dizocilpine-maleate has been researched along with Infarction--Middle-Cerebral-Artery* in 32 studies
1 review(s) available for dizocilpine-maleate and Infarction--Middle-Cerebral-Artery
1 trial(s) available for dizocilpine-maleate and Infarction--Middle-Cerebral-Artery
31 other study(ies) available for dizocilpine-maleate and Infarction--Middle-Cerebral-Artery
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Homocysteine can aggravate depressive like behaviors in a middle cerebral artery occlusion/reperfusion rat model: a possible role for NMDARs-mediated synaptic alterations.
Post-stroke depression (PSD), the most frequent psychiatric complication following stroke, could have a negative impact on the recuperation of stroke patients. Hyperhomocysteinemia (HHCY) has been reported to be a modifiable risk factor of stroke.. The study tries to explore the effect of HHCY on PSD and the role of N-methyl-d-aspartate receptors (NMDARs)-mediated synaptic alterations.. Forty-five adult male Sprague-Dawley rats were randomly allocated into five groups: sham operation group, middle cerebral artery occlusion group (MCAO), HCY-treated MCAO group HCY and MK-801 co-treated MCAO group and MK-801-treated MCAO group. 1.6 mg/kg/d D, L-HCY was administered by tail vein injection for 28 d prior to SHAM or MCAO operationand up to 14 d after surgery. The MK-801 (3 mg/kg) was administered by intraperitoneal injection 15 min prior to MCAO operation.. HCY treatment aggravated depressive-like disorders of post-stroke rats by the open field test and sucrose preference test. Further, HCY significantly decreased central monoamines levels in the MCAO rats by HPLC. The transmission electron microscopy results showed that the number of synapses and the area of postsynaptic density decreased in the hippocampus of the HCY-treated MCAO rats. Additionally, HCY augmented ischemia-induced up-regulation of NMDARs, decreased the levels of synaptic structure-related marker PSD-95and the synaptic transmission-associated synaptic proteins (VGLUT1, SNAP-25 and Complexin Ι/ΙΙ). These effects of HCY were partly reversed by the NMDA antagonist MK-801.. The current study suggested that NMDARs-mediated synaptic plasticity may be involved in the adverse effect of HCY on PSD. Topics: Animals; Dizocilpine Maleate; Homocysteine; Infarction, Middle Cerebral Artery; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reperfusion; Stroke | 2023 |
Hypothermia but not NMDA receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion in mice.
Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials. Topics: Animals; Cerebral Infarction; Disease Models, Animal; Dizocilpine Maleate; Hypothermia, Induced; Infarction, Middle Cerebral Artery; Male; Mice; Neuroprotective Agents; Peptides; Receptors, N-Methyl-D-Aspartate; Treatment Outcome | 2020 |
Involvement of the paraventricular nucleus in the occurrence of arrhythmias in middle cerebral artery occlusion rats.
Ischemic stroke complicating with arrhythmia is one of the main causes of sudden death. To investigate the association between ischemic stroke-induced arrhythmia and the activity of paraventricular nucleus (PVN), we used Fos protein as an objective indicator to illustrate the functional state of PVN neurons in middle cerebral artery occlusion (MCAO) rats, in single intracerebroventricular injection of l-glutamate rats and in application of MK-801 before l-glutamate injection and MCAO rats.. The standard limb II electrocardiography was continuously recorded by a biological signal collecting and processing system. The experimental cerebral ischemic animal model was established by occluding the right middle cerebral artery. The Fos protein expression was detected by immunohistochemistry and Western blot.. The incidence of arrhythmia was significantly higher than that of controls (75.89% versus 0%), and Fos protein expression in the PVN also increased significantly in MCAO rats; both of them could be blocked by prior application of MK-801. Intracerebroventricular injection of l-glutamate induced changes in Fos protein expression and arrhythmia similar to that in the stroke, which could also be blocked by prior application of MK-801.. It was concluded that activation of the PVN in MCAO rats is likely mediated by glutamate via activation of N-methyl-D-aspartic acid (NMDA) receptors, which causes arrhythmias. Topics: Animals; Arrhythmias, Cardiac; Disease Models, Animal; Dizocilpine Maleate; Electrocardiography; Gene Expression Regulation; Glutamic Acid; Heart Rate; Infarction, Middle Cerebral Artery; Injections, Intraventricular; Male; Nervous System Diseases; Neuroprotective Agents; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Time Factors | 2015 |
MRI heralds secondary nigral lesion after brain ischemia in mice: a secondary time window for neuroprotection.
Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes' occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies. Topics: Animals; Brain Ischemia; Cell Count; Dizocilpine Maleate; Immunohistochemistry; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Mice; Mice, 129 Strain; Nerve Degeneration; Neuroprotective Agents; Substantia Nigra; Tacrolimus | 2015 |
Acid-sensing ion channels activation and hypoxia upregulate Homer1a expression.
Recent studies have indicated that dynamic alterations in the structure of postsynaptic density (PSD) are involved in the pathogenesis of many central nervous system disorders, including ischemic stroke. Homer is the newly identified scaffolding protein located at PSD and regulates synaptic function. Homer1a, an immediate early gene, has been shown to be induced by several stimulations, such as glutamate, brain-derived neurotrophic factor, and trauma. However, whether acidosis mediated by acid-sensing ion channels (ASICs) and hypoxia during cerebral ischemia can change Homer1a expression remains to be determined.. We investigated that acidosis and hypoxia selectively and rapidly upregulated Homer1a expression, but not Homer1b/c in cultured cortical neurons. We also found that Homer1a exhibited induction expression in brain cortex of the middle cerebral artery occlusion (MCAO) rats. Additionally, acid-evoked Homer1a mRNA induction depended on extracellular signal-regulated kinase1/2 (ERK1/2) and Akt activity, and ASIC1a-mediated calcium influx whereas hypoxia depended only on ERK1/2 activity. Also, we demonstrated that continuous acidosis and hypoxia resulted in pronounced cell injury and Homer1a knockdown with small interfering RNA aggravated this damage induced by 3 h acid and hypoxia incubation in neuro-2a cells.. Homer1a might act as an activity-dependent regulator responding to extracellular stimuli during cerebral ischemia. Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Amiloride; Animals; Carrier Proteins; Cell Survival; Cells, Cultured; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Homer Scaffolding Proteins; Hypoxia; Infarction, Middle Cerebral Artery; Neurons; Peptides; Rats; Rats, Sprague-Dawley; Signal Transduction; Spider Venoms; Time Factors; Up-Regulation | 2014 |
The major cholesterol metabolite cholestane-3β,5α,6β-triol functions as an endogenous neuroprotectant.
Overstimulation of NMDA-type glutamate receptors is believed to be responsible for neuronal death of the CNS in various disorders, including cerebral and spinal cord ischemia. However, the intrinsic and physiological mechanisms of modulation of these receptors are essentially unknown. Here we report that cholestane-3β,5α,6β-triol (triol), a major metabolite of cholesterol, is an endogenous neuroprotectant and protects against neuronal injury both in vitro and in vivo via negative modulation of NMDA receptors. Treatment of cultured neurons with triol protects against glutamate-induced neurotoxicity, and administration of triol significantly decreases neuronal injury after spinal cord ischemia in rabbits and transient focal cerebral ischemia in rats. An inducible elevation of triol is associated with ischemic preconditioning and subsequent neuroprotection in the spinal cord of rabbits. This neuroprotection is effectively abolished by preadministration of a specific inhibitor of triol synthesis. Physiological concentrations of triol attenuate [Ca(2+)]i induced by glutamate and decrease inward NMDA-mediated currents in cultured cortical neurons and HEK-293 cells transiently transfected with NR1/NR2B NMDA receptors. Saturable binding of [(3)H]triol to cerebellar granule neurons and displacement of [(3)H]MK-801 binding to NMDA receptors by triol suggest that direct blockade of NMDA receptors may underlie the neuroprotective properties. Our findings suggest that the naturally occurring oxysterol, the major cholesterol metabolite triol, functions as an endogenous neuroprotectant in vivo, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS. Topics: Adult; Animals; Brain Injuries; Cells, Cultured; Central Nervous System; Cholestanols; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Humans; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Protein Binding; Rabbits; Rats; Rats, Sprague-Dawley; Spinal Cord Ischemia; Time Factors; Tissue Distribution; Young Adult | 2014 |
The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit.
Microinfarctions are present in the aged and injured human brain. Their clinical relevance is controversial, with postulated sequelae ranging from cognitive sparing to vascular dementia. To address the consequences of microinfarcts, we used controlled optical methods to create occlusions of individual penetrating arterioles or venules in rat cortex. Single microinfarcts, targeted to encompass all or part of a cortical column, impaired performance in a macrovibrissa-based behavioral task. Furthermore, the targeting of multiple vessels resulted in tissue damage that coalesced across cortex, even though the intervening penetrating vessels were acutely patent. Post-occlusion administration of memantine, a glutamate receptor antagonist that reduces cognitive decline in Alzheimer's disease, ameliorated tissue damage and perceptual deficits. Collectively, these data imply that microinfarcts likely contribute to cognitive decline. Strategies that have received limited success in the treatment of ischemic injury, which include therapeutics against excitotoxicity, may be successful against the progressive nature of vascular dementia. Topics: Animals; Brain Infarction; Brain Mapping; Calcium; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Glial Fibrillary Acidic Protein; Humans; Imaging, Three-Dimensional; Infarction, Middle Cerebral Artery; Male; Memantine; Microscopy, Confocal; Microvessels; Models, Biological; Neural Pathways; Neuroprotective Agents; Phosphopyruvate Hydratase; Psychomotor Performance; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Somatosensory Cortex; Vibrissae | 2013 |
N-Methyl-D-aspartate receptor antagonists memantine and MK-801 attenuate the cerebral infarct accelerated by intracorpus callosum injection of lipopolysaccharides.
Inflammatory responses have been shown to modulate the pattern and degree of ischemic injury. Previously, we demonstrated that intracorpus callosum microinjection of lipopolysaccharide (LPS, a well-known endotoxin) markedly induced inflammatory responses confined to ipsilateral hemisphere and aggravated cerebral ischemic injury. Here we report that LPS injection increases the degree of N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, one of major causes of cerebral ischemic injury. Intracorpus callosum microinjection of LPS 1 day prior to ischemic insults augmented intraneuronal Ca(2+) rise in rat brains subjected to transient occlusion of middle cerebral artery. Intraperitoneal administration of memantine, a NMDA receptor antagonist, reduced the LPS-enhanced calcium response as well as ischemic tissue damage. Western blot and immunohistochemistry data showed that the level of IL-1β was enhanced in LPS-injected rat brains, particularly in isolectin-B4 immunoreactive cells. Intraventricular microinjection of recombinant rat IL-1β aggravated cerebral ischemic injury, which was significantly reduced by memantine. Intraventricular injection of anti-IL-1β antibody significantly reduced the cerebral infarction aggravated by LPS preinjection. The results indicate that IL-1β released from isolectin-B4 immunoreactive cells enhanced excitotoxicity, consequently aggravating ischemic brain injury. Topics: Animals; Anti-Inflammatory Agents; Cerebral Infarction; Corpus Callosum; Dizocilpine Maleate; Drug Synergism; Indicators and Reagents; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intraventricular; Interleukin-1beta; Ischemic Attack, Transient; Male; Memantine; Microinjections; Plant Lectins; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate | 2013 |
Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion.
Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO. Topics: Animals; Brain Damage, Chronic; Deferoxamine; Disease Models, Animal; Dizocilpine Maleate; Free Radicals; Infarction, Middle Cerebral Artery; Iron; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate | 2012 |
Lack of protection with a novel, selective melanocortin receptor subtype-4 agonist RY767 in a rat transient middle cerebral artery occlusion stroke model.
Previous studies utilizing alpha-melanocyte-stimulating hormone (alpha-MSH) or the synthetic analog [Nle(4), D-Phe(7)] alpha-MSH have reported beneficial effects in animal models of ischemic stroke, with the latter studies suggesting melanocortin receptor subtype-4 (MC4R) activation as a protective mechanism. The present study directly addresses the hypothesis that MC4R activation may ameliorate ischemic brain injury by assessing the efficacy of a novel small molecule MC4R agonist RY767, administered in a pharmacokinetically guided and pharmacologically validated dosing regimen, in a rat stroke model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to 90-min tMCAO followed by 72 h of reperfusion. Treatments were i.p. pretreatment with MK-801 (15 min prior to occlusion, positive control), or combined i.v. and p.o. daily administrations of vehicle, dextrose (negative control) or RY767 in blinded fashion initiated 2 h after occlusion. Infarct volume in MK-801-treated rats (158.7 +/- 22.3 mm(3)) was reduced significantly compared to vehicle infarct volume (243.4 +/- 12.5 mm(3)), whereas infarct volumes in dextrose- (224.3 +/- 16.5 mm(3)) and RY767- (262.1 +/- 19.2 mm(3)) treated rats did not differ from vehicle infarct volume. These results indicate that selective MC4R activation provides no significant neuroprotection, as reflected by infarct volume, in a rat stroke model utilizing a 90-min ischemic insult. Topics: Administration, Oral; Animals; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dizocilpine Maleate; Humans; Infarction, Middle Cerebral Artery; Injections, Intravenous; Male; Neuroprotective Agents; Piperazines; Piperidines; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Reperfusion Injury | 2009 |
Neither in vivo MRI nor behavioural assessment indicate therapeutic efficacy for a novel 5HT(1A) agonist in rat models of ischaemic stroke.
5HT1A agonists have previously been shown to promote recovery in animal models of stroke using ex vivo outcome measures which have raised the hopes for a potential clinical implementation. The purpose of this study was to evaluate the potential neuroprotective properties of a novel 5HT1A agonist DU123015 in 2 different models of transient focal ischaemic stroke of varying severities using both in vivo neuroimaging and behavioural techniques as primary outcome measures. For these studies, the NMDA receptor antagonist MK-801 was also utilized as a positive control to further assess the effectiveness of the stroke models and techniques used.. In contrast to MK-801, no significant therapeutic effect of DU123015 on lesion volume in either the distal MCAo or intraluminal thread model of stroke was found. MK-801 significantly reduced lesion volume in both models; the mild distal MCAo condition (60 min ischaemia) and the intraluminal thread model, although it had no significant impact upon the lesion size in the severe distal MCAo condition (120 min ischaemia). These therapeutic effects on lesion size were mirrored on a behavioural test for sensory neglect and neurological deficit score in the intraluminal thread model.. This study highlights the need for a thorough experimental design to test novel neuroprotective compounds in experimental stroke investigations incorporating: a positive reference compound, different models of focal ischaemia, varying the duration of ischaemia, and objective in vivo assessments within a single study. This procedure will help us to minimise the translation of less efficacious compounds. Topics: Animals; Cerebral Cortex; Cytoprotection; Dizocilpine Maleate; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Neurons; Neuropsychological Tests; Outcome Assessment, Health Care; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Time Factors | 2009 |
CaMKII phosphorylates collapsin response mediator protein 2 and modulates axonal damage during glutamate excitotoxicity.
Intracellular calcium influx through NMDA receptors triggers a cascade of deleterious signaling events which lead to neuronal death in neurological conditions such as stroke. However, it is not clear as to the molecular mechanism underlying early damage response from axons and dendrites which are important in maintaining a network essential for the survival of neurons. Here, we examined changes of axons treated with glutamate and showed the appearance of betaIII-tubulin positive varicosities on axons before the appearance of neuronal death. Dizocilpine blocked the occurrence of varicosities on axons suggesting that these microstructures were mediated by NMDA receptor activities. Despite early increased expression of pCaMKII and pMAPK after just 10 min of glutamate treatment, only inhibitors to Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and calpain prevented the occurrence of axonal varicosities. In contrast, inhibitors to Rho kinase, mitogen-activated protein kinase and phosphoinositide 3-kinase were not effective, nor were they able to rescue neurons from death, suggesting CaMKII and calpain are important in axon survival. Activated CaMKII directly phosphorylates collapsin response mediator protein (CRMP) 2 which is independent of calpain-mediated cleavage of CRMP2. Over-expression of CRMP2, but not the phosphorylation-resistant mutant CRMP2-T555A, increased axonal resistance to glutamate toxicity with reduced numbers of varicosities. The levels of both pCRMP2 and pCaMKII were also increased robustly within early time points in ischemic brains and which correlated with the appearance of axonal varicosities in the ischemic neurons. Collectively, these studies demonstrated an important role for CaMKII in modulating the integrity of axons through CRMP2 during excitotoxicity-induced neuronal death. Topics: Animals; Axons; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Embryo, Mammalian; Enzyme Activation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glutamic Acid; Green Fluorescent Proteins; Infarction, Middle Cerebral Artery; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mutation; Nerve Tissue Proteins; Neurons; Phosphorylation; Semaphorin-3A; Signal Transduction; Transfection; Tubulin | 2009 |
Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation.
Several studies have suggested that a potential mechanism for estrogen-mediated neuroprotection following experimental stroke is a result of modulating glutamate-mediated excitotoxicity. Our laboratory has shown that in male rats, estrogen injection (systemic or direct intracortical injection) resulted in an immediate depolarization of cortical neurons. Therefore, the present study was designed to investigate whether the estrogen-induced depolarization of cortical neurons was required in mediating the early events associated with this neuroprotection. We tested this hypothesis by co-injecting selective antagonists of the NMDA (MK-801) or AMPA (DNQX) glutamatergic receptors with estrogen. Systemic injection of estrogen significantly attenuated the MK-801-induced decrease in infarct volume following middle cerebral artery occlusion (MCAO). Similarly, when estrogen and MK-801 were co-injected directly into the cortex, no neuroprotection was observed. However, when estrogen or MK-801 was injected centrally 10 min prior to the injection of the other drug, significant neuroprotection was observed. This led us to hypothesize that estrogen-mediated neuroprotection required an initial activation of NMDA receptors. Furthermore, our results suggest that this estrogen-mediated neuroprotection was also associated with a significant increase in m-calpain and activation of an endoplasmic reticulum (ER) specific caspase-12. Finally, the results of current clamp experiments showed that estrogen significantly depolarized cortical neurons as well as enhanced NMDA-induced depolarization. Taken together, these results suggest that estrogen pretreatment may activate NMDA receptors resulting in modification of ER-associated molecular mechanisms involved in neuroprotection following MCAO. Topics: Analysis of Variance; Animals; Blood Pressure; Calpain; Caspase 12; Cerebral Cortex; Dizocilpine Maleate; Drug Interactions; Enzyme Activation; Estrogens; Excitatory Amino Acid Agonists; Heart Rate; In Vitro Techniques; Infarction, Middle Cerebral Artery; Male; Membrane Potentials; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate | 2007 |
Quantitative assessments of cerebral vascular damage with a silicon rubber casting method in photochemically-induced thrombotic stroke rat models.
Previous studies have described microvascular disturbances downstream of occluded large vessels arising during the acute phase (several hours) following cerebral ischemic insult. Prolonged microvascular disturbances may cause delayed neuronal cell death in ischemic penumbral regions, leading to expanded brain infarctions and poor neurological and functional outcomes. The lack of simple and quantitative methods for investigating this microcirculation failure suggests the need to develop a new method for clarifying the precise distribution and persistence of post-ischemic microvascular disturbances. The present study used a silicone rubber casting method in quantitative analyses of microvascular conditions in photochemically-induced thromboembolic (PIT) stroke rat models. After the casting procedure in rats with PIT stroke, a 6 microm-thick coronal section was obtained, and quantitative analyses of microvascular density and measurements of the infarct area in the serial section were performed. The major findings of the present study are as follows: (1) Silicone rubber casting techniques can be applied to precise quantitative analyses of microvessels in the same individual in whom brain infarct volume was measured; (2) the persistence and spatial distribution of microvascular disturbances assessed at the ischemic core, ischemic penumbra, and non-ischemic regions strongly suggest that microvascular disturbances affect brain infarct expansion; (3) the current method demonstrated the protective effects of MK-801 on microvessels, indicating that the technique may be useful in investigating factors that provide vascular protection. The experimental procedure introduced here would facilitate future evaluations of vascular protective agents. Topics: Animals; Brain; Disease Models, Animal; Dizocilpine Maleate; Infarction, Middle Cerebral Artery; Light; Male; Microcirculation; Middle Cerebral Artery; Photochemistry; Rats; Rats, Wistar; Rose Bengal; Silicone Elastomers | 2007 |
Hydrogen sulfide is a mediator of cerebral ischemic damage.
We observed recently that elevated plasma cysteine levels are associated with poor clinical outcome in acute stroke patients. In a rat stroke model, cysteine administration increased the infarct volume apparently via its conversion to hydrogen sulfide (H2S). We therefore investigated the effects of H2S and the inhibition of its formation on stroke.. Cerebral ischemia was studied in a rat stroke model created by permanent occlusion of the middle cerebral artery (MCAO). The resultant infarct volume was measured 24 hours after occlusion.. Administration of sodium hydrosulfide (NaHS, an H2S donor) significantly increased the infarct volume after MCAO. The NaHS-induced increase in infarct volume was abolished by the administration of dizolcilpine maleate (an N-methyl-d-aspartate receptor channel blocker). MCAO caused an increase in H2S level in the lesioned cortex as well as an increase in the H2S synthesizing activity. Administration of 4 different inhibitors of H2S synthesis reduced MCAO-induced infarct volume dose dependently. The potency of these inhibitors in effecting neuroprotection in vivo appeared to parallel their potency as inhibitors of H2S synthesis in vitro. It also appeared that most of the H2S synthesizing activity in the cortex results from the action of cystathionine beta-synthase.. The present results strongly suggest that H2S plays a part in cerebral ischemic damage after stroke. Inhibition of H2S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy. Topics: Air Pollutants; Animals; Brain Injuries; Brain Ischemia; Cerebral Cortex; Cysteine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Humans; Hydrogen Sulfide; Infarction, Middle Cerebral Artery; Male; Models, Statistical; Neuroprotective Agents; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Time Factors; Treatment Outcome | 2006 |
Ginkgo biloba leaf extract (EGb761) combined with neuroprotective agents reduces the infarct volumes of gerbil ischemic brain.
Ginkgo biloba exerts many pharmacological actions. It possesses antioxidant properties, the ability of neurotransmitter/receptor modulation and antiplatelet activation factor. This research is designed to investigate the neuroprotective effects of long-term treatment with EGb761 (a standard form of the extract of Ginkgo biloba leaf) in combination with MgSO(4), FK506, or MK-801 on the infarct volume of male gerbils' brain induced by unilateral middle cerebral artery occlusion (MCAO). Thirty-five gerbils fed a standard diet were intragastrically given water or EGb761 (100 mg/kg/day) for one week. Five randomized groups were established: control (n = 7), EGb761 (n = 8), EGb761 + MgSO(4) (n = 7), EGb761 + FK506 (n = 7), and EGb761 + MK-801 (n = 6). The three drug-combination groups were injected with MgSO(4) (90 mg/kg), FK506 (0.5 mg/kg), or MK-801 (1 mg/kg), respectively 30 min before MCAO. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation for 24 hours. Postmortem infarct volumes were determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections. Results showed that the total infarct volumes of the four treated groups either EGb761 alone or in combination with drugs were lower than the control group by 36.1% (EGb761 alone), 40.3% (EGb761 + MgSO(4)), 35.3% (EGb761 + FK506), and 56.4% (EGb761 + MK-801), respectively (p < 0.01). The main affected areas of the brain in the four treated groups were significantly focused between 4 and 6 mm from the frontal pole, when compared to the control group (p < 0.01). All animals in the five groups had infarctions in both cortex and subcortex. These results indicate that long-term pre-treatment of EGb761 administered either alone or in combination with drugs significantly effective neuroprotection on infarct volume in gerbil ischemic brains. Topics: Animals; Brain Infarction; Brain Ischemia; Dizocilpine Maleate; Drug Therapy, Combination; Gerbillinae; Ginkgo biloba; Infarction, Middle Cerebral Artery; Magnesium Sulfate; Male; Neuroprotective Agents; Plant Extracts; Random Allocation; Tacrolimus; Treatment Outcome | 2006 |
Long-term protective effect of atorvastatin in permanent focal cerebral ischemia.
Statins exert beneficial effects in brain diseases including stroke. Here, we investigated whether oral prophylactic atorvastatin provides long-term neuroprotection and functional recovery in permanent middle cerebral artery occlusion (pMCAO), and whether cerebral hemodynamics are affected. Male Long-Evans rats were treated with 10 mg/kg oral atorvastatin for 14 days and subjected to pMCAO. Cerebral hemodynamics were measured by bolus tracking MRI and laser Doppler flowmetry (LDF). Infarct volume was quantified at 1 week by T2-MRI and at 3 weeks by histology. Rats were also subjected to neuroscoring and cylinder test. The number of animals per group was 10. The infarct volumes were 100.8 +/- 8.2 and 47.3 +/- 5.5 mm(3) in vehicle, and 68.7 +/- 11.0 and 28.6 +/- 3.82 mm(3) in atorvastatin group at 7 and 21 days post-ischemia, respectively (mean +/- SEM). Atorvastatin significantly reduced infarct volume both at 7 and 21 days (P = 0.04 and 0.03, respectively, 1-way ANOVA). Interestingly, no improvement in cerebral hemodynamic parameters was observed in atorvastatin treated animals. The vehicle group recovered normal neuroscore at day 13, whereas atorvastatin group recovered already at day 10 after pMCAO. All treatment groups preferred to use the unaffected forelimb for rearing in Cylinder test, whereas the defected forelimb use was minimal in all groups. These results suggest that oral atorvastatin protects cerebral tissue against the subsequent pMCAO without influencing cerebral hemodynamic parameters, and it may well be that persons with ongoing atorvastatin treatment benefit in the incidence of stroke. Topics: Animals; Atorvastatin; Behavior, Animal; Blood Circulation; Brain Infarction; Brain Ischemia; Dizocilpine Maleate; Heptanoic Acids; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Motor Activity; Neuroprotective Agents; Psychomotor Performance; Pyrroles; Rats; Rats, Long-Evans; Recovery of Function; Staining and Labeling; Time; Time Factors | 2005 |
The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice.
The pre-ischaemic neuroprotective potential of a novel polyamine/NMDA antagonist N1-dansyl-spermine (1-5 mg kg(-1)) was studied in a transient focal cerebral ischaemia model in mice in comparison to a reference compound, MK-801 (1 or 3 mg kg(-1)). The intraluminal suture transient middle cerebral artery occlusion (MCAO) model was used. N1-dansyl-spermine and MK-801 were administered (i.p.) 30 min prior to ischaemia. A range of histological and behavioural assessments was employed. N1-dansyl-spermine had a comparable effect to MK-801 at reducing the percentage hemisphere lesion volume (%HLV) at the doses tested. Furthermore, N1-dansyl-spermine reduced the ischaemic brain oedema, which MK-801 did not. N1-dansyl-spermine significantly reversed the decrease of locomotor activity (LMA) caused by the MCAO and showed a significant effect at improving the rotarod performance impaired by MCAO. In contrast, MK-801 had no beneficial effect on sensorimotor function and even worsened the LMA. These results clearly demonstrate the pre-ischaemic neuroprotective effect of N1-dansyl-spermine in a transient focal cerebral ischaemia model. Topics: Animals; Brain; Brain Edema; Dansyl Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mice; Motor Activity; Neuroprotective Agents; Rotarod Performance Test; Spermine; Tetrazolium Salts; Time Factors | 2005 |
Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats.
Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly (P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA. Topics: Aging; Animals; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Kainic Acid; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Telencephalon | 2003 |
Cytotoxic edema is independent of NMDA ion channel activation following middle cerebral artery occlusion (MCAO). An in vivo autoradiographic and MRI study.
Massive glutamate release is an important factor leading to ionic imbalance after occlusive stroke, which in turn contributes to cytotoxic edema formation. Currently, measurements of cytotoxic edema using 'diffusion weighted' MRI, is being used in human stroke studies, as a 'surrogate' end point for neuroprotective drug trials, including studies with glutamate antagonists. However, it is not fully understood to what extent glutamate-mediated N-methyl-D-aspartate (NMDA) receptor activation is related to 'cytotoxic' edema formation, and thus, to what degree apparent diffusion coefficient (ADC) changes, assessed by magnetic resonance imaging with 'ACD mapping', represent NMDA receptor activation. To study this relationship, four cats underwent permanent middle cerebral artery occlusion (MCAO). Edema formation was investigated using MRI with 'ACD mapping', while NMDA receptor activation was simultaneously detected in the same animals, using radio labeled 125IodoMK-801, which binds only in activated and open NMDA channels. At 5 h post-occlusion, a large area of edema could be found with significantly lower ADC values in the core and penumbral area of the ischemic lesion when compared to contralateral values. On corresponding sections of the feline brains, increased 125I-MK-801 binding was found in the infarct penumbra. However, there was no significant topographical correlation between ADC values and measured radioactivity. The results indicate that there is not a significant linkage between NMDA receptor activation and 'cytotoxic' edema following permanent MCAO. The detection of a large area of NMDA channel activation within regions of low ADC does however indicate an area of 'penumbral' ischemia susceptible to treatment with NMDA channel blockers. Topics: Animals; Autoradiography; Brain Edema; Cats; Diffusion Magnetic Resonance Imaging; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Infarction, Middle Cerebral Artery; Iodine Radioisotopes; Male; Radionuclide Imaging; Receptors, N-Methyl-D-Aspartate | 2003 |
Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance.
Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia.. Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining).. Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III.. Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method. Topics: Animals; Body Temperature; Disease Models, Animal; Disease Progression; Dizocilpine Maleate; Fever; Hypothalamus; Infarction, Middle Cerebral Artery; Ligation; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Titanium; Treatment Outcome | 2003 |
Changes in dopaminergic and glutamatergic excitatory mechanisms of micturition reflex after middle cerebral artery occlusion in conscious rats.
Previous reports have shown that N-methyl-d-aspartate (NMDA) glutamatergic and D2 dopaminergic mechanisms have independent excitatory effects on bladder activity in normal and cerebral infarcted (CI) rats under urethane anesthesia. The study presented here was undertaken to investigate the interaction between these two mechanisms on bladder activity in conscious Sprague-Dawley female rats with or without cerebral infarction. Occlusion of the left middle cerebral artery or a sham operation (SO) was performed under halothane anesthesia. After recovery from the anesthesia, bladder activity was monitored continuously by means of infusion cystometrography in awake rats. The effects of cumulative intravenous doses of quinpirole (0.001-1 mg/kg), a D2 dopamine receptor agonist, were studied in awake SO and CI rats with or without dizocilpine (10 mg/kg) pretreatment. The effects of dizocilpine (1 or 10 mg/kg) were also examined in other SO or CI rats pretreated with 1 mg/kg of quinpirole. Bladder capacity in CI rats was significantly smaller (0.18 ml) than that in SO rats (0.48 ml). Quinpirole (0.1 and 1 mg/kg) further reduced bladder capacity in both types of rats, an effect blocked by sulpiride (20 mg/kg), a D2 dopamine receptor antagonist. The effect of quinpirole was also antagonized by dizocilpine (1 mg/kg) to a significantly (P < 0.01) greater degree in CI than in SO rats. In SO rats pretreated with 1 mg/kg of quinpirole, dizocilpine significantly increased bladder capacity in a dose-dependent manner. After the maximum dose (10 mg/kg) of dizocilpine, sulpiride did not produce any changes in bladder activity. In CI rats pretreated with 1 mg/kg of quinpirole, 1 mg/kg of dizocilpine increased bladder capacity. After administration of the maximum dose of dizocilpine (10 mg/kg), which did not produce an additional effect, sulpiride (20 mg/kg) increased bladder capacity by 58.3%. These results indicate that in awake rats D2 dopaminergic excitatory effects on the urinary bladder are mediated in part by NMDA glutamatergic mechanisms and in part by non-NMDA mechanisms. The latter type was more prominent in CI rats, indicating that the bladder hyperactivity induced by cerebral infarction may be mediated by an alteration in dopaminergic-glutamatergic interactions in the brain. Topics: Animals; Dizocilpine Maleate; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Infarction, Middle Cerebral Artery; Quinpirole; Rats; Rats, Sprague-Dawley; Reflex; Sulpiride; Urinary Bladder; Urinary Bladder, Neurogenic; Urination; Wakefulness | 2002 |
Role of caspase-3 activation in cerebral ischemia-induced neurodegeneration in adult and neonatal brain.
These studies have addressed the role of caspase-3 activation in neuronal death after cerebral ischemia in different animal models. The authors were unable to show activation of procaspase-3 measured as an induction of DEVDase (Asp-Glu-Val-Asp) activity after focal or transient forebrain ischemia in rats. DEVDase activity could not be induced in the cytosolic fraction of the brain tissue obtained from these animals by exogenous cytochrome c/dATP and Ca2+. However, the addition of granzyme B to these cytosolic fractions resulted in a significant activation of DEVDase, confirming that the conditions were permissive to analyze proteolytic cleavage of the DEVD-AMC (7-amino-4-methyl-coumarin) substrate. Consistent with these findings, zVal-Ala-Asp-fluoromethylketone administered after focal ischemia did not have a neuroprotective effect. In contrast to these findings, a large increase in DEVDase activity was detected in a model of hypoxic-ischemia in postnatal-day-7 rats. Furthermore, in postnatal-day-7 animals treated with MK-801, in which it has been suggested that excessive apoptosis is induced, the authors were unable to detect activation of DEVDase activity but were able to induce it in vitro by the addition of cytochrome c/dATP and Ca2+ to the cytosolic fraction. Analysis of cytochrome c distribution did not provide definitive evidence for selective cytochrome c release in the permanent focal ischemia model, whereas in the transient model a small but consistent amount of cytochrome c was found in the cytosolic fraction. However, in both models the majority of cytochrome c remained associated with the mitochondrial fraction. In conclusion, the authors were unable to substantiate a role of mitochondrially derived cytochrome c and procaspase-3 activation in ischemia-induced cell death in adult brain, but did see a clear induction of caspase-3 in neonatal hypoxia. Topics: Amino Acid Chloromethyl Ketones; Animals; Animals, Newborn; Brain; Brain Ischemia; Caspase 3; Caspases; Cell Death; Cytochrome c Group; Dizocilpine Maleate; Enzyme Activation; Granzymes; Humans; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Peptide Hydrolases; Protein Precursors; Rats; Rats, Sprague-Dawley; Rats, Wistar; Serine Endopeptidases | 2002 |
Comet assay as a novel approach for studying DNA damage in focal cerebral ischemia: differential effects of NMDA receptor antagonists and poly(ADP-ribose) polymerase inhibitors.
The single-cell gel electrophoresis (comet assay) was used to evaluate the possibility of detecting single-strand breaks of brain DNA in the early phase of ischemia. Four hours after occlusion of the middle cerebral artery (MCAO) in rats, the percentage of DNA migrating into the comet tail (indicating the presence of breaks) increased from 11.4 +/- 4.70 to 34.7 +/- 9.2 (means +/- SD) in the caudate and from 9.9 +/- 4.3 to 42.8 +/- 14.1 in the cortex. Interestingly, a subpopulation of cells exhibiting higher resistance to the ischemic insult was present in the caudate putamen, but not in the cortex. Administration of MK801, an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, (1 mg/kg subcutaneously, 10 minutes before MCAO), reduced the ischemia-induced DNA breaks and the infarct volume, suggesting that excessive stimulation of NMDA receptors contributes to the formation of both DNA damage and infarct volume. In contrast, DPQ, an inhibitor of poly(ADP-ribose) polymerase (PARP) (10 mg/kg intraperitoneally, 2 hours before and 1 hour after MCAO), reduced the infarct volume but not DNA damage, suggesting that the neuroprotective actions of PARP inhibitors occur at a later step of the processes leading to postischemic neuronal death. Topics: Animals; Brain Ischemia; Comet Assay; Dizocilpine Maleate; DNA; DNA Damage; DNA, Single-Stranded; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Isoquinolines; Male; Neuroprotective Agents; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate | 2002 |
Calcium ion transients in peri-infarct depolarizations may deteriorate ion homeostasis and expand infarction in focal cerebral ischemia in cats.
Harmful effects of peri-infarct depolarizations (PIDs) may depend on recurrent Ca(2+) influx. Thus far, few studies have documented the relevance of PIDs in gyrencephalic animals, and the progressive nature of this process has not been investigated over extended periods. We therefore studied in prolonged focal ischemia in cats spatial and temporal profiles of extracellular calcium ([Ca(2+)](o)) shifts in relation to direct current (DC) potential, nitric oxide (NO) concentration and regional cerebral blood flow alterations, and final pathological outcome.. In halothane-anesthetized cats receiving either vehicle (n=12) or MK-801 treatment (5 mg/kg IV; n=10), the left middle cerebral artery was permanently occluded. Laser-Doppler probes, ion-selective microelectrodes, and NO electrodes measured simultaneously regional cerebral blood flow, DC potential, electrocorticogram, [Ca(2+)](o), and NO concentrations in ectosylvian and suprasylvian gyri of the left cerebral cortex.. Persistent depolarization immediately after middle cerebral artery occlusion occurred in 10 ectosylvian and 4 suprasylvian gyri of vehicle-treated animals and in 9 ectosylvian and 3 suprasylvian gyri of MK-801-treated animals. PIDs associated with transient decreases of [Ca(2+)](o) were detected in suprasylvian gyri of only 4 vehicle-treated animals, of which 3 developed recurrent PIDs. Electrocorticogram was suppressed during PIDs, and electrocorticogram recovery worsened in a stepwise manner with consecutive depolarizations. PID duration increased slightly with ongoing ischemia and evolved to persistent depolarization at a final stage. NO transients were not detected during PID, and regional cerebral blood flow transients were not pronounced. Infarction was larger with initial persistent depolarization than with PID and was smallest in MK-801-treated animals.. PID is not a common finding in peri-infarct zones in cats, and it is suppressed by the N:-methyl-D-aspartate antagonist MK-801. However, if repeated PIDs are generated, they result in a stepwise, progressive breakdown of neuronal function and ion homeostasis, probably contributing to the growth of infarction in focal cerebral ischemia. Recurrent Ca(2+) influx is a mechanism that presumably contributes to this process. Topics: Animals; Blood Flow Velocity; Brain Ischemia; Calcium; Cats; Cerebral Cortex; Cerebrovascular Circulation; Cortical Spreading Depression; Disease Models, Animal; Disease Progression; Dizocilpine Maleate; Electroencephalography; Female; Homeostasis; Infarction, Middle Cerebral Artery; Ion Transport; Laser-Doppler Flowmetry; Male; Membrane Potentials; Microelectrodes; Neuroprotective Agents; Nitric Oxide | 2001 |
Interaction between D2 dopaminergic and glutamatergic excitatory influences on lower urinary tract function in normal and cerebral-infarcted rats.
Previous studies showed that bladder hyperactivity after cerebral infarction in Sprague-Dawley (SD) rats was mediated in part by D2 dopaminergic and NMDA glutamatergic mechanisms. In the present experiments, the interaction between dopaminergic and glutamatergic excitatory mechanisms in the control of bladder and external urethral sphincter (EUS) reflexes was investigated in urethane-anesthetized sham-operated (SO) and cerebral-infarcted (CI) SD rats. Occlusion of the left middle cerebral artery or a sham operation was performed under halothane anesthesia. Two hours after either of the two procedures, rats were anesthetized with urethane. Dizocilpine, an N-methyl-d-aspartate (NMDA) glutamatergic antagonist, was administered intravenously in doses of 0.3 or 3 mg/kg to CI rats and 3 mg/kg to SO rats. These doses completely inhibited bladder and EUS activity. The effects of apomorphine (a dopamine agonist with greater efficacy at D2 than D1 receptors) or quinpirole (a selective D2 dopamine receptor agonist) were examined on the dizocilpine-induced depression of bladder contractions and EUS EMG activity. Apomorphine did not antagonize the dizocilpine depression of EUS activity, but it did reestablish the micturition reflex after dizocilpine blockade and did increase the amplitude of bladder contractions and voided volume in a dose-dependent manner (0.0001-10 mg/kg, iv), in both CI rats and SO rats pretreated with dizocilpine. There were no differences between SO rats and CI rats in the apomorphine responses in rats pretreated with doses of 0.3 or 3 mg/kg dizocilpine. A larger dose of dizocilpine (10 mg/kg) did not affect the bladder contractions after apomorphine administration. Quinpirole (0.001-1 mg/kg, iv) also partially reversed the dizocilpine depression of bladder activity in SO and CI rats. These results indicate that NMDA glutamatergic and D2 dopaminergic mechanisms exert independent excitatory influences on bladder activity in both SO and CI rats. D2 dopamine receptor agonists can reverse the effect of NMDA receptor blockade on bladder activity but were ineffective in reversing the block of sphincter activity. Topics: Anesthesia; Animals; Apomorphine; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Electromyography; Excitatory Amino Acid Antagonists; Female; Infarction, Middle Cerebral Artery; Injections, Intravenous; Muscle Contraction; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Reflex; Sulpiride; Urinary Bladder; Urinary Tract | 2001 |
Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620.
This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)(1) receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03-3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by BAY 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors. Topics: Animals; Anticonvulsants; Behavior, Animal; Body Temperature; Brain Ischemia; Cerebral Cortex; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Infarction, Middle Cerebral Artery; Male; Mice; Naphthalenes; Neural Inhibition; Neuroprotective Agents; Phencyclidine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Reflex, Startle; Seizures; Self Stimulation; Stereotyped Behavior | 2001 |
Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat.
In a recent study of focal cerebral ischemia in rats, pre-ischemic administration of the synthetic allosteric hemoglobin modifier RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl] methyl] phenoxy]-2-methylproprionic acid) reduced cerebral infarct size when combined with the NMDA receptor antagonist dizocilpine (MK-801) but not when given alone. We hypothesized that post-ischemic RSR13 administration would enhance neuroprotection afforded by NMDA receptor antagonism in a rat model of transient middle cerebral artery occlusion (MCAO). Fasted normothermic Wistar rats underwent 75 min of temporary MCAO. At onset of reperfusion, rats randomly received: (1) 0.9% NaCl (vehicle) i.v. alone (n=16); (2) 0.9% NaCl+dizocilpine (0.25 mg/kg) i.v. (n=16); or (3) RSR13 (150 mg/kg)+dizocilpine (0.25 mg/kg) i.v. (n=17). Seven days later, neurologic deficit and cerebral infarct size were determined. Dizocilpine alone compared to vehicle reduced mean+/-S.D. subcortical (52+/-24 mm(3) vs. 122+/-64 mm(3), P=0.003) and cortical (35+/-35 mm(3) vs. 125+/-72 mm(3), P=0.00074) infarct volumes. When compared to dizocilpine alone, the combination of RSR13+dizocilpine further reduced subcortical (37+/-14 mm(3) vs. 52+/-24 mm(3), P=0. 034) and cortical (8+/-19 mm(3) vs. 35+/-35 mm(3), P=0.018) infarct size. RSR13+dizocilpine improved neurologic scores vs. either dizocilpine alone (P=0.0014) or vehicle (P=10(-7)). The combination of NMDA receptor antagonism and a RSR13 mediated rightward shift of the oxy-hemoglobin dissociation curve improved outcome from MCAO. Because this occurred after reperfusion, our results suggest that the post-ischemic brain continues to suffer from hypoperfusion defects, which are amenable to therapy by enhanced O(2) delivery. The results also support the concept that neuroprotective strategies, which combine drugs with different mechanisms of action, may yield cumulative benefits. Topics: Aniline Compounds; Animals; Blood Gas Analysis; Body Temperature; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Hemoglobins; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Neurologic Examination; Neuroprotective Agents; Propionates; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate | 2000 |
Role of the forebrain in bladder overactivity following cerebral infarction in the rat.
This study was undertaken to investigate the contribution of the forebrain to bladder overactivity induced by cerebral infarction (CI). CI was induced by left middle cerebral artery (MCA) occlusion in female SD rat. Two and a half hours after CI or a sham operation (SO) decerebration was performed in some animals to eliminate forebrain influences on voiding function. Then bladder activity was monitored during continuous infusion cystometrograms in awake rats for 2.5 h. The effects of cumulative intravenous doses of MK-801 (0.1-1.4 mg/kg), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, or sulpiride (0.1-41.1 mg/kg), D(2) selective dopaminergic receptor antagonists were studied over a 1.5-h period beginning 5 h after MCA occlusion. Bladder capacity was reduced by 57.5% after CI. In CI rats decerebration increased bladder capacity by 62.5% of predecerebration capacity. In SO rats bladder capacity was reduced by 25% after decerebration. MK-801 (0.4 and 1.4 mg/kg) increased bladder capacity in CI and CI-decerebrate rats, but did not change bladder capacity in SO-decerebrate rats. MK-801 decreased (60.7%) bladder capacity in SO-nondecerebrate rats. Sulpiride (11.1 and 41.1 mg/kg) significantly increased bladder capacity in CI, CI-decerebrate, and SO-decerebrate rats, but had no effect in SO-nondecerebrate rats. These results indicate that CI-induced decrease in bladder capacity is mediated by two mechanisms: (1) upregulation of an excitatory pathway from the forebrain, an effect blocked by decerebration and (2) downregulation of a tonic inhibitory pathway from the forebrain. The latter effect which can be induced by decerebration as well as CI unmasks a D(2) dopaminergic excitatory mechanism. An NMDA excitatory mechanism also contributes to the bladder overactivity after CI, but not after decerebration. Topics: Animals; Decerebrate State; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Female; Infarction, Middle Cerebral Artery; Prosencephalon; Rats; Rats, Sprague-Dawley; Sulpiride; Urinary Bladder, Neurogenic; Urinary Incontinence | 2000 |
Diethylmaleate decreased ascorbic acid release induced by cerebral ischemia in cerebral cortex of the anesthetized rat.
The effect of diethylmaleate administration on ascorbic acid release following cerebral ischemia was investigated in anesthetized rat brain cortex. Cerebral ischemia, induced by ligating bilateral common carotid arteries and unilateral middle cerebral artery, significantly increased the extracellular ascorbic acid levels. Diethylmaleate (4 mmoles/kg, i.p.), which has been shown in earlier studies to decrease the ischemia-induced glutamate release, significantly reduced the ischemia-induced ascorbic acid release. The ischemia-induced ascorbic acid release was unaffected by perfusing NMDA receptor antagonist MK 801 (75 microM). Additionally, elevated extracellular glutamate levels, achieved by either externally applied glutamate solutions or by perfusing L-trans-pyrrolidine-2,4-dicarboxylate (PDC) (31.4 mM and 15.7 mM) to inhibit the glutamate uptake transporter, also significantly increased the extracellular ascorbic acid levels. These results suggested that ascorbic acid release in cerebral ischemia might be related to the elevated extracellular glutamate levels, which occurs following cerebral ischemia. Topics: Amino Acid Transport System X-AG; Anesthesia; Animals; Ascorbic Acid; Brain Chemistry; Brain Ischemia; Carrier Proteins; Cerebral Cortex; Dicarboxylic Acids; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamate Plasma Membrane Transport Proteins; Glutamic Acid; Glutathione; Infarction, Middle Cerebral Artery; Male; Maleates; Microdialysis; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Symporters | 2000 |
Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia.
Inflammatory mediators are involved in the pathogenesis of focal ischemic brain damage. In this study we used quantitative reverse transcriptase-polymerase chain reaction to analyze the spatiotemporal pattern of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and inducible nitric oxide synthase (iNOS) expression in focal ischemia of the rat brain. Focal ischemia of the rat parietal cortex was induced noninvasively by photothrombosis of cortical microvessels. In a proportion of the animals NMDA receptor signaling was blocked by the noncompetitive receptor antagonist MK-801. Within 4 h after ischemia we found induction of TNF-alpha and IL-1beta mRNA not only in the infarcts but also in all representative tissue samples removed from noninfarcted frontal, lateral, and occipital cortex of the ipsilateral, but not contralateral hemisphere. Contrastingly, the expression of iNOS mRNA remained restricted to the evolving infarcts. Pretreatment with MK-801 strongly inhibited remote cytokine expression (mean reduction by 80% relative to vehicle treated animals at 4 h; P<0.001) whereas in the lesions only partial reductions in the expression of IL-1beta and iNOS mRNA were found. Our data for the first time demonstrate remote cytokine induction following focal brain ischemia and suggest that NMDA receptor-mediated signaling can activate inflammatory gene expression independently from the occurrence of neuronal cell death. Topics: Animals; Brain Ischemia; Cerebral Cortex; Cortical Spreading Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation, Enzymologic; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-1; Intracranial Thrombosis; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Photochemistry; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha | 2000 |