Alkalemia reduces recovery from global cerebral ischemia by NMDA receptor-mediated mechanism

1997 ◽  
Vol 272 (6) ◽  
pp. H2557-H2562
Author(s):  
P. D. Hurn ◽  
R. C. Koehler ◽  
R. J. Traystman
Keyword(s):  
Energy Metabolism ◽  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Nmda Receptor Antagonist ◽  
Global Cerebral Ischemia ◽  
Resonance Spectroscopy ◽  
Mk 801 ◽  
Sagittal Sinus

In vitro data suggest that low tissue pH reduces, whereas extracellular alkalosis potentiates, cerebral anoxic injury via excitotoxic mechanisms. We tested the hypothesis that in vivo metabolic alkalemia potentiates defects in energy metabolism after global incomplete cerebral ischemia (12 min) and reperfusion (180 min) by an N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. Brain ATP, phosphocreatine, and intracellular pH (pHi) were measured by 31P magnetic resonance spectroscopy in anesthetized dogs treated with 1) preischemic intravenous carbicarb buffer (NaHCO3+Na2CO3, Carb, n = 7); 2) carbicarb infusion plus NMDA receptor antagonist MK-801 (MK-801 + Carb, n = 7); 3) an osmotically equivalent volume of 5% NaCl (NaCl, n = 8); or 4) equivalent volume of 0.9% NaCl (Sal, n = 3). Sagittal sinus pH was raised to 7.82 +/- 0.04 before and 7.65 +/- 0.03 during ischemia in Carb vs. 7.72 +/- 0.01 and 7.60 +/- 0.01 in MK-801+Carb, 7.25 +/- 0.02 and 7.15 +/- 0.03 in NaCl, and 7.31 +/- 0.00 and 7.26 +/- 0.01 in Sal, respectively. Ischemic cerebral blood flow (CBF, radiolabeled microspheres), pHi, and ATP reduction were similar among groups. By 180 min of reperfusion, recovery of ATP was greater in MK-801+Carb (104 +/- 6% of baseline), NaCl (93 +/- 6%), and Sal (94 +/- 6%) than in Carb (47 +/- 6%). Intraischemic pHi was similar among groups, and pHi recovery did not vary among groups despite differences in sagittal sinus pH. In Carb, CBF was restored but with delayed hypoperfusion. We conclude that extracellular alkalosis is deleterious to postischemic CBF and energy metabolism, acting by NMDA receptor-mediated mechanisms.

Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive (NMDA) receptor antagonist, in vitro and in vivo

1992 ◽  
Vol 135 (2) ◽  
pp. 149-152 ◽  
Author(s):  
Michael L. Vazquez ◽  
Danny J. Garland ◽  
Eric T. Sun ◽  
Julie A. Cler ◽  
Steve J. Mick ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Receptor Antagonist

scholarly journals Characterization of Metabotropic Glutamate Receptor-Mediated Nitric Oxide Production in Vivo

1997 ◽  
Vol 17 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Anish Bhardwaj ◽  
Frances J. Northington ◽  
Lee J. Martin ◽  
Daniel F. Hanley ◽  
Richard J. Traystman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Calcium Release ◽  
Nmda Receptor Antagonist ◽  
No Production ◽  
Calcium Release Channel ◽  
Mk 801 ◽  
Metabotropic Glutamate

We tested the hypothesis that stimulation of metabotropic glutamate receptors (mGluRs) increases nitric oxide (NO) production in the hippocampus in vivo. Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of adult Sprague–Dawley rats under pentobarbital anesthesia. Probes were perfused for 5 h with artificial cerebrospinal fluid (CSF) containing 3 μM [14C]-L-arginine. Recovery of [14C]-L-citrulline in the effluent was used as a marker of NO production. In nine groups of rats, increases in [14C]-L-citrulline recovery were compared between right- and left-sided probes perfused with various combinations of the selective mGluR agonist, trans-(1 S,3 R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD); the mGluR antagonist, (±)- α-methyl-4-carboxyphenylglycine (MCPG); the NO synthase inhibitor, N-nitro-L-arginine (LNNA); the ryanodine sensitive calcium-release channel inhibitor dantrolene, the non- N-methyl-D-aspartate (NMDA); receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d] cyclohepten-5,10-imine (MK-801); and the Na+ channel blocker, tetrodotoxin. Recovery of [14C]-L-citrulline during perfusion with artificial CSF progressively increased to 90 ± 21 fmol/min (± SD) over 5 h. Perfusion in the contralateral hippocampus with 1 m M ACPD augmented [14C]-L-citrulline recovery to 250 ± 81 fmol/min. Perfusion of 1 m M nitroarginine + ACPD inhibited [14C]-L-citrulline recovery compared to that with ACPD alone. Perfusion with 1 m M MCPG + ACPD attenuated ACPD enhanced [14C]-L-citrulline recovery. Perfusion of 1 m M dantrolene + ACPD inhibited the ACPD-evoked increase in [14C]-L-citrulline recovery. Perfusion of 1 m M MCPG or dantrolene without ACPD did not decrease [14C]-L-citrulline recovery as compared to CSF alone. ACPD-enhanced [14C]-L-citrulline recovery was not attenuated by CNQX, MK-801, or tetrodotoxin (TTX). Using an indirect method of assessing NO production in vivo, these data demonstrate that mGluR stimulation enhances NO production in rat hippocampus. Inhibition with dantrolene suggests that calcium-induced calcium release amplifies the inositol triphosphate-mediated calcium signal associated with mGluR stimulation, thereby resulting in augmented calcium-dependent NO production.

Brain monoamine oxidase A in hyperammonemia is regulated by NMDA receptors

2009 ◽  
Vol 4 (3) ◽  
pp. 321-326
Author(s):  
Elena Kosenko ◽  
Yury Kaminsky
Keyword(s):  
Oxidative Stress ◽  
Nmda Receptor ◽  
Monoamine Oxidase ◽  
Nmda Receptors ◽  
Monoamine Oxidase A ◽  
Mk 801 ◽  
Mao A ◽  
Vitro Effect

AbstractMitochondrial enzyme monoamine oxidase A (MAO-A) generates hydrogen peroxide (H2O2) and is up-regulated by Ca2+ and presumably by ammonia. We hypothesized that MAO-A may be under the control of NMDA receptors in hyperammonemia. In this work, the in vivo effects of single dosing with ammonia and NMDA receptor antagonist MK-801 and the in vitro effect of Ca2+ on MAO-A activity in isolated rat brain mitochondria were studied employing enzymatic procedure. Intraperitoneal injection of rats with ammonia led to an increase in MAO-A activity in mitochondria indicating excessive H2O2 generation. Calcium added to isolated mitochondria stimulated MAO-A activity by as much as 84%. MK-801 prevented the in vivo effect of ammonia, implying that MAO-A activation in hyperammonemia is mediated by NMDA receptors. These data support the conclusion that brain mitochondrial MAO-A is regulated by the function of NMDA receptors. The enzyme can contribute to the oxidative stress associated with hyperammonemic conditions such as encephalopathy and Alzheimer’s disease. The attenuation of the oxidative stress highlights MAO-A inactivation and NMDA receptor antagonists as sources of novel avenues in the treatment of mental disorders.

scholarly journals Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1139 ◽  
Author(s):  
Alessandra Grossert ◽  
Narges Zare Mehrjardi ◽  
Sarah J. Bailey ◽  
Mark A. Lindsay ◽  
Jürgen Hescheler ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Nmda Receptor Antagonist ◽  
Insulin Like Growth Factor

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of our study was to investigate the molecular mechanism of ketamine at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). Notably, ketamine increased the proliferation of NPCs independent of the NMDA receptor, while transcriptome analysis revealed significant upregulation of insulin-like growth factor 2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 h after ketamine treatment. Ketamine (1 µM) was able to increase cyclic adenosine monophosphate (cAMP) signaling in NPCs within 15 min and cell proliferation, while ketamine-induced IGF2 expression was reduced after PKA inhibition with cAMPS-Rp. Furthermore, 24 h post-administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes the proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

scholarly journals Cellular Origin and Regulation of D-and L-Serine in in Vitro and in Vivo Models of Cerebral Ischemia

2014 ◽  
Vol 34 (12) ◽  
pp. 1928-1935 ◽  
Author(s):  
Takato Abe ◽  
Masataka Suzuki ◽  
Jumpei Sasabe ◽  
Shinichi Takahashi ◽  
Miyuki Unekawa ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Cultured Cells ◽  
Long Term Potentiation ◽  
Artery Occlusion ◽  
In Vitro Experiments ◽  
In Vivo Models ◽  
Cellular Origin

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-Serine from L-Serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-Serine remain elusive. The D-/L-Serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-Serine is derived from neurons, while L-Serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-Serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-Serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

scholarly journals Effect of Dichloroacetate on Recovery of Brain Lactate, Phosphorus Energy Metabolites, and Glutamate during Reperfusion after Complete Cerebral Ischemia in Rats

1992 ◽  
Vol 12 (6) ◽  
pp. 1030-1038 ◽  
Author(s):  
Lee-Hong Chang ◽  
Hiroaki Shimizu ◽  
Hisashi Abiko ◽  
Raymond A. Swanson ◽  
Alan I. Faden ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Water Content ◽  
Serum Lactate ◽  
Resonance Spectroscopy ◽  
Therapeutic Effects ◽  
Ischemic Period ◽  
Complete Cerebral Ischemia ◽  
Brain Lactate

The effects of dichloroacetate (DCA) on brain lactate, intracellular pH (pHi), phosphocreatine (PCr), and ATP during 60 min of complete cerebral ischemia and 2 h of reperfusion were investigated in rats by in vivo 1H and 31P magnetic resonance spectroscopy; brain lactate, water content, cations, and amino acids were measured in vitro after reperfusion. DCA, 100 mg/kg, or saline was infused before or immediately after the ischemic period. Preischemic treatment with DCA did not affect brain lactate or pHi during ischemia, but reduced lactate and increased pHi after 30 min of reperfusion ( p < 0.05 vs. controls) and facilitated the recovery of PCr and ATP during reperfusion. Postischemic DCA treatment also reduced brain lactate and increased pHi during reperfusion compared with controls ( p < 0.05), but had little effect on PCr, ATP, or Pi during reperfusion. After 30 min of reperfusion, serum lactate was 67% lower in the postischemic DCA group than in controls ( p < 0.05). The brain lactate level in vitro was 46% lower in the postischemic DCA group than in controls ( p < 0.05). DCA did not affect water content or cation concentrations in either group, but it increased brain glutamate by 40% in the preischemic treatment group ( p < 0.05). The potential therapeutic effects of DCA on brain injury after complete ischemia may be mediated by reduced excitotoxin release related to decreased lactic acidosis during reperfusion.

NMDA receptor antagonist effects of the stereoisomers of β-cyclazocine in rats, in vivo and in vitro

1991 ◽  
Vol 192 (3) ◽  
pp. 337-342 ◽  
Author(s):  
John Church ◽  
John D. Millar ◽  
Martyn G. Jones ◽  
David Lodge
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Receptor Antagonist
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