Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis

In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm butdid not improve functional outcome after subarachnoid hemorrhage (SAH). Weassessed the effects of treatment with ETRAs on clinically relevant outcomes inanimal studies modelling SAH by performing a systematic review of the literaturefor controlled animal studies of ETRAs for the treatment of SAH. Primaryoutcomes were neurobehavioral outcomes and case fatality. Secondary outcomeswere cerebral vasospasm and cerebral blood flow. Summary estimates werecalculated using normalized mean difference random effects meta-analysis. Weincluded 27 studies (55 experiments, 639 animals). Neurobehavioral scores werereported in none of the experiments, and case fatality in 8 (15%).Treatment with ETRAs was associated with a pooled odds ratio for case fatalityof 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54%increase (95% CI, 39 to 69) in cerebral arterial diameter; and a93% increase (95% CI, 58 to 129) in cerebral blood flow. Weconclude that there is no evidence from animal studies that treatment with anETRA improves clinically relevant outcomes after SAH. The reduction in cerebralvasospasm observed in animal studies is consistent with that observed inclinical trials, an effect that is not associated with better functional outcomein patients.     

Effect of glutamate receptor antagonists on excitatory postsynaptic potentials in striatum

Glutamate, as the main transmitter of corticostriatal pathway, has a crucial role in the regulation of the activity of striatal cells as well as in pathogenesis of some diseases characterized by striatal malfunction caused by overexcitation of neurons. In the present study, the role of ionotropic excitatory amino acid receptors was investigated in the striatal synaptic transmission. Using conventional intracellular electrophysiological methods in brain slices, we have investigated the effects of the N-methyl-D-aspartate (NMDA) antagonist (±) 2-amino-5-phosphono-valerate (APV) and the α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) antagonist (±) 1-(4-aminophenyl)-3-methyl-carbamoyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 53655) on the excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of corpus callosum. The AMPA antagonist significantly decreased electrically evoked responses and a weak inhibition was also observed after APV application. The results were compared to similar data obtained in a cortical slice study.     

Effect of opioid receptor antagonists on hypothalamic-pituitary-adrenal activity in rhesus monkeys

Some opioid antagonists increase the release of adrenocorticotropic hormone (ACTH) and cortisol in humans and, therefore, may indicate that endogenous opioids modulate hypothalamic-pituitary-adrenal axis activity. The type of opioid receptor that may be related to these endocrine effects is unknown. The purpose of this experiment was to evaluate the ability of different opioid antagonists to increase ACTH and cortisol plasma levels in rhesus monkeys. Eight monkeys received intramuscular injections of various antagonists: 0.0032-1.0 mg/kg naltrexone, 0.1-3.2 mg/kg naltrindole (delta-selective), 0.032-0.32 mg/kg clocinnamox (mu-selective), and 1-3.2 mg/kg nor-binaltorphimine (kappa-selective). Naltrexone, 0.1-1.0 mg/kg, increased ACTH levels, whereas naltrindole and clocinnamox failed to increase ACTH levels. Nor-binaltorphimine, 1-3.2 mg/kg, increased ACTH concentrations on the day of injection, but not at a time when other assays continue to demonstrate kappa-antagonism (24 h). Cortisol concentrations generally followed the same pattern as the ACTH concentrations, but the incremental differences in cortisol release between doses were less clear. Thus, opioid modulation of ACTH and cortisol plasma levels is not clearly associated with a particular opioid receptor. Although the kappa-antagonist increased ACTH and cortisol release on the day of injection, some evidence suggests that this endocrine effect may be due to mechanisms other than those mediated by the kappa-receptor. Alternatively, the naltrexone-induced increase of ACTH and cortisol plasma levels may be caused by activity at multiple opioid receptors or some uncharacterized receptor. Finally, the increased release of ACTH and cortisol may be a response to naltrexone's aversive properties.     

Effect of glutamate receptor antagonists on migrating neural progenitor cells

Neurotransmitters such as glutamate are potential regulators of neurogenesis. Interference with defined glutamate receptor subtypes affects proliferation, migration and differentiation of neural progenitor cells. The cellular targets for the actions of different glutamate receptor ligands are less well known. In this study we have combined calcium imaging, measurement of membrane potential, time‐lapse imaging and immunocytochemistry to obtain a spatial overview of migrating mouse embryonic neural progenitor cell‐derived cells responding to glutamate receptor agonists and antagonists. Responses via metabotropic glutamate receptor 5 correlated with radial glial cells and dominated in the inner migration zones close to the neurosphere. Block of metabotropic glutamate receptor 5 resulted in shorter radial glial processes, a transient increase in neuron‐like cells emerging from the neurosphere and increased motility of neuron‐like cells. α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate receptors are present on the majority of migrating neuronal cells, which with time accumulate at the outer edge of the migration zone. Blocking these receptors leads to an enhanced extension of radial glial processes and a reduced motility of neuron‐like cells. Our results indicate that functional glutamate receptors have profound effects on the motility of neural progenitor cells. The main target for metabotropic glutamate receptor 5 appears to be radial glial cells while AMPA/kainate receptors are mainly expressed in newborn neuronal cells and regulate the migratory progress of these cells. The results suggest that both metabotropic glutamate receptor 5 and AMPA/kainate receptors are of importance for the guidance of migrating embryonic progenitor cells.     

The role of endothelin in the pathogenesis of vasospasm following subarachnoid haemorrhage

The purpose of the present study was to evaluate the vasocontractile activity of endothelin, a newly isolated endothelium-derived constrictor peptide, in canine basilar arteries in vitro and in vivo. Endothelin at concentrations of 10(-12) M approximately 3 X 10(-8) M elicited dose-dependent contractions of canine basilar arteries in vitro. The maximum tension was larger than that induced by 40 mM KCl. The EC50 value was 1.9 +/- 0.6 X 10(-9) M (mean +/- SEM). The endothelin-induced contraction was reversed by 10(-8) M nicardipine or 10(-5) M approximately 10(-4) M papaverine. An intracisternal injection of 0.6 approximately 1.2 X 10(-12) mol/kg of endothelin caused biphasic contraction of the basilar artery lasting for more than 24 h. The initial phase of the contraction accompanied remarkable changes in vital signs such as an acute rise of blood pressure, bradycardia and respiratory arrest. An intracisternal injection of 2.0 X 10(-12) mol/kg of endothelin also induced acute contraction of the basilar artery. However, all of the dogs which received an intracisternal injection of 2.0 X 10(-12) mol/kg of endothelin died from sustained respiratory insufficiency. The present results demonstrate that endothelin induces strong and long-lasting contractions of cerebral arteries. Therefore, endothelin may play an important role in the pathogenesis of vasospasm.     

Glutamate receptor antagonists and benzodiazepine inhibit the progression of granule cell dispersion in a mouse model of mesial temporal lobe epilepsy

PURPOSE: Unilateral intrahippocampal injection of kainic acid (KA) in adult mice induces the progressive dispersion of dentate granule cells, one of the characteristic pathologic changes of mesial temporal lobe epilepsy. However, little is known about the mechanisms that trigger this dispersion. In this study, the possible involvement of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmissions in the development of granule cell dispersion (GCD) was examined in this model. METHODS: Antagonists of N-methyl-d-aspartate (NMDA) receptor (MK-801) and non-NMDA receptor (GYKI52466), and an agonist of benzodiazepine-GABA(A) receptor (midazolam) were injected before and after KA in various ways, and the morphologic changes of the hippocampus, especially GCD, were examined. RESULTS: MK-801 (5 mg/kg, i.p.) did not reduce GCD when injected 2 h before KA injection but inhibited GCD almost completely for 相似文献   

Effect of GABA receptor agonists or antagonists on morphine-induced Straub tail in mice

The effects of GABA receptor agents on Straub tail induced by morphine were investigated in mice. Subcutaneous injection of different doses of morphine (10-60 mg/kg) induced a dose-dependent Straub tail in mice. Maximum response was obtained with 40 mg/kg of the drug, 30 min after the drug administration. The morphine response was decreased by subcutaneous injection of naloxone (0.5-2 mg/kg). Intraperitoneal administration of different doses of baclofen (2-8 mg/kg) reduced Straub tail induced by morphine (40 mg/kg). The response of baclofen was decreased by Intraperitoneal injection of CGP35348 (150 mg/kg). CGP35348 by itself did not elicit any response. Different Intraperitoneally doses of muscimol (1-4 mg/kg) bicuculline (1-3 mg/kg), or picrotoxin (1-3 mg/kg) also reduced morphine effect. The effect of muscimol was not altered by bicuculline pretreatment. It is concluded that both GABAA and GABAB receptor activation reduced Straub tail induced by morphine.     

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

The antagonist pharmacology of glutamate neurotoxicity was quantitatively examined in murine cortical cell cultures. Addition of 1-3 mM DL-2-amino-5-phosphonovalerate (APV), or its active isomer D-APV, acutely to the exposure solution selectively blocked the neuroexcitation and neuronal cell selectively blocked the neuroexcitation and neuronal cell loss produced by N-methyl-D-aspartate (NMDA), with relatively little effect on that produced by either kainate or quisqualate. As expected, this selective NMDA receptor blockade only partially reduced the neuroexcitation or acute neuronal swelling produced by the broad-spectrum agonist glutamate; surprisingly, however, this blockade was sufficient to reduce glutamate-induced neuronal cell loss markedly. Lower concentrations of APV or D-APV had much less protective effect, suggesting that the blockade of a large number of NMDA receptors was required to acutely antagonize glutamate neurotoxicity. This requirement may be caused by the amplification of small amounts of acute glutamate-induced injury by subsequent release of endogenous NMDA agonists from injured neurons, as the "late" addition of 10-1000 microM APV or D-APV (after termination of glutamate exposure) also reduced resultant neuronal damage. If APV or D-APV were present both during and after glutamate exposure, a summation dose-protection relationship was obtained, showing substantial protective efficacy at low micromolar antagonist concentrations. Screening of several other excitatory amino acid antagonists confirmed that the ability to antagonize glutamate neurotoxicity might correlate with ability to block NMDA-induced neuroexcitation: The reported NMDA antagonists ketamine and DL-2-amino-7-phosphono-heptanoate, as well as the broad-spectrum antagonist kynurenate, were all found to attenuate glutamate neurotoxicity substantially; whereas gamma-D-glutamylaminomethyl sulfonate and L-glutamate diethyl ester, compounds reported to block predominantly quisqualate or kainate receptors, did not affect glutamate neurotoxicity. The present study suggests that glutamate neurotoxicity may be predominantly mediated by the activation of the NMDA subclass of glutamate receptors--occurring both directly, during exposure to exogenous compound, and indirectly, due to the subsequent release of endogenous NMDA agonists. Given other studies linking NMDA receptors to channels with unusually high calcium permeability, this suggestion is consistent with previous data showing that glutamate neurotoxicity depends heavily on extracellular calcium.     

The effects of glutamate receptor antagonists on cerebellar granule cell survival and development

N-Methyl-d-aspartate (NMDA) receptor stimulation promotes neuronal survival and differentiation under both in vitro and in vivo conditions. We studied the effects of various NMDA receptor antagonists acting at different NMDA receptor binding sites and non-NMDA receptor antagonists on the development and survival of cerebellar granule cell (CGC) culture. Only three of the drugs tested induced neurotoxicity-MK-801 (non-competitive NMDA channel blocking antagonist), ifenprodil (an antagonist of the NR2B site and polyamine site of the NMDA receptor) and L-701.324 (full antagonist at glycine site), while CGP-37849 (a competitive NMDA antagonist), (+)-HA-966 (a partial agonist of the glycine site of the NMDA receptor), and NBQX (a competitively acting AMPA receptor antagonist) were not toxic at any concentration (1-100 microM) used. Among these drugs, only MK-801 was toxic for the immature CGC on second day in vitro (2DIV), and toxicity was diminished parallel to the neuronal maturation. In more mature neurons (7DIV), MK-801 demonstrated some neuroprotection, which diminished spontaneously occurring neuronal death in culture. Neither NMDA nor glutamate were able to prevent the neurotoxic effect of MK-801 at 2DIV. MK-801, ifenprodil and L-701.324 induced DNA fragmentation on 2DIV in CGC culture measured by the TUNEL method. The BOC-D-FMK, the universal caspase inhibitor, completely reversed MK-801-induced DNA fragmentation, suggesting an apoptotic pathway of MK-801-induced cell death. Neurite outgrowth as a characteristic feature of the development of CGC was diminished after treatment with MK-801, ifenprodil and L-701.324. In conclusion, the results of the present study demonstrate that only nonselective channel blocker MK-801 decreases cell viability, induces apoptosis and inhibits neurite outgrowth of CGC in a development-dependent manner.     

Effect of N-acetylcysteine on vasospasm in subarachnoid hemorrhage

Vasospasm remains an extremely serious complication that affects patients presenting with subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms. The current therapeutic armamentarium is still insufficient in many cases, and the search for new therapies is necessary. In this study, we evaluated the effect of N-acetylcysteine (NAC) on cerebral arterial vasospasm using an experimental model. Twenty-four wistar rats were divided into 4 groups: [1] Control, [2] SAH, [3] SAH+NAC and [4] SAH+Placebo. The experimental model employed double subarachnoid injections of autologous blood. The proposed dose of NAC was 250 mg/kg intraperitoneally per day. We analyzed the inner area of the basilar artery to assess the action of NAC. The experimental model proved to be very adequate, with a mortality rate of 4%. The inner area of the basilar artery in the SAH group showed significant difference to the control group (p=0.009). The use of NAC significantly reduced vasospasm as compared to the untreated group (p=0.048) and established no significant difference to the control group (p=0.098). There was no significant improvement with the administration of placebo (p=0.97). The model of the dual hemorrhage proved to be very useful for vasospasm simulation, with overall low mortality. The administration of NAC significantly reduced vasospasm resulting from SAH, and may represent a new therapeutic alternative.     

Experimental model of symptomatic vasospasm in rabbits

The common carotid arteries were ligated bilaterally 2 weeks before induction of subarachnoid hemorrhage in rabbits. The rabbits were observed closely for clinical symptoms, and angiographic and pathologic investigations were performed. Thirteen experimental rabbits showed a progressing neurologic deficit that was worst on the fourth or fifth day after the subarachnoid hemorrhage. This symptomatic change did not occur in five rabbits without previous carotid ligation. Presumably, the rabbits with carotid ligation became symptomatic because they no longer had a collateral blood flow to compensate for the reduced blood flow in the basilar artery after subarachnoid hemorrhage. Our model of symptomatic vasospasm after subarachnoid hemorrhage may be beneficial for future studies.     

不同剂量利多卡因在蛛网膜下腔出血脑血管痉挛抑制中的作用

目的：比较枕大池注入不同剂量的利多卡因对蛛网摸下腔出血的脑保护作用,确定最佳的利多卡因枕大池注入剂量。方法：56只新西兰大白兔随机分为假手术组（sham）、蛛网膜下腔出血组（SAH）、利多卡因1mg组（LD1）、利多卡因2mg组（LD2）、利多卡因4mg组（LD4）、利多卡因6mg组（LD6）,假手术组6只,其余每组10只。各组动物均在全麻下行手术操作,出血组和各利多卡因治疗组的动物取自体动脉血1.5ml注入枕大池,而假手术组注入1.5ml生理盐水。半小时后假手术组和出血组的动物再次从枕大池注入0.3ml生理盐水,各治疗组（C-F）分别注入2%的利多卡因0.05ml、0.1ml、0.2ml、0.3ml。72小时后所有动物在深麻醉下行心脏全身灌注固定取脑基底动脉以及海马组织行病理检查测定血管管腔面积和直径、海马正常神经元密度、C-FOS阳性细胞数目。所有数据采用（means ± SD）表示,采用单因素方差分析,以（P＜0.05）为显著差异。结果：蛛网膜下腔出血组的海马正常神经元密度比假手术组及各治疗组的低,而海马C-FOS阳性细胞比假手术组及各治疗组的多（P＜0.05、P＜0.01或P＜0.001）;蛛网膜下腔出血组脑基底动脉的直径及管腔面积比假手术组及各治疗组的小（P＜0.05或P＜0.01）。各个治疗组之间的神经元密度以及C-FOS阳性细胞比较没统计学差异,6mg组的基底动脉直径和管腔面积比1mg组的大（P＜0.05）。结论：枕大池给不同剂量利多卡因对蛛网膜下腔出血均有不同程度的脑保护作用,利多卡因6mg组的保护作用可能会更好。     

Effects of nonenzymatic glycosylation of extracellular matrix components on cell survival and sensory neurite extension in cell culture

Diabetic sensory polyneuropathy is characterized by a distal axonopathy of dying-back type. It is accompanied by a failure of axonal regeneration, in which nonenzymatic glycosylation (glycation) of the extracellular matrix may be involved. In the present study, the effects of glycation of collagen IV and laminin, major components of basal lamina, on neuron survival and neurite extension were investigated in tissue culture. Fast glycation of laminin was achieved by incubation with glycolaldehyde and glycation of collagen IV by incubation with glucose. The degree of glycation was estimated by fluorescence analysis. Glycated or nonglycated laminin or collagen IV were used as substrates for culture of dorsal root ganglion (DRG) neurons from neonatal rats. Cultures were assessed for the proportion of cells attaching to the substrate, surviving and bearing neurites. Cell attachment and the proportion bearing neurites were significantly reduced on collagen IV glycated for 2 weeks, but survival was only affected by glycation for 4 or 5 weeks. All 3 parameters were significantly reduced on glycated compared with unglycated laminin. Glycation of both laminin and collagen IV produced considerable morphological differences in the cultured neurons on scanning electron microscopy. Dissociated DRG neurons from adult animals with streptozotocin-induced diabetes cultured on nonglycated substrates survived less well and produced fewer neurites. Glycation of collagen IV and laminin thus affects neuronal survival, neurite production and cell morphology, and diabetes affects both the survival of sensory neurons in culture and their ability to extend neurites. Received: 21 May 2001, Received in revised form: 19 July 2001, Accepted: 21 August 2001     

The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model

We investigated the effect of two different doses of dexmedetomidine on vasospasm in a rat model of subarachnoid haemorrhage (SAH). SAH was induced by injecting 0.3 mL blood into the cisterna magna in all rat groups except the control (Group C). At 1 hour and 24 hours after SAH, 5 μg/kg dexmedetomidine was given to group D5, and 10 μg/kg dexmedetomidine was given to group D10. No medication was administered to the haemorrhage group (Group H). Malondialdehyde (MDA) and paraoxonase (PON) levels were measured at 48 hours after SAH. Mean wall thickness (MWT), mean luminal diameter (MLD), and proliferating cell nuclear antigen (PCNA) expression of the basilar artery were evaluated. MDA levels and MWT were lower in the dexmedetomidine groups. The lowest MDA levels and MWT were found in Group D10. The MLD was lowest in Group H. PCNA expression was observed only in Group D10. We concluded that dexmedetomidine reduces oxidative stress and vasospasm following SAH in a dose-dependent manner.     

Increased cerebrovascular sensitivity to endothelin-1 in a rat model of obstructive sleep apnea: a role for endothelin receptor B

Obstructive sleep apnea (OSA) is associated with cerebrovascular diseases. However, little is known regarding the effects of OSA on the cerebrovascular wall. We tested the hypothesis that OSA augments endothelin-1 (ET-1) constrictions of cerebral arteries. Repeated apneas (30 or 60 per hour) were produced in rats during the sleep cycle (8 hours) by remotely inflating a balloon implanted in the trachea. Four weeks of apneas produced a 23-fold increase in ET-1 sensitivity in isolated and pressurized posterior cerebral arteries (PCAs) compared with PCAs from sham-operated rats (EC₅₀=10^−9.2 mol/L versus 10^−10.6 mol/L; P<0.001). This increased sensitivity was abolished by the ET-B receptor antagonist, BQ-788. Constrictions to the ET-B receptor agonist, IRL-1620, were greater in PCAs from rats after 2 or 4 weeks of apneas compared with that from sham-operated rats (P=0.013). Increased IRL-1620 constrictions in PCAs from OSA rats were normalized with the transient receptor potential channel (TRPC) blocker, {"type":"entrez-protein","attrs":{"text":"SKF96365","term_id":"1156357400","term_text":"SKF96365"}}SKF96365, or the Rho kinase (ROCK) inhibitor, Y27632. These data show that OSA increases the sensitivity of PCAs to ET-1 through enhanced ET-B activity, and enhanced activity of TRPCs and ROCK. We conclude that enhanced ET-1 signaling is part of a pathologic mechanism associated with adverse cerebrovascular outcomes of OSA.     

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats

Summary Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and -methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.     

Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists

Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.