈总动脉夹闭组大鼠的凝闭侧瞳孔散大、对光反射消失、海马CA1区神经元大量死亡;而未凝闭侧未见上述相关变化。结论：凝闭双侧椎动脉本身也具有脑缺血预处理样作用,对其后48h内夹闭双侧颈总动脉所致的严重脑缺血具有一定程度的保护作用;大鼠椎动脉对脑干及海马的血液供应均存在明显的同侧优势效应,     

A Dual-Probe Microdialysis Study in Simultaneously Monitoring Extracellular Pyruvate, Lactate, and Biogenic Amines in Gerbil Striata during Unilateral Cerebral Ischemia

A dual-probe microdialysis technique coupled with liquid chromatographic assays was developed for the simultaneous monitoring of neurochemicals in gerbil striata during cerebral ischemia. Isocratic separation of lactate and pyruvate was achieved within 5 min whereas the separation of biogenic amines was completed within 30 min. An unilateral ligation was produced by occlusion of the right common carotid artery for 30 mins in anethetized gerbils to perform a typical focal cerebral ischemia. Microdialysis probes were inserted in both sides of the striata to simultaneously monitor biogenic amines, lactate and pyruvate during cerebral ischemia. Dynamic and comparative changes of these analytes in ipsilateral and contralateral sides of the brain can be simultaneously measured by the assay. The present assay can be used as a research tool to explore neurochemical substances and their relationships during cerebral ischemia.     

Brain cholecystokinin-8 immunoreactivity in rats with experimental liver cirrhosis

Cholecystokinin-8 like immunoreactivity (CCK-8 IR) was measured in different brain regions of rats with experimental liver cirrhosis. A statistically significant reduction of CCK-8 content was observed in the hypothalamus of cirrhotic rats. No significant modification of brain CCK fractionation pattern was observed in treated animals as compared to controls. The decrease of CCK-8 IR parallels the recently reported hypothalamic depletion of beta endorphin in cirrhotic rats confirming that central neuropeptides are affected by chronic liver failure.     

Elevated γ-Aminobutyric Acid Levels Attenuate the Metabolic Response to Biateral Ischemia

Bilateral ischemia has been shown to alter the net brain levels of energy metabolites such as ATP, phosphocreatine, glucose, and glycogen. The amino acid neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on neural activity. The present studies were designed to evaluate the influence of elevated GABA levels on the metabolic sequelae of ischemia. The GABA transaminase inhibitor gamma-vinyl-GABA (GVG; vigabatrin) was administered to Mongolian gerbils before the production of a bilateral ischemic incident. GABA levels were elevated in all regions assayed. Levels of energy metabolites were also increased, an indication of reduced energy utilization. In control animals, in the absence of GVG, 1 min of bilateral ischemia produced decreases in the levels of all metabolites. In animals pretreated with GVG, the effects of 1 min of bilateral ischemia were attenuated. These data suggest that the level of ongoing activity may affect the response to an ischemic insult. Furthermore, GVG may have a clinical indication in reducing the effect of minor ischemic incidents.     

mito KATP和κ-阿片受体介导肢体缺血后处理对抗大鼠脑缺血／复灌损伤

目的：观察肢体缺血后处理（LIPC）在大鼠局灶性脑缺血／复灌损伤中的神经保护作用及其作用机制。方法：将大鼠随机分为6组：空白对照组,单侧LIPC组,双侧LIPC组（bLIPC）,bLIPC＋mito KATP阻断剂5-lydroxydecanoate（5-HD））预处理组,bLIPC＋κ-阿片受体拮抗剂nor-binaltorphimine（nor-BNI）预处理组,bLIPC＋双侧后肢体外循环组。采用线栓法建立大鼠大脑中动脉栓塞（MCAO）模型,术后进行神经系统症状评分,血浆强啡肽和脑啡肽水平测定,大脑梗死面积测定。结果：单侧L1PC能改善大鼠局灶性脑缺血／复灌损伤后的神经系统功能评分（P〈0．05）,并减少大脑梗死面积（P〈0．01）;而双侧12PC能显著提高大鼠局灶性脑缺血／复灌损伤后的神经系统功能评分,并显著减少大脑梗死面积（P〈0．01）,比单侧LIPC的作用更为明显（P〈0．05）。双侧L／PC后5、15、30min,1和2h这五个时间点,血浆强啡肽水平显著增高（P〈0．01）,12和24h这两个时间点恢复至正常水平;而血浆脑啡肽水平的改变与双侧LIPC前比较无显著差异（P〉0．05）。nor-BNI预处理（25nmol）和5-HD预处理（10mg／kg）均消除了双侧LIPC所致的神经系统功能评分增加和大脑梗死面积减少（P〈0．01）。结论：LIPC在大鼠局灶性脑缺血／复灌损伤中具有显著的神经保护作用,其作用可能与LIPC诱导内源性阿片激动剂释放和激活mito KATP有关。