Neuroprotective and deleterious effects of nitric oxide on focal cerebral ischemia-induced neurone death.
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Animals↗
Biomedical subjects
R G Boulu
Publications and source records attributed to R G Boulu.
Blockers of NMDA-operated channels decrease glutamate and aspartate extracellular accumulation in striatum during forebrain ischaemia in rats.
Brain microdialysis was used to study changes in the glutamate and aspartate extracellular concentrations in the striatum of conscious rats submitted to 30 minutes cerebral ischaemia, using the four-vessel occlusion model. Perfusion of the N-methyl-D-aspartate (NMDA) receptor channel blockers, dizocilpine (MK-801; 75 microM) and Mg2+ (2.5 mM), inhibited the ischaemia-induced accumulation of glutamate and aspartate. The AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamylbenzo (F) quinoxaline (NBQX; 15 microM and 450 microM) had no effect on glutamate and aspartate levels during ischaemia. On the other hand, omission of Ca2+ from the perfusing solution did not alter the increases in glutamate and aspartate induced by ischaemia. These results suggest that the glutamate and aspartate accumulation in four-vessel occlusion ischaemia is mediated by activation of NMDA receptors in a Ca2+ independent manner.
Animals↗
Loss of NADPH-diaphorase containing neurones after reversible focal ischaemia in rats delayed by L-NAME.
In the present study, NADPH-diaphorase histochemistry was used to assess the temporal evolution of the number of nitric oxide (NO)-synthase containing neurones after reversible focal cerebral ischaemia in rats. The number of NADPH-diaphorase containing neurones was reduced by 50% and 90% respectively 6 and 24 h after ischaemia. L-NAME, a NO-synthase inhibitor, prevented the loss of NADPH-diaphorase containing neurones observed 6 h after ischemia but not 24 h after ischaemia, suggesting that in the early phase, nitric oxide is involved in this phenomenon.
Animals↗
Effect of pyridoxine and magnesium on stress-induced gastric ulcers in mice selected for low or high blood magnesium levels.
Gastric ulcers were induced by immobilization in adult female mice with genetically low (MGL) or high (MGH) blood magnesium levels, obtained by selective breeding at the CSAL-CNRS (Orléans, France). All animals, fed with the same standard diet rich in magnesium, were divided into four groups of 20 animals and injected subcutaneously every 2 days for 10 days with isotonic saline (group 1), pyridoxine chlorhydrate 1.11 mg/kg in saline (group 2), magnesium lactate 149 mg/kg in saline (group 3) or both pyridoxine and magnesium (group 4). Subsequently, animals were submitted to a complete fast and an immobilization stress for 17 h. Then, they were sacrificed and the gastric mucosa was dissected for ulcer count. Among the controls (group 1), the mean number of gastric ulcers per mouse was significantly larger in the MGL than in the MGH line (p = 0.0003). In the MGH line, no significant differences were observed between control and treated groups. In the MGL line, pyridoxine associated or not with magnesium (groups 2 and 4) significantly reduced the mean number of ulcers. Magnesium treatment alone (group 3) had little effect. These results can be compared with the greater vulnerability to stress previously observed in Swiss mice fed with a magnesium-deficient diet. However, in this latter group, the number of stress ulcers was reduced not only by pyridoxine but also by the sole magnesium treatment, contrary to our present findings in MGL mice.
Animals↗
Brain catecholamines, serotonin and their metabolites in mice selected for low (MGL) and high (MGH) blood magnesium levels.
Brain noradrenaline, dopamine, DOPAC (3-4 dihydroxyphenylacetic acid), HVA (homovanillic acid), serotonin and 5-HIAA (5-hydroxyindolacetic acid) were determined by high performance liquid chromatography with amperimetric detection in adult male mice from three different strains : mice with genetically low (MGL) or high (MGH) blood magnesium levels, obtained by selective breeding and outbred Swiss albino mice. Noradrenaline levels were significantly higher (P < or = 0.001) in MGL than in MGH and Swiss mice : DOPAC levels were lower (P < or = 0.001) in MGL than in MGH and Swiss. Little or no differences were found for these variables between MGH and Swiss mice. MGL and MGH animals had similar brain dopamine, HVA and serotonin contents. These results suggest that the mere selection for genetic traits inducing low blood magnesium levels increases the synthesis of noradrenaline or decreases its catabolism. The above data together with the higher urinary noradrenalin excretion previously observed in the MGL line might account for the higher sensitivity and/or reactivity of MGL animals to stress. Swiss mice had significantly lower (P < or = 0.001) brain dopamine and serotonin contents than both MGL and MGH lines; indeed Swiss mice and MGL/MGH mice were issued from very different populations and had vastly different stocks of genes. Brain 5-HIAA content was also found higher (P < or = 0.01) in MGH than in MGL and Swiss mice; this latter result needs to be confirmed by further research.
3,4-Dihydroxyphenylacetic Acid↗
Nitric oxide and cerebral ischemia.
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Amino Acid Oxidoreductases↗
L-NAME modulates glutamate accumulation induced by K(+)-depolarization but not by forebrain ischaemia in the rat striatum.
The accumulation of extracellular glutamate and aspartate in the striatum of rats during ischaemia was examined by perfusion with Ca(+)-free medium and treatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Male Wistar rats were subjected to 30 min ischaemia using the 4-vessel occlusion model or high K(+)-depolarization. Extracellular glutamate and aspartate were monitored by in vivo microdialysis. Perfusion with Ca(2+)-free medium and systemic administration or local perfusion of L-NAME reduced the K(+)-evoked glutamate accumulation but not the ischaemia-induced glutamate accumulation. The aspartate concentration was unaffected in both conditions. Our data suggest that the extracellular glutamate and aspartate originates from a Ca(2+)-independent pool during forebrain ischaemia and is not modulated by nitric oxide. In high K(+)-depolarization the accumulated glutamate may arise, at least in part, from enhanced vesicular release and is modulated by nitric oxide.
Amino Acid Oxidoreductases↗
Competitive NMDA receptor blockers reduce striatal glutamate accumulation in ischaemia.
Our previous studies have shown that kynurenic acid, a broad-spectrum antagonist of excitatory amino acid receptors, depressed the ischaemia-induced accumulation of glutamate and aspartate in rat striatum. In the present experiments we examined the effect of two competitive N-methyl-D-aspartate (NMDA) receptor antagonists on striatal extracellular glutamate concentrations induced by a 30 min '4-vessel occlusion' ischaemia in rats. Local perfusion with 2-amino-5-phosphonovalerate (AP5; 300 microM) and with 2-amino-7-phosphonoheptanoate (AP7; 300 microM), using a microdialysis fibre markedly reduced the ischaemia-induced increase in glutamate concentrations. These results indicate that, during forebrain ischaemia the NMDA receptor type mediates glutamate and aspartate accumulation in rat striatum.
2-Amino-5-phosphonovalerate↗
Effects of an A1 adenosine receptor agonist on the neurochemical, behavioral and histological consequences of ischemia.
Untreated rats and rats given the A1 receptor adenosine agonist, R-phenylisopropyladenosine (R-PIA), were subjected to four vessel ischemia. The effect of R-PIA on hippocampal amino acid release, hippocampal neuronal damage, exploratory behavior, learning capacity and global neurological score were evaluated. R-PIA decreased by half the glutamate released during ischemia and improved the global neurological scores 3, 24, 48, 78 h and 7 days after ischemia. But R-PIA had no effect on taurine/GABA release (during ischemia), hippocampal neuronal damage (7 days post-ischemia), exploratory behavior (48 h post-ischemia) or learning capacity (7 days post-ischemia). Thus, a decrease in glutamate release by R-PIA is not systematically correlated with an improvement of histological damage or learning capacity. Reduced glutamate release is not therefore a sufficient criterion on which to evaluate the neuroprotective capacity of a drug.
Amino Acids↗
Effect of kynurenic acid on the ischaemia-induced accumulation of glutamate in rat striatum.
We examined the effect of kynurenic acid, a broad spectrum antagonist of excitatory amino acid receptors, on striatal extracellular glutamate and aspartate accumulation induced by a 30 min forebrain ischaemia in rats. Kynurenic acid, given systemically (500 mg kg-1, i.p.) or administered in situ through the dialysis probe (10 mM), markedly depressed the ischaemia-induced increase in glutamate and aspartate concentrations. These results indicate that, during forebrain ischaemia, local glutamate receptors play a major role in glutamate and aspartate accumulation in the striatum. Ischaemia-induced increase in extracellular concentrations of these excitatory amino acids may be due in part to a positive glutamatergic feedback loop via activation of NMDA and/or non-NMDA receptors.
Animals↗
[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↗
Effect of riluzole on focal cerebral ischemia in rats.
The effects of riluzole, a putative inhibitor of glutamate release, on the histological and neurobehavioral consequences of middle cerebral artery occlusion were tested in Sprague-Dawley rats. Neurobehavioral studies (neurological examination, passive avoidance task) were carried out with sham-operated and occluded rats. Riluzole 4 and 8 mg/kg administered 30 min after occlusion reduced (P < 0.01) the cortical infarct (respectively 94 +/- 12 mm3 and 73 +/- 15 mm3 versus 139 +/- 8 mm3 for control rats). Striatum necrosis was not modified by the low dosage (46 +/- 3 mm3 versus 49 +/- 3 mm3 for control rats), whereas the high dosage increased it (61 +/- 3 mm3, P < 0.05). The ischemia-induced neurological and memory impairments were not improved by riluzole. Our results indicate that a drug depressing glutamatergic neurotransmission without blocking the glutamate receptors exerts anti-ischemic activity. Moreover, the results highlight the need for carrying out histological and neurobehavioral studies in parallel in this model.
Anesthetics↗
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↗
Anti-immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice.
The tail suspension test is a screening procedure recently used in mice to detect antidepressant activity of drugs. The ability of amine re-uptake inhibitors to decrease immobility in non-reserpinized and in reserpinized mice was studied. Reserpine (4 mg/kg ip) was injected 4 h previously. Anti-depressants were administered ip, 60 min before tail suspension. Animal activity was recorded for 6 min. Preferential serotonin re-uptake blockers (fluoxetine, fluvoxamine, clomipramine) were poorly active in non-reserpinized mice and inactive in reserpine-treated mice. Noradrenergic drugs (desipramine, demexiptiline, viloxazine) were more efficient in reserpinized than in non-reserpinized mice. The mixed serotonin-noradrenaline re-uptake inhibitor (imipramine) shows an activity which should be considered between serotonin re-uptake inhibitors and noradrenaline re-uptake inhibitors. DA re-uptake inhibitors (amineptine, GBR 12909) exhibited the highest anti-immobility effect in non reserpinized animals but were of low efficacy after reserpine treatment. Amphetamine differed from dopamine re-uptake inhibitors by its better activity in reserpinized animals. Moreover, it was the only drug showing an equal anti-immobility effect in non reserpinized and reserpinized mice because the dose of 8 mg/kg of amphetamine reduced immobility in reserpinized mice with the same intensity as the dose of 4 mg/kg in non reserpinized mice whereas no other drugs tested in this study achieved the same effect. Comparison of anti-immobility activities of putative anti-depressants in non-pre-treated and in reserpine-pre-treated mice, using the tail suspension test, may be useful to discriminate amphetamines from antidepressant drugs and to differentiate between categories of amine re-uptake blockers.
Amphetamine↗
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↗
Inhibition of glutamate release in rat hippocampus by kynurenic acid does not protect CA1 cells from forebrain ischemia.
We assessed the effect of a broad spectrum glutamatergic receptor antagonist, kynurenic acid (500 mg/kg) on ischemia-induced hippocampal glutamate release and neuronal damage. Kynurenic acid significantly decreased glutamate release during ischemia but had no effect on the hippocampal lesion. Some protection was observed in the cortex and in the striatum. These data suggested that the extracellular accumulation of glutamate during forebrain ischemia does not play a major role in the hippocampus.
Animals↗
Concomitant increases in the extracellular concentrations of excitatory and inhibitory amino acids in the rat hippocampus during forebrain ischemia.
The extracellular concentrations of aspartate, glutamate, glutamine, taurine and gamma-aminobutyric acid in the hippocampus were determined during and after forebrain ischemia (4-vessel model) in the unanaesthetized rat. Ischemia led to a large increase in both inhibitory (taurine and gamma-aminobutyric acid) and excitatory amino acids (aspartate, glutamate). These results suggest that in this model, as previously proposed in other models of ischemia, the large increase of inhibitory amino acids could counterbalance the excitotoxicity due to aspartate and glutamate.
Amino Acids↗
Striatal protection induced by lesioning the substantia nigra of rats subjected to focal ischemia.
Unilateral 6-hydroxydopamine lesion of the substantia nigra reduced the volume of striatal necrosis and suppressed the increase in extracellular glutamate concentration in the striatum induced by middle cerebral artery occlusion in rats. These results indicate that the dopaminergic nigrostriatal pathway is highly involved in the vulnerability of the striatum to ischemia and suggest that glutamate-dopamine interactions may play a key role in the striatal ischemic insult.
Animals↗