FeTPPS protects against global cerebral ischemic-reperfusion injury in gerbils.

Neuronal damage following cerebral ischemia is mediated by various mechanisms, among which nitrosative stress plays an important role. Peroxynitrite, a powerful oxidant, contributes heavily to the neuronal damage in cerebral ischemic-reperfusion (IR) injury. In the present study, we have investigated the neuroprotective effects of a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] in global cerebral IR injury in gerbils. Neurological damage was significantly attenuated by FeTPPS treatment (1 and 3mgkg(-1), i.p.) as evident from reduction in neurological symptoms, hyperlocomotion, memory impairment and CA1 hippocampal neuronal damage in IR challenged gerbils. FeTPPS treatment also attenuated the increased malondialdehyde (MDA) levels and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells after cerebral IR injury. Results of this study demonstrates the neuroprotective activity of FeTPPS in global cerebral IR injury and its neuroprotective effects may be attributed to reduction in oxidative stress and DNA fragmentation.     

Neuroprotective effects of FeTMPyP: a peroxynitrite decomposition catalyst in global cerebral ischemia model in gerbils.

Peroxynitrite involvement has been implicated in the neuronal damage. In the present study, we have investigated the neuroprotective effects of peroxynitrite decomposition catalyst (FeTMPyP) on global cerebral ischemia. Global cerebral ischemia-reperfusion (IR) injury was produced by 5 min occlusion of both common carotid arteries followed by reperfusion of 96 h in the adult male Mongolian gerbils. The extent of injury was assessed behaviorally by measuring neurological functions, locomotor activity, passive avoidance test and by histopathological evaluation of extent of damage to CA1 hippocampal pyramidal region. FeTMPyP (1 and 3 mgkg(-1), i.p., administered 30 min prior to ischemia) treatment improved the neurological functions, reduced the hyperlocomotion and memory impairment in IR challenged gerbils. The loss of neurons from the pyramidal layer of the CA1 region caused by global IR injury was attenuated with FeTMPyP. FeTMPyP also inhibited lipid peroxidation as evident from reduction in brain malondialdehyde levels. These results suggest that peroxynitrite decomposition catalyst may be effective neuroprotective agent for global cerebral ischemia.     

Neuroprotective effect of MnTMPyP, a superoxide dismutase/catalase mimetic in global cerebral ischemia is mediated through reduction of oxidative stress and DNA fragmentation

Excessive generation of free radicals and decreased levels of the antioxidant enzymes such as superoxide dismutase (SOD) and catalase have been observed after brain ischemic reperfusion injury. In the present study, we have investigated the neuroprotective potential of MnTMPyP (Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), a SOD/Catalase mimetic in bilateral carotid artery occlusion model of global cerebral ischemia in Mongolian gerbils. Five minutes of bilateral carotid artery occlusion produced global cerebral ischemia, which was evident from the neurological deficits, spontaneous motor activity and the decrease in the number of viable hippocampal CA1 neurons. Global ischemia was also associated with increased levels of malondialdehyde, decreased levels of SOD and catalase, and increased TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) positive cells, indicating oxidative stress and DNA fragmentation. Administration of a single dose of MnTMPyP, 1 mg/kg i.p. (30 min before occlusion), produced no significant neuroprotection; however, 3 mg/kg i.p. (30 min before to occlusion) produced significant reduction in neurological score, spontaneous motor activity and CA1 pyramidal neuronal damage. MnTMPyP also attenuated the increased levels of malondialdehyde and improved the levels of SOD and catalase, and inhibited DNA fragmentation in the ischemic animals. Multiple administration of MnTMPyP, 3 mg/kg i.p. (three times: 30 min before, 1 h and 3 h after occlusion), produced better neuroprotection as compared to single dose administration. This study demonstrates that the neuroprotective effect of MnTMPyP in global ischemia is mediated through reduction in oxidative stress and DNA fragmentation.     

Therapeutic Effects of Policosanol and Atorvastatin against Global Brain Ischaemia-Reperfusion Injury in Gerbils

Stroke is the third cause of death and the first of permanent adult disability. Pretreatment with policosanol and atorvastatin has been effective in experimental models of cerebral ischaemia in rodents. The objective was to compare the therapeutic effects of policosanol and atorvastatin in a model of global cerebral ischaemia in gerbils. Gerbils were distributed into seven groups, a negative control and six with ischaemia-reperfusion-induced global cerebral ischemia (one vehicle positive control, two policosanol (100 and 200 mg/kg), two atorvastatin (10 and 20 mg/kg) and one aspirin (60 mg/kg) group). Treatments were given 4 h after ischaemia induction. Effects on ischemia-reperfusion-induced symptoms, hyperlocomotion, damage of pyramidal hipoccampal neurons and increased plasma oxidative markers were investigated. Positive, not negative controls, exhibited clinical symptoms, hyperlocomotion, neuronal damage and increased plasma oxidative markers. Policosanol (100 and 200 mg/kg) reduced significantly ischemia-reperfusion-induced symptoms, the frequency of symptomatic animals, histological scores of neuronal damage and plasma oxidative markers as compared with the positive control group. Atorvastatin (10 and 20 mg/kg) decreased significantly the symptoms and histological scores, but unchanged the frequency of symptomatic gerbils and oxidative variables. Only the highest dose of policosanol (200 mg/kg) and atorvastatin (20 mg/kg) reduced significantly ischemia reperfusion-induced hyperlocomotion, policosanol being the most effective. Aspirin 60 mg/kg lowered significantly symptom score, the rate of symptomatic gerbils and hyperlocomotion versus the positive controls, but failed to modify oxidative parameters. In conclusion, postreperfusion treatment with policosanol and atorvastatin was effective for ameliorating symptoms, hyperlocomotion and neurological damage of hippocampal CA1 neurons in gerbils with ischemia-reperfusion-induced global cerebral ischemia, but only policosanol reduced increased plasma oxidative variables.     

褪黑素对沙土鼠脑缺血再灌注损伤的保护作用

目的研究褪黑素(melatonin,MT)对沙土鼠脑缺血再灌注损伤的神经保护作用。方法用沙土鼠双侧颈总动脉结扎法建立全脑缺血再灌注损伤模型。用开场迷宫测试沙土鼠的定向运动活性的变化。用T迷宫测试沙土鼠的学习及工作记忆能力。光镜下观察缺血后d 7海马CA1区神经元组织形态学变化。结果缺血模型组沙土鼠定向运动活性较假手术组显著增高,学习及工作记忆能力降低。MT可降低沙土鼠的定向运动活性,提高沙土鼠的工作记忆能力;还可显著减轻海马CA1区锥体神经元的病理改变,且作用呈剂量依赖性。结论MT对沙土鼠全脑缺血再灌注损伤有保护作用。     

Protective effect of pifithrin-alpha on brain ischemic reperfusion injury induced by bilateral common carotid arteries occlusion in gerbils

Involvement of p53 has been implicated in apoptosis induced cell death in ischemic reperfusion injury. In the present study, we have investigated neuroprotective potential of pifithrin-alpha, a p53 inhibitor in bilateral common carotid arteries occlusion (5 min) model of global cerebral ischemia in Mongolian gerbils. Gerbils were treated with pifithrin-alpha 3 mg/kg, ip. 30 min prior to occlusion. There was a significant increase in neurological symptoms and locomotor activity in ischemic animals as compared with the sham-operated animals. Increase in neurological symptoms and locomotor activity was attenuated by pifithrin-alpha 3 mg/ kg, ip. Significant increase in the number of the surviving neurons in the hippocampal CA1 pyramidal region was observed in ischemic animals treated with pifithrin-alpha 3 mg/kg, ip. This study demonstrates the neuroprotective effect of pifithrin-alpha in global cerebral ischemia in gerbils.     

Suppression of hyperemia and DNA oxidation by indomethacin in cerebral ischemia

We investigated antioxidative activity and the effect of indomethacin, an agent that inhibits cyclooxygenase, on extracellular glutamate and cerebral blood flow in cerebral ischemia in gerbils. Pre-ischemic administration of indomethacin (5 mg/kg, i.p.) significantly rescued hippocampal CA1 neurons (9+/-6 cells/mm in the ischemia, 87+/-43 cells/mm in the indomethacin group, P<0.001). DNA fragmentation induced by ischemia was also examined using the terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) method and indomethacin reduced TUNEL positive cells (140+/-21 in the ischemia, 99+/-31 in the indomethacin group, P<0.01). In addition, indomethacin attenuated the increase in hippocampal blood flow during reperfusion, but not increased extracellular glutamate by ischemia. Eight-hydroxydeoxyguanosine (8-OH-dG), a highly sensitive marker of DNA oxidation, was measured 90 min following ischemia using high-pressure liquid chromatography. Indomethacin significantly decreased the level of ischemia-induced 8-OH-dG in the hippocampus (P<0.05). These results suggest that indomethacin may protect neurons by attenuating oxidative stress and reperfusion injury in ischemic insult.     

Systemic administration of a cholecystokinin analogue, ceruletide, protects against ischemia-induced neurodegeneration in gerbils.

The neuroprotective action of a cholecystokinin octapeptide analogue, ceruletide, was evaluated in models of cerebral ischemia using Mongolian gerbils. Ceruletide significantly suppressed the hyperactivity and amnesia induced by ischemia when injected s.c. 30 min before 5-min occlusion of the bilateral common carotid arteries at room temperature or immediately after their reperfusion. Ceruletide also reduced behavioral changes in ischemic gerbils whose body temperature was maintained at 37 degrees C during the 3-min occlusion. In these groups, delayed neuronal cell death in the hippocampal CA1 area following ischemia was markedly attenuated by s.c. administration of ceruletide. On the other hand, ceruletide could not inhibit the behavioral changes or the neurodegeneration induced in the hippocampal CA1 area by 5-min occlusion at 37 degrees C. These findings indicate that peripheral injection of ceruletide produces a neuroprotective action against moderate cerebral ischemia, which is the first evidence suggesting the efficacy of ceruletide in neurodegenerative diseases.     

Neuroprotective effects of trolox in global cerebral ischemia in gerbils

Stroke is a third leading cause of death and oxygen free radicals have been shown to be involved in its pathophysiology. In the present study, we have investigated neuroprotective potential of trolox, a free radical scavenger in bilateral carotid arteries occlusion (5 min) model of global cerebral ischemia in Mongolian gerbils. Gerbils were treated with trolox (3, 10 or 30 mg/kg, i.p.) 30 min prior to occlusion. There was a significant increase in neurological symptoms and locomotor activity in ischemic animals as compared with the sham-operated animals. These effects were attenuated by trolox 30 mg/kg, i.p. Significant increase in the number of the surviving neurons in the hippocampal CA1 pyramidal region was observed in ischemic animals treated with trolox 30 mg/kg, i.p. There was significant increase in the level of malondialdehyde (MDA) in ischemic animals indicating oxidative stress. Elevated levels of MDA in ischemic animals (25.79+/-3.34 microM/mg of protein) were reduced (16.43+/-3.32 microM/mg of protein) and (8.98+/-0.89 microM/mg of protein) by trolox 10 and 30 mg/kg, i.p., respectively. This study demonstrates the neuroprotective potential of trolox in global cerebral ischemia in gerbils.     

Effect of Pioglitazone on Excitotoxic Neuronal Damage in the Mouse Hippocampus

Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor γ agonist, is known to regulate inflammatory process and to have neuroprotective effects against neurological disorders. In the present study, we examined the effects of 30 mg/kg PGZ on excitotoxic neuronal damage and glial activation in the mouse hippocampus following intracerebroventricular injection of kainic acid (KA). PGZ treatment significantly reduced seizure-like behavior. PGZ had the neuroprotective effect against KA-induced neuronal damage and attenuated the activations of astrocytes and microglia in the hippocampal CA3 region. In addition, MPO and NFκB immunoreactivities in the glial cells were also decreased in the PGZ-treated group. These results indicate that PGZ had anticonvulsant and neuroprotective effects against KA-induced excitotocix injury, and that neuroprotective effect of PGZ might be due to the attenuation of KA-induced activation in astrocytes and microglia as well as KA-induced increases in MPO and NFκB.     

JNK通路在缺血预处理诱导海马神经元保护中的作用

目的探讨JNK通路在缺血预处理诱导海马神经元保护中的作用。方法♂蒙古沙土鼠,随机分为假手术组(SH)、缺血/再灌注组(I/R)、缺血预处理组(IP)、Anisomy-cin组(AN)、Curcumin组(CU)、Anisomycin复合IP组(AP)、Curcumin复合IP组(CP)及溶剂对照组(VE),每组据再灌注15min、2、4、6h、1、3、5及7d又分8个亚组。预定时间点行TUNEL海马CA1区凋亡细胞检测、免疫组化SP法检测p-JNK及Jun蛋白在海马CA1区的表达变化。结果IP、CU及CP可减少海马CA1区凋亡锥体细胞数(vsI/R,P<0.01),减弱CA1区再灌注各点p-JNK及Jun蛋白的表达水平(vsIR,P<0.01),该效应CP组>IP组>CU组。AN增加CA1区凋亡锥体细胞数(vsIR,P<0.01),增强CA1区再灌后1d内各点p-JNK及再灌后1～7d各点Jun蛋白表达水平(vsIR,P<0.01)。AP部分抵消IP保护效应。结论JNK通路激活参与沙土鼠海马CA1区缺血性神经元凋亡,缺血预处理可通过抑制CA1区JNK磷酸化、减少Jun蛋白表达而保护海马细胞和功能。抑制JNK通路激活可发挥缺血预处理相似的保护作用。     

Neuroprotective effects of genistein in Mongolian gerbils: estrogen receptor-β involvement

Genistein is a naturally occurring plant-derived phytoestrogen, present in the human diet, known to possess some beneficial effects. The present study investigated the effect of genistein on neuroprotection evaluated through electroencephalographic and behavioural correlates in a model of global cerebral ischemia in gerbils. Over the dose range tested, genistein (3 and 10 mg/kg), given 5 min after recirculation antagonized the ischemia-induced electroencephalographic total spectral power decrease 7 days after ischemia; fully prevented ischemia-induced hyperlocomotion evaluated 1 day after ischemia; reversed ischemia-induced memory impairment evaluated through both nest building behaviour and object recognition test; decreased malondialdehyde overproduction in the brain, evaluated 7 days after reperfusion; and fully promoted the survival of pyramidal cells in the CA(1) hippocampal subfield. The selective antagonist for estrogen receptor-β (ERβ), 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) given 30 min before carotid occlusion, fully prevented the neuroprotective effect of genistein at the dose of 3 mg/kg. These results demonstrate the neuroprotective effect of genistein through the activation of ERβ and provide further grounds for the growing interest concerning the true potential of phytoestrogens as compounds to beneficially affect brain injury without having the disadvantages of estrogens.     

Vanilloid VR1 receptor is involved in rimonabant-induced neuroprotection

Recently, a potential neuroprotective effect of rimonabant, independent of the CB1 receptor interaction, has been proposed. In the present study, the role of transient receptor potential channel vanilloid subfamily member 1, named VR1, on neuroprotective effect of rimonabant, on global cerebral ischemia in gerbils, was investigated. Rimonabant (0.05-3 mg kg-1), given i.p. 5 min after recirculation, dose dependently antagonized the ischemia-induced decrease in electroencephalographic (EEG) total spectral power and restored relative frequency band distribution 7 days after ischemia. Rimonabant (0.125-0.5 mg kg-1) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. At 7 days after ischemia, the survival of pyramidal cells, in the CA1 subfield, was respectively 91 and 96%, in the animals given rimonabant 0.25 and 0.5 mg kg-1, compared to the vehicle group. Higher doses were not protective.The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg-1. Capsazepine (0.01 mg kg-1), a selective VR1 vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA1 hippocampal neuronal loss. These findings suggest that VR1 vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.     

羟丁酸钠对沙土鼠脑缺血损伤的保护作用

目的　探讨羟丁酸钠 (SO)对沙土鼠全脑缺血有无保护作用 ,为其新的临床应用提供理论依据。方法　采用双侧颈总动脉结扎法制作全脑缺血 ( 10min)再灌注损伤模型 ,观察SO( 5 0 ,10 0 ,2 0 0mg·kg- 1,ip ,每日 1次 ,连续 7d)对脑缺血后神经功能和海马组织损伤的影响。缺血后d 3 ,d 7用开场行为测试法检测自发活动 ,d 4,d 5 ,d 6用T迷宫测试学习记忆能力 ,d 7进行海马CA1区神经元病理学检查。结果　SO能降低脑缺血沙土鼠的自发活动 ,提高其学习记忆能力 ,并且显著减轻海马CA1区锥体神经元的损伤 ,其作用呈剂量依赖性。结论　SO对脑缺血损伤有一定的保护作用。     

Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.     

米诺环素对沙鼠脑缺血再灌注脑组织病理变化的实验研究

目的：研究米诺环素对沙鼠脑缺血再灌注脑组织病理变化的影响。方法：采用夹闭双侧颈总动脉的方法制作沙鼠脑缺血再灌注模型,在电镜下观察米诺环素干预前后海马CA1区及额叶脑组织病理变化。结果与结论：随着沙鼠脑缺血再灌注时间的延长,线粒体、高尔基（氏）复合和内质网等肿胀程度加重,形成空泡、碎片、核固缩、核溶解等。米诺环素干预后损伤程度减轻,与缺血再灌注组比较有显著差异（P〈0．05）。     

美洛昔康对全脑缺血/再灌注大鼠脑损伤的作用观察

目的探讨美洛昔康对大鼠全脑缺血/再灌注损伤的保护作用。方法采用双侧颈总动脉夹闭合并低血压方法建立全脑缺血/再灌注大鼠模型。美洛昔康(1、3和5mg·kg-1)在缺血前30min腹腔注射给药。Morris水迷宫测定大鼠空间学习能力,病理切片HE染色观察海马神经元形态结构,免疫组化检测海马组织核转录因子NF-κB p65蛋白表达,生物酶学方法观察超氧歧化酶活性和丙二醛含量。结果美洛昔康能明显缩短全脑缺血/再灌注大鼠的寻台潜伏期,减轻全脑缺血/再灌注大鼠海马神经元损伤,降低海马神经元NF-κB p65蛋白表达,明显阻遏全脑缺血/再灌注大鼠海马MDA含量的升高和SOD活性的降低。结论美洛昔康对全脑缺血/再灌注致大鼠脑损伤有明显的保护作用,其机制可能与其抑制COX-2活性,减少PGs等代谢产物的产生,抑制NF-κB活性,从而抑制炎症反应和氧化应激功能有关。     

Protective effect of chronic ethyl docosahexaenoate administration on brain injury in ischemic gerbils

There is evidence that the excessive generation of reactive oxygen free radicals contributes to the brain injury associated with cerebral ischemia. In the present study, the protective effect of chronic administration of ethyl docosahexaenoate (E-DHA) against oxidative brain injury was evaluated in the gerbil model of transient cerebral ischemia. Weanling male gerbils were orally pretreated with either E-DHA (200 mg/kg) or vehicle, once a day, for 10 weeks and subjected to bilateral occlusion of common carotid arteries for 10 min. At the different reperfusion times, E-DHA pretreatment significantly inhibited the increases in the production of brain salicylate-derived 2,5-dihydroxybenzoic acid (2,5-DHBA) and content of brain malonildialdehyde (MDA). The superoxide dismutase (SOD) activity was not modified; however, pretreatment with E-DHA significantly prevented the level of brain-reduced glutathione (GSH) and activities of brain glutathione peroxidase (GSH-P(X)) and catalase (CAT) from declines caused by cerebral ischemia. Moreover, ischemia and reperfusion-induced delayed neuronal loss in the hippocampus CA1 sector and locomotor hyperactivity were also significantly attenuated by pretreatment with E-DHA. These results suggested that the neuroprotective effect of E-DHA might be due to its antioxidant property.     

Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats

Free radicals have been implicated in cerebral ischemia reperfusion (IR) injury. Massive production of nitric oxide and superoxide results in continuous formation of peroxynitrite even several hours after IR insult. This can produce DNA strand nicks, hydroxylation and/or nitration of cytosolic components of neuron, leading to neuronal death. Peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron (III) (FeTMPyP) and 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (FeTPPS) have been demonstrated to protect neurons in in vitro cultures; however, their neuroprotective efficacy in cerebral IR injury has not been explored. In the present study, we investigated the efficacy and the therapeutic time window of FeTMPyP and FeTPPS in focal cerebral ischemia (FCI). FCI was induced according to the middle cerebral artery occlusion (MCAO) method. After 2 h of MCAO and 70 h of reperfusion, the extent of neurological deficits, infarct and edema volume were measured in Sprague-Dawley rats. FeTMPyP and FeTPPS were administered at different time points 2, 6, 9 and 12 h post MCAO. FeTMPyP and FeTPPS (3 mg kg(-1), i.v.) treatment at 2 and 6 h post MCAO produced significant reduction in infarct volume, edema volume and neurological deficits. However, treatment at latter time points did not produce significant neuroprotection. Significant reduction of peroxynitrite in blood and nitrotyrosine in brain sections was observed on FeTMPyP and FeTPPS treatment. As delayed treatment of FeTMPyP and FeTPPS produced neuroprotection, we tested whether treatment had any influence over the apoptotic neuronal death. DNA fragmentation and in situ nick end-labeling assays showed that FeTMPyP and FeTPPS treatment reduced IR injury-induced DNA fragmentation. In conclusion, peroxynitrite decomposition catalysts (FeTMPyP and FeTPPS) produced prominent neuroprotection even if administered 6 h post MCAO and the neuroprotective effect is at least in part due to the reduction of peroxynitrite and apoptosis.     

Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils

Global ischemia, induced in Mongolian gerbils by bilateral occlusion of the carotid arteries for 5 min, produced a significant increase in locomotor activity at 1 day post-occlusion and a severe loss of hippocampal CA1 neurons at 4 days post-occlusion. To explore the pharmacological relationship between ischemia-induced hypermotility and CA1 cell death in the hippocampus, we evaluated the efficacy of diverse classes of putative neuroprotective agents for preventing hypermotility and delayed neuronal death. Administration of any drug 30 min before global ischemia dose-dependently, and with similar potency, ameliorated both hippocampal delayed neuronal death and locomotor hyperactivity, with a rank order: tacrolimus (FK506)>nizofenone>clonindine>dizocilpine (MK-801)>6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K)>phencyclidine>pentobarbital>2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride (E-2001)>cis-(+/-)-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755)>3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488H)>piroxicam>eliprodil>vinpocetine. Furthermore, potencies of the protective effect on delayed neuronal death and inhibitory effects on hypermotility were closely correlated (r=0.98). These results suggest that post-ischemic CA1 injury and hypermotility share common mechanisms, and further imply that it is possible to predict the neuroprotective efficacy of drugs more easily by examining the inhibitory effects on post-ischemic hypermotility in global ischemia model in gerbils.