scholarly journals Regional Neuroprotective Effects of the NMDA Receptor Antagonist MK-801 (Dizocilpine) in Hypoglycemic Brain Damage

1990 ◽  
Vol 10 (2) ◽  
pp. 270-276 ◽  
Author(s):  
M. P. Papagapiou ◽  
R. N. Auer
Keyword(s):  
Nmda Receptor ◽  
Brain Temperature ◽  
Neuroprotective Effect ◽  
Pyramidal Cells ◽  
Receptor Activation ◽  
Brain Regions ◽  
Current Evidence ◽  
Neuroprotective Effects ◽  
Neuronal Necrosis ◽  
Mk 801

Current evidence points to an important role of N-methyl-d-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 {dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5 H-di[ a,d]cyclohepten-5,10-imine} is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood–brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5–5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5–2.0 m M) at the stage of δ-wave (1–4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of δ-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.

Neuroprotective Effects of Alisol A 24-acetate on Cerebral Ischemia-reperfusion Injury by Regulating PI3K/AKT Pathway

2021 ◽  
Author(s):  
Taotao Lu ◽  
Huihong Li ◽  
Yangjie Zhou ◽  
Wei Wei ◽  
Linlin Ding ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Brain Regions ◽  
Global Cerebral Ischemia ◽  
Akt Pathway ◽  
Object Recognition Test ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion

Abstract BackgroundNeuroinflammation and apoptosis are involved in the pathogenesis of ischemic stroke. Alisol A 24-acetate (24A) has a strong inhibitory effect on inflammation and cell apoptosis. The neuroprotective effect of 24A in the global cerebral ischemia/ reperfusion (GCI/R) is still unclear. Methods GCI/R mice was used to investigated the neuroprotective effect of 24A. Modified neurological deficit scores, Morris Water Maze and object recognition test were used to evaluate behaviors. The metabolism in brain regions was detected by MRS. The changes of microglia, astrocytes and neurons was detected. The inflammation and apoptosis were measured.Results The results showed that 24A improved behavioral dysfunction and brain metabolism, alleviate neuroinflammation and apoptosis, inhibited microglia and astrocytes activation, which is associated with the activation of PI3K/AKT pathway. ConclusionsTaken together, our study demonstrated that 24A could alleviate GCI/R injury through anti-neuroinflammation and anti-apoptosis via regulating the PI3K/AKT pathway.

scholarly journals NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

1998 ◽  
Vol 84 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Patricia J. Ohtake ◽  
José E. Torres ◽  
Yair M. Gozal ◽  
Gavin R. Graff ◽  
David Gozal
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Sodium Cyanide ◽  
Respiratory Drive ◽  
Peripheral Chemoreceptor ◽  
Cardiorespiratory Control ◽  
Mk 801 ◽  
Ventilatory Responses ◽  
Before And After

N-methyl-d-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (V˙e) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (Vt) decreased while frequency increased, resulting in a modest reduction inV˙e. Inspiratory time (Ti) decreased, whereas expiratory time remained unchanged. TheV˙e responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (Vt/Ti) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas Vt was unaffected. Sodium cyanide doses associated with significantV˙eincreases were 5 and 50 μg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reducedV˙e during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.

Neuroprotective Effects of Propofol in a Model of Ischemic Cortical Cell Cultures

2003 ◽  
Vol 99 (2) ◽  
pp. 368-375 ◽  
Author(s):  
Lionel J. Velly ◽  
Benjamin A. Guillet ◽  
Frederique M. Masmejean ◽  
André L. Nieoullon ◽  
Nicolas J. Bruder ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Cell Cultures ◽  
Glutamate Uptake ◽  
Neuroprotective Effect ◽  
Glutamate Release ◽  
Cortical Cell ◽  
Neuroprotective Effects ◽  
Mk 801 ◽  
Lactate Dehydrogenase Release ◽  
Cortical Cell Cultures

Background During cerebral ischemia, excess of glutamate release and dysfunction of its high affinity transport induce an accumulation of extracellular glutamate, which plays an important role in neuronal death. The authors studied the relationship among propofol neuroprotection, glutamate extracellular concentrations, and glutamate transporter activity in a model of ischemic cortical cell cultures. Methods Thirteen-day-old primary cortical neuronal-glial cultures were exposed to a 90-min combined oxygen-glucose deprivation (OGD) in an anaerobic chamber, followed by reoxygenation. Propofol was added only during the OGD period, and its effect was compared to that of the N-methyl-d-aspartate receptor antagonist dizocilpine (MK-801). Twenty-four hours after the injury, cell death was quantified by lactate dehydrogenase release and cell viability by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). Extracellular concentrations of glutamate in culture supernatants and glutamate uptake were performed at the end of OGD period by high-performance liquid chromatography and incorporation of l-[3H]glutamate into cells, respectively. Results At clinically relevant concentrations (0.05-10 microm), propofol offered protection equivalent to that of MK-801. It significantly reduced lactate dehydrogenase release and increased the reduction of MTT. At the end of the ischemic injury, propofol was able to reverse the OGD-induced increase in glutamate extracellular concentrations and decrease of glutamate uptake. The inhibition of the glial GLT1 transporter by 3-methyl-glutamate did not further modify the effect of propofol on glutamate uptake, suggesting that GLT1 was not the major target of propofol. Conclusion Propofol showed a neuroprotective effect in this in vitro model of OGD, which was apparently mediated by a GLT1-independent restoration of the glutamate uptake impaired during the injury.

FC29-03 - Effects of chronic oral treatment with aripiprazole on expression of nmda receptor subunits and binding sites in rat brain

2011 ◽  
Vol 26 (S2) ◽  
pp. 1979-1979
Author(s):  
M. Zink ◽  
N. Segnitz ◽  
T. Ferbert ◽  
A. Schmitt ◽  
P. Gass ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Negative Symptoms ◽  
Oral Treatment ◽  
Antipsychotic Agents ◽  
Brain Regions ◽  
Relative Increase ◽  
Receptor Expression ◽  
Sprague Dawley ◽  
Adult Type ◽  
Mk 801

IntroductionThe glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.ObjectivesThe partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.AimsTo evaluate effects of APZ on NR mRNA and protein expressionMethodsWe treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.ResultsIncreased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.ConclusionsThe effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.

Spontaneous GABAA receptor-mediated inhibitory currents in adult rat somatosensory cortex

1996 ◽  
Vol 75 (4) ◽  
pp. 1573-1588 ◽  
Author(s):  
P. A. Salin ◽  
D. A. Prince
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Gabaa Receptor ◽  
Decay Time ◽  
High Frequency ◽  
Pyramidal Cells ◽  
Receptor Activation ◽  
Inhibitory Interneurons ◽  
Adult Rat ◽  
Bath Application

1. Spontaneous inhibitory synaptic currents (sIPSCs) were studied with whole cell voltage-clamp recordings from 131 pyramidal cells in adult rat somatosensory cortical slices. Neurons were intracellulary labeled with biocytin and classified as supragranular (SG, layers 2-3), layer IV (IV), or infragranular (IG, layer V) on the basis of the laminar localization of their somata. Somatic areas were similar for SG, IV, and IG neurons. All identified pyramidal cells generated high-frequency gamma-aminobutyric acid (GABAA) receptor-mediated synaptic events. 2. Bath application of bicuculline blocked the sIPSCs and resulted in a decrease of approximately 0.5 nS in resting conductance and an inward shift in baseline current. 3. sIPSC frequency was significantly lower in SG versus IG or IV neurons, and this difference was accounted for by the occurrence of a higher percentage of bursts of sIPSCs in the IG and IV neurons. 4. Bath application of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) decreased the frequency of sIPSCs by 13-21%. By contrast, application of the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovaleric acid (D-AP5) generally had no effect on spontaneous IPSC frequency, suggesting that AMPA rather than NMDA receptor activation contributed to resting discharge of inhibitory interneurons. 5. Addition of tetrodotoxin (TTX) to the perfusion medium reduced the spontaneous IPSC frequency by approximately 30-55%. The miniature IPSCs (mIPSCs) seen in TTX-containing solutions had a frequency of approximately 10 Hz and an average conductance of 0.42-0.48 nS. 6. The kinetic properties of mIPSCs generated in pyramidal cells of different layers were the same, with the rise times of approximately 0.9 ms and decay time constants of approximately 8 ms at a holding potential of 0 mV. The decay phase of mIPSCs was generally fitted by one exponential and displayed a voltage dependence with an e-fold increase in decay time constant for a every 198-mV depolarization. 7. These results show that there is ongoing spontaneous release of GABA in neocortical slices that gives rise to high-frequency impulse-related and non-impulse-related postsynaptic inhibitory currents. Activation of AMPA receptors on inhibitory interneurons accounts for only a small proportion of the GABAA receptor-mediated events. Judging from the distribution of mIPSC frequencies in neurons of different laminae, there is a relatively uniform distribution of inhibitory synapses throughout the cortex. Tonic activation of GABAA receptors on neocortical pyramidal neurons generates an increase in resting membrane conductance that may play an important role in vivo by preventing the development of hyperexcitability, modulating excitatory synaptic events, and controlling the rate and patterns of spike discharge.

NMDA Receptor–Dependent Increase of Cerebral Glucose Utilization after Hypoxia–Ischemia in the Immature Rat

1996 ◽  
Vol 16 (5) ◽  
pp. 1005-1013 ◽  
Author(s):  
Eric Gilland ◽  
Henrik Hagberg
Keyword(s):  
Nmda Receptor ◽  
Glucose Utilization ◽  
Neuroprotective Effect ◽  
Nmda Receptor Antagonist ◽  
Immature Rat ◽  
Mk 801 ◽  
Cerebral Glucose Utilization ◽  
Hypoxia Ischemia ◽  
Dg Method ◽  
Old Rats

Post-treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 reduces hypoxic–ischemic brain injury in immature animals. To elucidate possible mechanisms, cerebral glucose utilization (CMRglc) and cerebral blood flow (CBF) were measured 1–5 h after hypoxia–ischemia and administration of MK-801 in 7-day-old rats. After 100 min of unilateral hypoxia–ischemia, half of the pups were injected with MK-801. CMRglc was assessed by the [14C]deoxyglucose (2-DG) method. The brains were analyzed either by autoradiography or for energy metabolites and chromatographic separation of 2-DG-6-phosphate and 2-DG. CBF was measured by the autoradiographic [14C]iodoantipyrine method. Mean CMRglc in the cerebral cortex was increased ipsilaterally after hypoxia–ischemia to 15 ± 3.3 μmol 100 g−1 min−1 ( p < 0.01) and areas with CMRglc >20 μmol 100 g−1 min−1 amounted to 8.0 ± 7.7 mm2 in the ipsilateral hemisphere compared with 1.2 ± 1.6 mm2 contralateral ( p < 0.001). Treatment with MK-801 decreased CMRglc bilaterally ( p < 0.05) and reduced ipsilateral areas with increased CMRglc by 64% ( p < 0.01). CBF was unaltered after hypoxia–ischemia and by MK-801 treatment. In conclusion, regional glucose hyper-utilization in the parietal cortex after hypoxia–ischemia was attenuated by MK-801; this may have relevance to the neuroprotective effect of NMDA-receptor antagonists in this model.

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