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A Buisson

Publications and source records attributed to A Buisson.

At least 19 recordsLinked to original sources
PubMed2001

A soluble transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses.

Transforming growth factor-beta (TGF-beta) signaling requires a ligand-dependent interaction of TGF-beta receptors Tau beta R-I and Tau beta R-II. It has been previously demonstrated that a soluble TGF-beta type II receptor could be used as a TGF-beta antagonist. Here we have generated and investigated the biochemical and signaling properties of a soluble TGF-beta type I receptor (Tau beta RIs-Fc). As reported for the wild-type receptor, the soluble Tau beta R-I does not bind TGF-beta 1 on its own. Surprisingly, in the absence of TGF-beta1, the Tau beta RIs-Fc mimicked TGF-beta 1-induced transcriptional and growth responses in mink lung epithelial cells (Mv1Lu). Signaling induced by the soluble TGF-beta type I receptor is mediated via the obligatory presence of both TGF-beta type I and type II receptors at the cell surface since no signal was observed in Mv1Lu-derivated mutants for TGF-beta receptors R-1B and DR-26. The comparison between the structures of TGF-betas and a three-dimensional model of the extracellular domain of Tau beta RI has shown that five residues of the supposed binding site of TGF-beta 1 (Lys(31), His(34), Glu(5), Tyr(91), and Lys(94)) were found with equivalent biochemical properties and similar spatial positions.

Amino Acid Sequence↗
PubMed2001

Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway.

The glial cell line-derived neurotrophic factor (GDNF) is first characterized for its trophic activity on dopaminergic neurons. Recent data suggested that GDNF could modulate the neuronal death induced by ischemia. The purpose of this study was to characterize the influence of GDNF on cultured cortical neurons subjected to two paradigms of injury (necrosis and apoptosis) that have been identified during cerebral ischemia and to determine the molecular mechanisms involved. First, we demonstrated that both neurons and astrocytes express the mRNA and the protein for GDNF and its receptor complex (GFRalpha-1 and c-Ret). Next, we showed that the application of recombinant human GDNF to cortical neurons and astrocytes induces the activation of the MAP kinase (MAPK) pathway, as visualized by an increase in the phosphorylated forms of extracellular signal-regulated kinases (ERKs). Thereafter, we demonstrated that GDNF fails to prevent apoptotic neuronal death but selectively attenuates slowly triggered NMDA-induced excitotoxic neuronal death via a direct effect on cortical neurons. To further characterize the neuroprotective mechanisms of GDNF against NMDA-mediated neuronal death, we showed that a pretreatment with GDNF reduces NMDA-induced calcium influx. This effect likely results from a reduction of NMDA receptor activity rather than an enhanced buffering or extrusion capacity for calcium. Finally, we also demonstrated that an ERKs activation pathway is necessary for GDNF-mediated reduction of the NMDA-induced calcium response. Together, these results describe a novel mechanism by which the activation of MAPK induced by GDNF modulates NMDA receptor activity, a mechanism that could be responsible for the neuroprotective effect of GDNF in acute brain injury.

Animals↗
PubMed2001

Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death.

The anaphylatoxin C3a is a potent inflammatory polypeptide released at sites of complement activation. To test whether C3a might alter neuronal outcome following an ischemic insult, we determined the effects of purified human C3a on murine primary cortical cell cultures exposed to apoptotic or excitotoxic paradigms. C3a prevented neither serum deprivation-induced apoptotic neuronal death, nor AMPA/kainate-mediated excitotoxicity. However, in mixed cultures of neurons and astrocytes, C3a dose-dependently protected neurons against NMDA toxicity (47% neuroprotection using 100 nM C3a, p < 0.01, n = 12). The neuroprotective effect of C3a was observable only in the presence of astrocytes. These observations suggest that C3a is involved in excitotoxicity-mediated neuronal death through astrocyte stimulation and extend its role beyond immune functions.

Anaphylatoxins↗
PubMed2001

The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.

Tissue-plasminogen activator (t-PA) is now available for the treatment of thrombo-embolic stroke but adverse effects have been reported in some patients, particularly hemorrhaging. In contrast, the results of animal studies have indicated that t-PA could increase neuronal damage after focal cerebral ischemia. Here we report for the first time that t-PA potentiates signaling mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor. When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor. Moreover, the treatment with recombinant t-PA leads to a 37% increase in NMDA-stimulated fura-2 fluorescence, which may reflect an increased NMDA-receptor function. These results were confirmed in vivo by the intrastriatal injection of recombinant-PA, which potentiated the excitotoxic lesions induced by NMDA. These data provide insight into the regulation of NMDA-receptor-mediated signaling and could initiate therapeutic strategies to improve the efficacy of t-PA treatment in man.

Animals↗
PubMed2001

Increased expression of transforming growth factor-beta after cerebral ischemia in the baboon: an endogenous marker of neuronal stress?

There has been an increasing interest in recent years in the evaluation of the neuronal and glial responses to ischemic insult. Some cytokines, including transforming growth factor-beta (TGF-beta), that are overexpressed after experimental stroke in rodents are thought to be implicated in the neuronal processes that lead to necrosis. Thus, such cytokines could predict tissue fate after stroke in humans, although data are currently sparse for gyrencephalic species. The current study addressed the expression pattern of TGF-beta1 in a nonhuman primate model of middle cerebral artery occlusion. Focal permanent ischemia was induced for 1 or 7 days in 6 baboons and the following investigations were undertaken: cerebral oxygen metabolism (CMRO2) positron emission tomography studies, magnetic resonance imaging, postmortem histology, and reverse transcription-polymerase chain reaction. The aim of the current study was to correlate the expression of TGF-beta1 to the underlying metabolic and histologic state of the threatened cerebral parenchyma. The authors evidenced increased TGF-beta1 mRNA levels (up to 25-fold) in those regions displaying a moderate (20% to 49%) reduction in CMRO2. The current findings suggest that the greatly enhanced expression of TGF-beta1 in the penumbral zones that surround tissue destined to infarction may represent a robust index of potentially salvageable brain. The current investigation, in the nonhuman primate, strengthens the authors' hypothesis, derived from rodent models, that TGF-beta1 may be involved in the physiopathology of human stroke.

Animals↗
PubMed2000

Serine protease inhibitors: novel therapeutic targets for stroke?

Although the thrombolytic activity of tissue-type plasminogen activator (t-PA) may be beneficial in the acute treatment of stroke, recent studies have suggested that this serine protease could also play a critical role in determining the extent of neuronal death after injury to the central nervous system (CNS). This hypothesis is based on several experimental results: t-PA-deficient mice are resistant to excitotoxic neuronal death induced by the intrahippocampal injection of kainate; the infarct volume induced by occlusion of the middle cerebral artery is reduced in t-PA knockout mice; and the intravenous injection of t-PA can under certain circumstances potentiate the infarct volume in animals subjected to middle cerebral artery occlusion. In the CNS, the serine proteases have been identified to occur both in neurons and glial cells. Their enzymatic activity regulates the balance between the accumulation and the degradation of the extracellular matrix. They are involved in many physiologic functions, ranging from synaptic outgrowth during perinatal development to plasticity in adults. For instance, thrombin and t-PA are known to modulate neurite outgrowth and tissue remodeling in the early stages of development. In the adult brain, t-PA may contribute to the late phase of long-term potentiation and to the subsequent synaptic growth in the hippocampal mossy fiber pathway. This balance between the degradation and accumulation of the extracellular matrix may also be integral to various pathologic processes involved in acute brain injury. For example, compounds that modulate the activity of serine proteases exhibit neuroprotective activity. Based on the above, numerous studies have focused on the production and modulation of the endogenously produced serine protease inhibitors, termed serpins, such as type 1 plasminogen activator inhibitor, neuroserpin, and protease nexin-1. In the present review, we will discuss the need to distinguish between the potentially neurotoxic effects of t-PA and its beneficial effect on reperfusion. We will present data supporting the idea that the modulation of serine protease activity may represent a novel and efficient strategy for the treatment of acute cerebral injury in humans.

Animals↗
PubMed2000

Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain.

In the brain, the expression of the pleiotropic cytokine interleukin-6 (IL-6) is enhanced in various chronic or acute central nervous system disorders. However, the significance of IL-6 production in such neuropathologic states remains controversial. The present study investigated the role of IL-6 after cerebral ischemia. First, the authors showed that focal cerebral ischemia in rats early up-regulated the expression of IL-6 mRNA, without affecting the transcription of its receptors (IL-6Ralpha and gp130). Similarly, the striatal injection of N-methyl-D-aspartate (NMDA) in rats, a paradigm of excitotoxic injury, activated the expression of IL-6 mRNA. The involvement of glutamatergic receptor activation was further investigated by incubating cortical neurons with NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). NMDA and ionomycin (a calcium ionophore) up-regulated IL-6 mRNA, suggesting that neurons may produce IL-6 in response to the calcium influx mediated through NMDA receptors. The potential role of IL-6 during ischemic/excitotoxic insults was then studied by testing the effect of IL-6 against apoptotic or excitotoxic challenges in cortical cultures. IL-6 did not prevent serum deprivation- or staurosporine-induced apoptotic neuronal death, or AMPA/kainate-mediated excitotoxicity. However, in both mixed and pure neuronal cultures, IL-6 dose-dependently protected neurons against NMDA toxicity. This effect was blocked by a competitive inhibitor of IL-6. Overall, the results suggest that the up-regulation of IL-6 induced by cerebral ischemia could represent an endogenous neuroprotective mechanism against NMDA receptor-mediated injury.

Animals↗
PubMed1999

Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia.

The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-beta1 (TGF-beta1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-beta1 treatment via a TGF-beta-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-beta1 action with other members of the TGF-beta family by using luciferase reporter genes. These data show that TGF-beta and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-beta may be neuroprotective.

Amyloid beta-Protein Precursor↗
PubMed1999

A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury.

Various studies describe increased concentrations of transforming growth factor-beta (TGF-beta) in brain tissue after acute brain injury. However, the role of endogenously produced TGF-beta after brain damage to the CNS remains to be clearly established. Here, the authors examine the influence of TGF-beta produced after an episode of cerebral ischemia by injecting a soluble TGF-beta type II receptor fused with the Fc region of a human immunoglobulin (TbetaRIIs-Fc). First, this molecular construct was characterized as a selective antagonist of TGF-beta. Then, the authors tested its ability to reverse the effect of TGF-beta1 on excitotoxic cell death in murine cortical cell cultures. The addition of 1 microg/mL of TbetaRIIs-Fc to the exposure medium antagonized the neuroprotective activity of TGF-beta1 in N-methyl-D-aspartate (NMDA)-induced excitotoxic cell death. These results are consistent with the hypothesis that TGF-beta1 exerts a negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine the role of TGF-beta1 produced in response to brain damage, the authors used a model of an excitotoxic lesion induced by the intrastriatal injection of 75 nmol of NMDA in the presence of 1.5 microg of TbetaRIIs-Fc. The intrastriatal injection of NMDA was demonstrated to induce an early upregulation of the expression of TGF-beta1 mRNA. Furthermore, when added to the excitotoxin, TbetaRIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observations were strengthened by the fact that an intracortical injection of TbetaRIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia aggravated the volume of infarction. In the group injected with the TGF-beta1 antagonist, a 3.5-fold increase was measured in the infarction size (43.3 +/- 9.5 versus 152.8 +/- 46.3 mm3; P < 0.05). In conclusion, by antagonizing the influence of TGF-beta in brain tissue subjected to excitotoxic or ischemic lesion, the authors markedly exacerbated the resulting extent of necrosis. These results suggest that, in response to such insults, brain tissue responds by the synthesis of a neuroprotective cytokine, TGF-beta1, which is involved in the limitation of the extent of the injury. The pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic-ischemic cerebral injury.

Animals↗
PubMed1998

Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia.

The peptides of the transforming growth factor-beta (TGF-beta) family transduce their signal through ligand-induced heteromeric complexes that consist of type I and type II serine/threonine kinases. Both TGF-beta receptors are abundant in many peripheral tissues, but clear evidence of their expression in cortical astrocytes and neurons has not been published so far. In this study, we investigated the expression of type I and type II TGF-beta receptors and their potential ligands (TGF-beta1, TGF-beta2, and TGF-beta3) in the CNS by using RT-PCR and immunohistochemistry. Moreover, to further the study of those cell types that exhibit TGF-beta isoforms and related receptors, we examined through the use of RT-PCR whether cortical neurons and astrocytes in culture express the mRNAs for TGF-betas and their receptors. We show that the three TGF-beta isoform mRNAs are present in the CNS. However, although astrocytes in culture display all three isoforms, neurons in culture express only TGF-beta2. We have demonstrated that both type I and type II TGF-beta receptor mRNAs and proteins are present in the CNS and in cultures of cortical neurons and astrocytes. Thus, TGF-betas may act as autocrine and paracrine signals in the CNS between both neurons and astrocytes via the same receptor systems as those found in peripheral tissues. TGF-beta1 has been shown to be induced following hypoxic-ischemic brain injury and may play a critical role in the pathophysiology of degenerative processes in the CNS. In the present investigation, we confirmed that the expression of TGF-beta1 was increased markedly up until 24 h and thereafter was stable over the first 3 days following permanent occlusion of the middle cerebral artery in mice. However, whereas the expression of the type I TGF-beta receptor was not altered by the ischemic insult, the pattern of the type II TGF-beta receptors was modified dramatically in the ischemic area 3 days after the occlusion. These data show that, even if ligands are present, they may not be able to transduce their signal. Finally, the present study clearly demonstrates that a knowledge of the expression of ligand-specific receptors following brain injury is a fundamental step in clarifying the involvement of cytokines in neurodegenerative diseases.

Activin Receptors, Type I↗
PubMed1998

Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1.

Serine proteases play a key role in the fundamental biology of the central nervous system (CNS), and recent data suggest their involvement in the pathophysiology of neurodegenerative diseases. Little is known about the physiological regulation of these proteases in the CNS. Among the multiple growth factors present in the brain, transforming growth factor beta1 (TGF-beta1) has been described as an injury-related growth factor. However, its beneficial or deleterious role remains unclear. In the present study, we investigated the influence of TGF-beta1 in apoptosis and necrosis, two mechanisms involved in ischemic neuronal death. We show that TGF-beta1 exerts a neuroprotective role restricted to necrosis induced by N-methyl-D-aspartate. This effect is observable only in the obligatory presence of TGF-beta1-responsive astrocytes. We demonstrate that this neuroprotective activity is mediated through an up-regulation of a serine protease inhibitor (PAI-1) in astrocytes. These results underline the involvement of serine proteases and extracellular matrix components such as the PAI-1/t-PA axis in the excitotoxic cascade. Moreover, regardless of the underlying mechanisms of t-PA involvement in excitotoxic injury, our observations might warn against the use of tissular plasminogen activator as an alternative therapy for the treatment of hypoxic-ischemic injury in the brain.

Animals↗
PubMed1997

Membrane-delimited modulation of NMDA currents by metabotropic glutamate receptor subtypes 1/5 in cultured mouse cortical neurons.

1. Modulation of NMDA receptors by metabotropic glutamate receptors (mGluRs) in cultured mouse cortical neurons was investigated using whole-cell and single-channel recordings. 2. NMDA whole-cell current was reversibly attenuated by selective mGluR1/5 agonists (S)-3-hydroxyphenylglycine (3HPG; 10-200 microM), (S)-3,5-dihydroxyphenylglyeine (S-DHPG; 100 microM) and other mGluR agonists: (1S,3R)-1-aminocyclopentane-1,3-decarboxylic acid (1S,3R-ACPD; 200 microM), quisqualate (10 microM) and (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 100 microM). 3. The attenuation of NMDA current by 3HPG was totally eliminated by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM) and by the selective mGluR1/5 antagonist (S)-4-carboxyphenylglycine (4CPG; 300 microM). 4. mGluR2/3 agonists (2S,1'R,2'R'3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 3 microM), (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG; 100-200 microM) and (S)-4-carboxyphenylglycine (4CPG; 300 microM) did not reduce NMDA current. 5. The NMDA-induced increase in intracellular free Ca2+ measured by fura-2 Ca2+ imaging was attenuated by 3HPG (300 microM). 6. The suppression of NMDA current by 3HPG was not affected by treatments that altered intracellular Ca2+ or cAMP levels, or by the protein kinase inhibitor, staurosporine (0.1-0.5 microM). 7. The open probability (NPo) of the NMDA receptor channel in excised outside-out patches was attenuated by 3HPG but not by 4C3HPG. This 3HPG effect was blocked by MCPG. 8. The 3HPG-induced reduction of NMDA whole-cell and single-channel currents was prevented by GDP beta S (200-400 microM). Intracellular dialysis of GTP gamma S (100 microM) also reduced NMDA whole-cell current, and rendered irreversible further reduction induced by 3HPG. 9. These data suggest that a selective activation of mGluR1/5 downmodulates the NMDA receptor channel in a membrane-delimited manner, mediated by G proteins, but not by diffusible second messengers.

Animals↗
PubMed1996

DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons.

Molecular cloning has revealed the existence of at least eight subtypes of metabotropic glutamate receptors (mGluRs). We examined the effect of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a selective agonist of the mGluR 2/3 subtype, on excitotoxicity in mouse cortical cell cultures. Addition of DCG-IV to the exposure medium partially attenuated the rapidly triggered excitotoxic death induced by a 5 min exposure to 200 microM NMDA. This neuroprotective effect was reversed by coapplication of alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of mGluRs, by pertussis toxin pretreatment and also by preincubation with dibutyryl cAMP, a stable analogue of cAMP. These results suggest that the activation of mGluR 2/3 is neuroprotective in our system. However, DCG-IV did not attenuate the slowly triggered neuronal death induced by 24 h exposure to low concentrations of NMDA, alpha-amino-1,3-cyclopentanedicarboxylic acid (AMPA) or kainate. The failure of DCG-IV to block slowly triggered NMDA neurotoxicity is likely due to weak NMDA agonist activity, as demonstrated in whole-cell recording.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death.

We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: S-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and S-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPG attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the "inhibitory" mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.

Animals↗
PubMed1994

[Nitric monoxide, a new neurotransmitter in the central nervous system].

Nitric oxide (NO) is a recently discovered endogenous molecule considered as an unconventional biological messenger. Experimental evidence indicates that, in the brain, NO is produced enzymatically (calcium-dependent mechanism) in response to stimulation of postsynaptic excitatory amino cid receptors. NO activates soluble guanylate cyclase, that results in increases of cGMP levels in target cells. NO is physiologically involved in synaptic plasticity mechanisms. In situation of excessive production, NO can exert neurotoxic effects, suggesting a role in neurodegenerative disorders, including post-ischemic damage.

Animals↗
PubMed1993

Mechanisms involved in the neuroprotective activity of a nitric oxide synthase inhibitor during focal cerebral ischemia.

We have reported previously that posttreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the nitric oxide synthase, reduced the volume of cortical and striatal infarct induced by middle cerebral artery occlusion in rats. In the present study, we investigated the mechanisms by which L-NAME (3 mg/kg i.p.) is neuroprotective in this model of cerebral ischemia. First, we have shown the reversal of the neuroprotective effect of L-NAME by a coinjection of L-arginine. Second, in order to determine by which mechanism nitric oxide exacerbates neuronal damage produced by focal cerebral ischemia, we studied the effect of the inhibition of nitric oxide synthase by L-NAME on the histological consequences of a focal injection of N-methyl-D-aspartate (NMDA) in the striatum, and on the striatal overflow of glutamate and aspartate induced either by K+ depolarization or by focal cerebral ischemia. We have found that L-NAME treatment reduced the excitotoxic damage produced by NMDA injection. By using microdialysis, we have shown that the K(+)- and the ischemia-induced glutamate efflux was reduced by 52 and 30%, respectively, after the L-NAME treatment. These results indicate that nitric oxide synthesis induced by the NMDA receptor overstimulation is one of the major events leading to neuronal damage. One possible mechanism by which nitric oxide may contribute to the excitotoxic process is by facilitating the ischemia-induced glutamate overflow.

Amino Acid Oxidoreductases↗
PubMed1993

Nitric oxide: an endogenous anticonvulsant substance.

In the present study, we examine the involvement of the L-arginine-nitric oxide pathway in seizure activity termination. Convulsions were induced reproducibly by intracerebroventricular administration of N-methyl-D-aspartate to conscious mice. The duration of the seizure activity was increased by inhibition of the NO-pathway or by intracerebroventricular injection of methylene blue, an inhibitor of guanylate cyclase activity. This increased duration in seizure activity was reversed by co-administration of L-arginine or by intracerebroventricular injection of guanosine 3':5' cyclic monophosphate (cGMP). These results suggest that nitric oxide produced in response to NMDA receptor activation leads to an increase in cGMP which induces the seizure activity termination.

Amino Acid Oxidoreductases↗