摘要:

Background and Purpose—Fibroblast growth factor 18 (FGF18) is expressed in rodent brain and is a trophic factor for neuron-derived cells in culture. The purpose of the present study was to evaluate whether FGF18 was neuroprotective in a rat model of cerebral ischemia and to compare the results with those obtained with FGF2.Methods—Cerebral ischemia was produced in rats by a transient 2-hour occlusion of the middle cerebral artery (MCAo) with an intraluminal filament followed by 22-hour reperfusion. Starting 15 minutes after MCAo, FGF18 or FGF2 was administered by a 3-hour intravenous infusion. Infarct volumes and behavioral deficits were measured 24 hours after MCAo.Results—Infusion of FGF18 produced dose-dependent reductions in infarct volumes and improvements in tests of reference and working memory, motor ability, and exploratory behavior. FGF18 was more efficacious than FGF2 on virtually all measures examined. The reductions in infarct volume and behavioral deficit were associated with FGF-mediated increases in regional cerebral blood flow.Conclusions—These results demonstrate that FGF18 is an effective neuroprotective agent in a rat model of transient MCAo.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—The serine-threonine kinase Akt is activated by phosphorylation at serine-473. After phosphorylation, activated Akt inactivates BAD or caspase-9 or other apoptogenic components, thereby inhibiting cell death. In this study we examined the relationship between Akt phosphorylation and oxidative stress after transient focal cerebral ischemia (FCI) using copper-zinc superoxide dismutase (SOD1) transgenic (Tg) mice.Methods—The mice were subjected to 60 minutes of middle cerebral artery occlusion by intraluminal suture blockade followed by 1, 4, and 24 hours of reperfusion. Phospho-Akt expression was examined by immunohistochemistry and Western blot analysis. Production of superoxide anion was assessed by the hydroethidine method in both wild-type mice and SOD1 Tg mice. DNA fragmentation was evaluated by terminal deoxynucleotidyl transferase–mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL).Results—Immunohistochemistry demonstrated that phospho-Akt was constitutively expressed and was decreased in the ischemic core as early as 1 hour after reperfusion, whereas it was temporally increased in the cortex at 4 hours. Phospho-Akt expression was enhanced in the SOD1 Tg mice. Western blot analysis showed that phospho-Akt was maximized 4 hours after reperfusion in the wild-type mice, whereas phospho-Akt was increased as early as 1 hour after ischemia in the SOD1 Tg mice. There was a significant decrease in TUNEL-positive cells in the SOD1 Tg mice compared with the wild-type mice.Conclusions—The present study suggests that SOD1 may contribute to the early activation of the Akt cell survival signaling pathway and may attenuate subsequent DNA damage after transient FCI.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Progenitor cells continue to generate neurons in the adult mammalian brain, and cerebral ischemia induces neurogenesis. We examined the efficacy of the intraventricular injection of a recombinant adenovirus-expressing fibroblast growth factor-2 (FGF-2) (AxCAMAssbFGF) on neurogenesis in both normal and ischemic brains.Methods—We used a gerbil model of transient global ischemia and counted the number of BrdU-positive cells after injection of AxCAMAssbFGF into the brain with or without ischemia.Results—Intraventricular AxCAMAssbFGF produced robust FGF-2 protein increases in diverse regions of the brain and markedly increased FGF-2 concentrations in cerebrospinal fluid 2 days after administration and evoked significant proliferation of BrdU-positive cells not only in the subventricular zone and dentate gyrus of the hippocampus but also in the cerebral cortex, and some BrdU-positive cells differentiated into neurons. Continuous intraventricular infusion of FGF-2 protein increased FGF-2 concentration in cerebrospinal fluid but not in brain tissues and produced BrdU-positive cell proliferation only in the subventricular zone of the lateral ventricle.Conclusions—Adenovirally mediated transfer of the FGF-2 gene promoted progenitor cell proliferation more efficiently in widespread regions of the brain after transient global ischemia than continuous intraventricular infusion of FGF-2 protein.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—A combined therapeutic approach has been advocated repeatedly for treatment of focal cerebral ischemia. A clinical example of combined therapy is administration of nimodipine, mannitol, dexamethasone, and barbiturates during temporary occlusion of a cerebral artery in neurovascular surgery. We have recently demonstrated outstanding neuroprotective properties of a combination therapy with magnesium (calcium antagonist and glutamate antagonist), tirilazad (antioxidant), and mild hypothermia (MTH). In this study we compared this treatment strategy with the customary treatment options in a rat model of transient focal cerebral ischemia.Methods—Sprague-Dawley rats (n=120) were subjected to 90 minutes of middle cerebral artery occlusion by an intraluminal filament (n=10 per group). In experiment 1, the customary treatment options (nimodipine, mannitol, dexamethasone, methohexital) were evaluated as monotherapy and in combination. In experiment 2, the customary and the new combination therapy (MTH) were compared. Mild hypothermia (33°C) was maintained for 2 hours. Neurological examinations were performed daily. Infarct size was assessed histologically after 7 days.Results—In experiment 1, infarct volume was attenuated by 34% at maximum, with mannitol and methohexital being the most effective drugs given as monotherapy. In experiment 2, combined administration of the customary treatment options had no additive effect (infarct volume −36%). Combination therapy with MTH reduced total infarction by 73% and almost completely abolished cortical infarction (−91%). None of the animals of this group had any residual neurological deficit at the end of the observation period (P<0.05 versus all other groups).Conclusions—The efficacy of drugs (monotherapy or in combination) most commonly used for neuroprotection during neurovascular surgery is limited. The newly proposed combination therapy (magnesium, tirilazad, and mild hypothermia), which is based on pathophysiological considerations, seems to be a promising alternative for neuroprotection in cerebrovascular surgery.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—&kgr;-Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl) methylpiperidine], on infarct volume and nitric oxide production after transient focal ischemia in the rat.Methods—With the use of the intraluminal filament technique, halothane-anesthetized male Wistar rats (weight, 250 to 300 g) were subjected to 2 hours of focal cerebral ischemia confirmed by Doppler flowmetry. In a blinded randomized fashion, rats were treated with intravenous saline or 1 mg/kg per hour BRL 52537 infusion, initiated 15 minutes before occlusion and maintained until 2 hours of reperfusion. In a second experiment, rats were treated during reperfusion with saline or 1 mg/kg per hour BRL 52537, initiated at onset of reperfusion and continued for 22 hours. In a final experiment, in vivo striatal nitric oxide production was estimated via microdialysis by quantification of citrulline recovery after labeled arginine infusion in striatum of intravenous BRL 52537– or saline-treated rats.Results—In rats treated with BRL 52537 during ischemia and early reperfusion, infarct volume was significantly attenuated in cortex (16±6% versus 40±7% of ipsilateral cortex in saline group) and in caudoputamen (30±8% versus 66±6% of ipsilateral caudoputamen in saline group). Infarct volume was also reduced by treatment administered only during reperfusion in cortex (19±8% in BRL 52537 group [n=10] versus 38±6% in saline group) and in caudoputamen (35±9% versus 66±4% in saline group). BRL 52537 treatment markedly attenuated NO production in ischemic striatum compared with saline-treated controls.Conclusions—These data demonstrate that (1) the selective KOR agonist BRL 52537 provides significant neuroprotection from focal cerebral ischemia when given as a pretreatment or as a posttreatment and (2) attenuation of ischemia-evoked nitric oxide production in vivo may represent one mechanism of ischemic neuroprotection.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The development of acute stroke therapy has proven to be a daunting task, with a few successful and many unsuccessful trials. New strategies need to be considered to enhance the chances for success in future trials.Summary of Review—The third Stroke Therapy Academic Industry Roundtable (STAIR) conference focused on issues related to increasing the percentage of acute stroke patients who might be included in acute stroke therapy trials and ultimately treated with drugs proven to be effective. A second focus was directed at the need for implementing multimodality stroke trials and potential ways to organize such trials in the near future. Finally, concepts for organizing and implementing acute stroke trials that incorporate current, state of the art trial methodology were discussed.Conclusions—It is hoped that these suggestions will enhance future stroke trials and the development of effective, new acute stroke treatments that are maximally effective and utilized.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—In brain blood vessels, electrophysiological studies proving the existence of ATP-sensitive potassium channels (KATP) are scarce. However, numerous pharmacological studies establish the importance of KATPchannels in these blood vessels. This review emphasizes the data supporting the importance of vascular KATPin the responses of brain blood vessels.Summary of Review—Electrophysiological data show the existence of KATPin smooth muscle and endothelium of brain vessels. A much larger number of studies in virtually all experimental species have shown that classic openers of KATPdilate brain arteries and arterioles. This response can by blocked by glibenclamide, a selective inhibitor of KATPopening. Several physiological or pathophysiological responses are also blocked by glibenclamide. KATPcontains a multiplicity of potential sites of interaction with drugs of diverse, sometimes unrelated, structures. Drugs with imidazole or guanidinium groups are particularly likely to have effects on KATP. This complicates interpretation of the actions of such drugs when used as supposedly selective pharmacological probes for other putative targets. A pH-sensitive site on the internal surface of cloned channels may explain the glibenclamide-inhibitable dilation produced by intracellular acidosis and perhaps by CO2. In some situations KATPappears to be involved in either the synthesis/release or action of endothelium-derived mediators of cerebrovascular tone. The importance of KATPmay be dependent on the portion of the cerebrovascular tree being studied and on diverse experimental conditions, age, species, and the presence of disease.Conclusions—KATPhave been shown to mediate a wide range of cerebrovascular response in physiologic or pathologic circumstances in a variety of experimental conditions. Their relevance to cerebrovascular responses in humans remains to be explored.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The precise mechanisms of and biological basis for motor recovery after stroke in adults are still largely unknown. Reorganization of the motor system after stroke as assessed by functional neuroimaging is an intriguing but challenging new field of research. Provocative but equivocal findings have been reported to date.Summary of Review—We present an overview of functional neuroimaging studies (positron emission tomography or functional MRI) of motor tasks in patients recovered or still recovering from motor deficit after stroke. After a brief account of the connectivity of motor systems and the imaging findings in normal subjects, the literature concerning stroke patients is reviewed and discussed, and a general model is proposed.Conclusions—Both cross-sectional and longitudinal studies have demonstrated that the damaged adult brain is able to reorganize to compensate for motor deficits. Rather than a complete substitution of function, the main mechanism underlying recovery of motor abilities involves enhanced activity in preexisting networks, including the disconnected motor cortex in subcortical stroke and the infarct rim after cortical stroke. Involvement of nonmotor and contralesional motor areas has been consistently reported, with the emerging notion that the greater the involvement of the ipsilesional motor network, the better is the recovery. This hypothesis is supported by the enhanced activity of the ipsilesional primary motor cortex induced by motor training and acute pharmacological interventions, in parallel with improved motor function. Further longitudinal studies assessing the relationships between such changes and actual recovery, as well as manipulating such changes by rehabilitation or pharmacological maneuvers, should provide further information on these fundamental questions. This review closes with some perspectives for future research.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID