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Evaluating the efficacy of citicoline in embolic ischemic stroke in rats: Neuroprotective effects when used alone or in combination with urokinase

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EXPERIMENTAL NEUROLOGY 2000年第2期161卷 733-739页

作者： Shuaib, A Yang, Y Li, Q Univ Alberta Dept Med Neurol Edmonton AB T6G 2G7 Canada Univ Alberta Stroke Res Unit Edmonton AB T6G 2G7 Canada

The combination of thrombolysis with neuroprotection, because of different mechanisms, would be expected to show better results when used after onset of focal ischemia, In this study we report our experience with the neuronal protective effects of citicoline alone and in combination with urokinase in a model of focal ischemia. Both medications were injected 2 h after onset of a focal occlusion of the middle cerebral artery (MCA) in rats. Focal ischemia was produced with embolization of a clot into the origin of the MCA. This produces a large infarction involving the cortex and the basal ganglia. Animals were observed for neuronal deficts at 2 and 24 h after surgery and were sacrificed 72 h after onset of ischemia, Saline-treated animals showed a large infarction involving the cerebral cortex and basal ganglion in most animals (volume 33.1 +/- 9.7%). Animals treated with citicoline alone were divided in two groups, The first group of animals were treated with a single injection (300 mg/kg, ip) of the medication 2 h after the arterial occlusion. The second group was treated with the active medication intermittently (3 x 300 mg/kg, ip) over a 72-h period. There was a significant decrease in the neuronal damage in the cortex in the animals treated with citicoline (single dose, 20.9 +/- 9.7%, P = 0.01;intermittent injection, 18.9 +/- 11.4%, P < 0.008), The last experiment evaluated the usefulness of the combination of citicoline with intraarterial urokinase, The combination showed significantly more protection than with urokinase or citicoline alone (volume 13.6 +/- 9.1%, P < 0.001), We conclude from our experiments that citicoline may offer significant neuronal protection that may be further enhanced with the addition of a thrombolytic agent. (C) 2000 Academic Press.

关键词：大脑梗死/病理学大脑梗死/预防和控制胞苷二磷酸胆碱/治疗应用药物疗法联合颅内栓塞/药物疗法颅内栓塞/病理学颅内栓塞/病理生理学脑缺血发作短暂性/药物疗法脑缺血发作短暂性/病理学脑缺血发作短暂性/病理生理学运动活动/药物作用神经元/药物作用神经元/病理学神经保护药/治疗应用大鼠 Wistar 尿纤溶酶原激活物/治疗应用动物男(雄)性大鼠

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Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第13期97卷 7597-7602页

作者： Duan, ML Agerman, K Ernfors, P Canlon, B Karolinska Inst Dept Physiol & Pharmacol Mol Neurobiol Unit S-17177 Stockholm Sweden Karolinska Inst Dept Med Biochem & Biophys Mol Neurobiol Unit S-17177 Stockholm Sweden

Recent progress has been made regarding the prevention of hearing loss. However, the complete protection of both hair cells and spiral ganglion neurons, with restored function, has not yet been achieved. It has been shown that spiral ganglion neuronal loss can be prevented by neurotrophin 3 (NT3) and hair cell damage by N-methyl-D-aspartate (NMDA) receptor antagonists. Here we demonstrate that the combined treatment with MK801. a NMDA antagonist, and NT3 protect both cochlear morphology and physiology from injury. Pretreatment with MK801 prevented hearing loss and the dendrites of the spiral ganglion neurons from swelling after noise-induced damage. The acute phase of insult with the aminoglycoside antibiotic amikacin resulted in swollen afferent dendrites beneath the inner hair cells. The chronic phase resulted in complete hair cell loss and near-complete loss of spiral ganglion neurons. This damage caused a near-complete loss of hearing sensitivity as displayed by elevated (>90-dB sound pressure levels) auditory brainstem response thresholds. The treatment of amikacin-exposed animals with MK801 gave only a partial protection of hearing. However, the combined treatment with NT3 and MK801 in the amikacin-comprised ear resulted in improved mean hearing within 20 dB of normal. Furthermore, hair cell loss was prevented in these animals and spiral ganglion neurons were completely protected. These results suggest that the NMDA antagonist MK801 protects against noise-induced excitotoxicity in the cochlea whereas the combined treatment of NT3 and MK801 has a potent effect on preserving both auditory physiology and morphology against aminoglycoside toxicity.

关键词：耳蜗/药物作用耳蜗/病理学耳蜗/生理学聋/预防和控制地卓西平马来酸盐/药理学地卓西平马来酸盐/治疗应用药物疗法联合 N-甲基天冬氨酸/拮抗剂和抑制剂神经保护药/药理学神经保护药/治疗应用神经营养因子3/药理学神经营养因子3/治疗应用动物豚鼠

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Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 399-408页

作者： Tortella, FC Britton, P Williams, A Lu, XCM Newman, AH Walter Reed Army Inst Res Dept Neuropharmacol & Mol Biol Div Neurosci Washington DC 20307 USA NIDA Addict Res Ctr Drug Dev Grp Baltimore MD 21224 USA

AHN649, an analog of dextromethorphan (DM) and a relatively selective low-affinity N-methyl-D-aspartate antagonist, was evaluated for neuroprotective effects using the rat intraluminal filament model of temporary middle cerebral artery occlusion. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. In vehicle-treated rats, middle cerebral artery occlusion resulted in neurological deficits and severe infarction measuring 232 +/- 25 mm(3), representing approximately 25% contralateral hemispheric infarction. Post-treatment with AHN649 (0.156-20 mg/kg i.v.) or DM (0.156-10 mg/kg i.v.) significantly reduced cortical infarct volume by 40 to 60% compared with vehicle-control treatments. AHN649 neuroprotection was linear and dose dependent (ED50 = 0.80 mg/kg), whereas DM neuroprotection (ED50 = 1.25 mg/kg) was nonlinear and less effective at the higher doses (2.5-10 mg/kg). Although impaired neurological function scores improved in all groups by 24 to 72 h, the most dramatic improvement was associated with AHN649 treatments. In a rat electroencephalographic model of brain function, separate neurotoxicity experiments revealed that acute i.v. doses of DM caused seizures (ED50 = 19 mg/kg) and death (LD50 = 27 mg/kg). In contrast, AHN649 failed to induce seizure activity at doses up to 100 mg/kg (LD50 = 79 mg/kg). Collectively, AHN649 is described as a potent, efficacious neuroprotective agent devoid of serious central nervous system neurotoxicity and possessing potential therapeutic value as antistroke treatment. Furthermore, the feasibility of targeting low-affinity N-methyl-D-aspartate-site ligands as postinjury therapy for ischemic brain injury has been confirmed.

关键词：脑缺血/预防和控制脑动脉右美沙芬/类似物和衍生物右美沙芬/药理学右美沙芬/治疗应用剂量效应关系药物脑电描记术/药物作用兴奋性氨基酸拮抗剂/药理学兴奋性氨基酸拮抗剂/治疗应用兴奋性氨基酸类神经保护药/药理学神经保护药/治疗应用神经毒素类/药理学大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂再灌注动物男(雄)性大鼠

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Oxidative injury in diseases of the central nervous system:: Focus on Alzheimer's disease

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AMERICAN JOURNAL OF MEDICINE 2000年第7期109卷 577-585页

作者： Praticò, D Delanty, N Beaumont Hosp Royal Coll Surg Ireland Dept Clin Neurol Sci Dublin 9 Ireland Univ Penn Dept Pharmacol Philadelphia PA 19104 USA Univ Penn Ctr Expt Therapeut Philadelphia PA 19104 USA Beaumont Hosp Div Neurol Dublin 9 Ireland

Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease. Am J Med. 2000;109:577-585. (C) 2000 by Excerpta Medica, Inc.

关键词：阿尔茨海默病/药物疗法阿尔茨海默病/代谢淀粉样β蛋白/代谢动物基因修饰抗氧化剂/治疗应用抗坏血酸/治疗应用苯醌类/治疗应用中枢神经系统/药物作用中枢神经系统/代谢中枢神经系统疾病/药物疗法中枢神经系统疾病/代谢药物疗法联合自由基/代谢银杏/治疗应用脂质过氧化作用/药物作用神经保护药/治疗应用氧化还原/药物作用植物药疗法植物药用司立吉林/治疗应用维生素E/治疗应用动物人类

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Alzheimer's disease and oxidative stress: Implications for novel therapeutic approaches

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PROGRESS IN NEUROBIOLOGY 1999年第3期57卷 301-323页

作者： Behl, C Max Planck Inst Psychiat D-80804 Munich Germany

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a deadly outcome. AD is the leading cause of senile dementia and although the pathogenesis of this disorder is not known, various hypotheses have been developed based on experimental data accumulated since the initial description of this disease by Alois Alzheimer about 90 years ago. Most approaches to explain the pathogenesis of AD focus on its two histopathological hallmarks, the amyloid beta protein- (A beta-) loaded senile plaques and the neurofibrillary tangles, which consist of the filament protein tau. Various lines of genetic evidence support a central role of A beta in the pathogenesis of AD and an increasing number of studies show that oxidation reactions occur in AD and that A beta may be one molecular link between oxidative stress and AD-associated neuronal cell death. A beta itself can be neurotoxic and can induce oxidative stress in cultivated neurons. A beta is, therefore, one player in the concert of oxidative reactions that challenge neurons besides inflammatory reactions which are also associated with the AD pathology. Consequently, antioxidant approaches for the prevention and therapy of AD are of central interest. Experimental as well as clinical data show that lipophilic antioxidants, such as vitamin E and estrogens, are neuroprotective and may help patients suffering from AD. While an additional intensive elucidation of the cellular and molecular events of neuronal cell death in AD will, ultimately, lead to novel drug targets, various antioxidants are already available for a further exploitation of their preventive and therapeutic potential. (C) 1998 Elsevier Science Ltd. All rights reserved.

关键词：阿尔茨海默病/药物疗法阿尔茨海默病/遗传学阿尔茨海默病/代谢阿尔茨海默病/病理学淀粉样β蛋白/生理学消炎药/治疗应用抗氧化剂/治疗应用雌激素类/治疗应用神经保护药/治疗应用氧化性应激/生理学人类

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Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第19期97卷 10526-10531页

作者： Brines, ML Ghezzi, P Keenan, S Agnello, D de Lanerolle, NC Cerami, C Itri, LM Cerami, A Kenneth S Warren Labs Tarrytown NY 10591 USA Mario Negri Inst Pharmacol Res Lab Neuroimmunol I-20157 Milan Italy Yale Univ Sch Med Dept Neurosurg New Haven CT 06520 USA Ortho Biotech Inc Raritan NJ 08869 USA

Erythropoietin (EPO), recognized for its central role in erythropoiesis, also mediates neuroprotection when the recombinant form (r-HuEPO) is directly injected into ischemic rodent brain. We observed abundant expression of the EPO receptor at brain capillaries, which could provide a route for circulating EPO to enter the brain. In confirmation of this hypothesis, systemic administration of r-Hu-EPO before or up to 6 h after focal brain ischemia reduced injury by approximate to 50-75%. R-Hu-EPO also ameliorates the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate, Given r-Hu-EPO's excellent safety profile, clinical trials evaluating systemically administered r-HuEPO as a general neuroprotective treatment are warranted.

关键词：生物素/代谢血脑屏障脑损伤/预防和控制红细胞生成素/代谢红细胞生成素/药代动力学红细胞生成素/治疗应用红藻氨酸/毒性小鼠近交BALBC 神经保护药/代谢神经保护药/药代动力学神经保护药/治疗应用大鼠近交Lew 大鼠 Sprague-Dawley 受体红细胞生成素/代谢重组蛋白质类发作/化学诱导发作/病理生理学发作/预防和控制动物女(雌)性男(雄)性小鼠大鼠

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Role for GDNF in biochemical and behavioral adaptations to drugs of abuse

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NEURON 2000年第1期26卷 247-257页

作者： Messer, CJ Eisch, AJ Carlezon, WA Whisler, K Shen, L Wolf, DH Westphal, H Collins, F Russell, DS Nestler, EJ Yale Univ Sch Med Lab Mol Psychiat New Haven CT 06508 USA Yale Univ Sch Med Yale Ctr Genes & Behav New Haven CT 06508 USA Connecticut Mental Hlth Ctr New Haven CT 06508 USA NIH Lab Mammalian Genes & Dev Bethesda MD 20892 USA Amgen Inc Thousand Oaks CA 91320 USA

The present study examined a role for GDNF in adaptations to drugs of abuse. Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic brain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusion of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of phosphoRet, the protein kinase that mediates GDNF signaling, in the VTA. Together, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increases the behavioral sensitivity to subsequent drug exposure.

关键词：行为成瘾/药物疗法行为成瘾/代谢可卡因/药理学多巴胺摄取抑制剂/药理学胶质细胞源性神经营养因子小鼠基因敲除吗啡/药理学运动活动/药物作用运动活动/生理学麻醉品/药理学神经生长因子类神经组织蛋白质类/代谢神经组织蛋白质类/药理学神经组织蛋白质类/治疗应用神经保护药/代谢神经保护药/药理学神经保护药/治疗应用大鼠 Sprague-Dawley 江湖药/代谢腹侧被盖区/药物作用腹侧被盖区/代谢动物男(雄)性小鼠大鼠

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Cerebral protection in severe brain injury: physiological determinants of outcome and their optimisation

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BRITISH MEDICAL BULLETIN 1999年第1期55卷 226-258页

作者： Menon, DK Univ Cambridge Addenbrookes Hosp Dept Anaesthesia Sch Clin Cambridge CB2 2QQ England

The primary role of intensive care in acute head injury lies in the prevention, detection and reversal of secondary neuronal injury. The maintenance of optimal systemic and cerebrovascular physiology can substantially contribute to these aims. There is, however, a role for novel neuroprotective interventions, many of which are currently under investigation.

关键词：脑损伤/病理生理学脑损伤/治疗内环境稳定重症监护/方法监测生理学/方法神经保护药/治疗应用预后危险因素人类

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New perspectives on developing acute stroke therapy

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ANNALS OF NEUROLOGY 2003年第1期53卷 10-20页

作者： Fisher, M Ratan, R Univ Massachusetts Sch Med Dept Neurol Worcester MA 01605 USA Harvard Univ Sch Med Dept Neurol Neurosci Boston MA USA Beth Israel Deaconess Med Ctr Boston MA 02215 USA

The development of additional acute stroke therapies to complement and supplement intravenous recombinant tissue-type plasminogen activator within the first 3 hours after stroke onset remains an important and pressing need. Much has been teamed about the presumed target of acute stroke therapy, the ischemic penumbra, and clinically available imaging modalities such as magnetic resonance imaging and computed tomography hold great promise for at least partially identifying this region of potentially salvageable ischemic tissue. Understanding the biology of ischemia-related cell injury has also evolved rapidly. New treatment approaches to improve outcome after focal brain ischemia will likely be derived by looking at naturally occurring adaptive mechanisms such as those related to ischemic preconditioning and hibernation. Many clinical trials previously performed with a variety of neuroprotective and thrombolytic drugs provide many lessons that will help to guide future acute stroke therapy trials and enhance the likelihood of success in future trials. Combining knowledge from these three areas provides optimism that additional acute stroke therapies can be developed to maximize beneficial functional outcome in the greatest proportion of acute stroke patients possible.

关键词：急性病纤维蛋白溶解药/治疗应用神经保护药/治疗应用动物人类

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Optimization of magnesium therapy after severe diffuse axonal brain injury in rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1311-1316页

作者： Heath, DL Vink, R James Cook Univ N Queensland Dept Physiol & Pharmacol Townsville Qld 4811 Australia

A number of studies have demonstrated that magnesium salts given after traumatic brain injury improve subsequent neurologic outcome. However, given that these earlier studies have used a number of different salts, dosages, and routes of administration, follow-up studies of the neuroprotective properties of magnesium are complicated, with comparisons to the earlier literature virtually impossible. The present study has therefore characterized the dose-response characteristics of the most commonly used sulfate and chloride salts of magnesium in a severe model of diffuse traumatic axonal injury in rats. Both magnesium salts improved neurologic outcome in rats when administered as a bolus at 30 min after injury. The i.v. and i.m. optima of each salt was 250 mu mol/kg and 750 mu mol/kg, respectively. The identical concentrations required for improved neurologic outcome suggest that improvement in outcome was dependent on the magnesium cation and not the associated anion. Subsequent magnetic resonance studies demonstrated that the administered magnesium penetrated the blood-brain barrier after injury and resulted in an increased brain intracellular free magnesium concentration and associated bioenergetic state as reflected in the cytosolic phosphorylation potential. Both of these metabolic parameters positively correlated with resultant neurologic outcome measured daily in the same animals immediately before the magnetic resonance determinations.

关键词：脑/代谢脑损伤/药物疗法脑损伤/代谢剂量效应关系药物氯化镁/治疗应用镁化合物/代谢镁化合物/治疗应用硫酸镁/治疗应用磁共振波谱学神经病学检查神经保护药/治疗应用大鼠 Sprague-Dawley 时间因素动物男(雄)性大鼠

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