Melatonin therapy in fibromyalgia.
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Adult↗
Biomedical subjects
G Escames
Publications and source records attributed to G Escames.
Mechanisms of N-methyl-D-aspartate receptor inhibition by melatonin in the rat striatum.
N-methyl-D-aspartate (NMDA) receptor activation comprises multiple regulatory sites controlling Ca2+ influx into the cell. NMDA-induced increases in intracellular [Ca(+2)] lead to nitric oxide (NO) production through activation of neuronal NO synthase (nNOS). Melatonin inhibits either glutamate or NMDA-induced excitation, but the mechanism of this inhibition is unknown. In the present study, the mechanism of melatonin action in the rat striatum was studied using extracellular single unit recording of NMDA-dependent neuronal activity with micro-iontophoresis. Melatonin inhibited neuronal excitation produced by either NMDA or L-arginine. The effects of both NMDA and L-arginine were blocked by nitro-L-arginine methyl ester, suggesting that nNOS participates in responses to NMDA. However, excitation of NMDA-sensitive neurones induced by the NO donor sodium nitroprusside was only slightly modified by melatonin. Melatonin iontophoresis also counteracted excitation induced by tris(2-carboxyethyl)phosphine hydrochloride, showing that the redox site of the NMDA receptor may be a target for melatonin action. The lack of effects of the membrane melatonin receptor ligands luzindole, 4-phenyl-2-propionamidotetralin and 5-methoxycarbonylamino-N-acetyltryptamine, and the nuclear melatonin ligand, CGP 52608, a thiazolidine dione, excluded the participation of known membrane and nuclear receptors for melatonin. The data suggest that inhibition of NMDA-dependent excitation by melatonin involves both nNOS inhibition and redox site modulation.
Animals↗
Melatonin, mitochondria, and cellular bioenergetics.
Aerobic cells use oxygen for the production of 90-95% of the total amount of ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxidative phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidase, under normal conditions a small percentage of oxygen may be reduced by one, two, or three electrons only, yielding superoxide anion, hydrogen peroxide, and the hydroxyl radical, respectively. The main radical produced by mitochondria is superoxide anion and the intramitochondrial antioxidant systems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production. During aging and some neurodegenerative diseases, oxidatively damaged mitochondria are unable to maintain the energy demands of the cell leading to an increased production of free radicals. Both processes, i.e., defective ATP production and increased oxygen radicals, may induce mitochondrial-dependent apoptotic cell death. Melatonin has been reported to exert neuroprotective effects in several experimental and clinical situations involving neurotoxicity and/or excitotoxicity. Additionally, in a series of pathologies in which high production of free radicals is the primary cause of the disease, melatonin is also protective. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress. The discoveries of new actions of melatonin in mitochondria support a novel mechanism, which explains some of the protective effects of the indoleamine on cell survival.
Adenosine Triphosphate↗
Effect of propranolol plus exercise on melatonin and growth hormone levels in children with growth delay.
The pineal gland in humans is under both alpha- and beta-adrenergic control, although it seems that beta1-adrenoceptors are mainly implicated in melatonin secretion. In the present study, we evaluated the role of beta-adrenergic innervation on melatonin production and its relation with the production of growth hormone (GH). Thirty-four children (15 males and 19 females, mean age 10.5 +/- 0.8 years) from the University of Granada Hospital were studied. The children were included in a protocol for the evaluation of growth delay using the propranolol + exercise test. This standardized test allowed us to study simultaneously the role of an unspecific beta-adrenergic blocker such as propranolol and of an adrenergic stimulus such as exercise on the pineal production of melatonin. Changes in plasma levels of melatonin and GH were determined at basal, 120 and 140 min after the test was applied. Hormonal determinations were carried out by commercial radioimmunoassay kits previously standardized in our laboratory. The results show a significant decrease in plasma melatonin levels at 120 and 140 min after the test (P < 0.05), whereas GH levels increased significantly at 140 min (P < 0.001). The decrease of melatonin levels was a consequence of the test, since in a control group, the circadian decay of melatonin was significantly less pronounced (P < 0.05). These data suggest an inverse relationship between melatonin and GH after the propranolol + exercise test, and the reduction in melatonin may be related to its depletion by exercise-induced oxidative stress.
Adolescent↗
Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum.
The effects of melatonin, amlodipine, diltiazem (L-type Ca2+ channel blockers) and omega-conotoxin (N-type Ca2+ channel blocker) on the glutamate-dependent excitatory response of striatal neurones to sensory-motor cortex stimulation was studied in a total of 111 neurones. Iontophoresis of melatonin produced a significant attenuation of the excitatory response in 85.2% of the neurones with a latency period of 2 min. Iontophoresis of either L- or N-type Ca2+ channel blocker also produced a significant attenuation of the excitatory response in more than 50% of the recorded neurones without significant latency. The simultaneous iontophoresis of melatonin + amlodipine or melatonin + diltiazem did not increase the attenuation produced by melatonin alone. However, the attenuation of the excitatory response was significantly higher after ejecting melatonin + omega-conotoxin than after ejecting melatonin alone. The melatonin-Ca2+ relationship was further supported by iontophoresis of the Ca2+ ionophore A-23187, which suppressed the inhibitory effect of either melatonin or Ca2+ antagonists. In addition, in synaptosomes prepared from rat striatum, melatonin produced a decrease in the Ca2+ influx measured by Fura-2AM fluorescence. Binding experiments with [3H]MK-801 in membrane preparations from rat striatum showed that melatonin did not compete with the MK-801 binding sites themselves although, in the presence of Mg2+, melatonin increased the affinity of MK-801. The results suggest that decreased Ca2+ influx is involved in the inhibitory effects of melatonin on the glutamatergic activity of rat striatum.
Amlodipine↗
Melatonin and beta-endorphin changes in children sensitized to olive and grass pollen after treatment with specific immunotherapy.
BACKGROUND: Specific immunotherapy for respiratory allergy, a seasonal disease, significantly reduces the inflammatory process, attenuating the clinical symptoms. The mechanism for the clinical beneficial effect of immunotherapy has not yet been clarified. Melatonin shows a circadian and seasonal variation and together with the endogenous opioid system plays an immunomodulatory role acting on both specific and nonspecific immunity responses. Thus, the possibility that immunotherapy involved changes in the melatonin-opioid system was investigated. METHODS: Thirty-five children aged 3-15 years with rhinitis and asthma due to olive + grass pollen sensitization were studied. The patients were treated with depot extracts containing the identified allergens with increasing doses from 1 to 1,000 IU/ml during 3 months. Melatonin, beta-endorphin, total and specific IgE and IgG4 were determined before and after treatment. RESULTS: All children showed a significant improvement of their symptoms at the end of the treatment, coinciding with a significant drop of both melatonin and beta-endorphin levels. Total IgE decreased in most of the cases although the mean values did not show significant changes. Specific IgE and IgG4 were also unchanged. A significant correlation between melatonin and beta-endorphin and between beta-endorphin and IgG4 was found before immunotherapy, and these correlations disappeared when the treatment was finished. CONCLUSIONS: The decrease in the levels of melatonin and beta-endorphin suggests the disappearance of their stimulating influence on the immune system. Thus, hyposensitization after immunotherapy may involve, at least in part, the inhibition of the immunoenhancing properties of the melatonin-opioid system.
Adolescent↗
Characterization of nocturnal ultradian rhythms of melatonin in children with growth hormone-dependent and independent growth delay.
To assess the existence of a possible nocturnal ultradian rhythm of melatonin in children, we analyzed 28 pediatric patients (mean age, 9.08 +/- 2.2 yr) with GH-dependent and GH-independent growth delay. Plasma melatonin was measured by RIA in children sampled every 30 min between 2100-0900 h. Statistical analysis consisted of cluster analysis to examine the presence of peaks and troughs. The pattern of melatonin levels was related to the cause of growth delay, although the means of the nocturnal concentrations of melatonin were similar in all children. Interestingly, children with a GH deficit showed a nearly normal melatonin profile, whereas children with normal GH values but abnormal growth displayed atypical profiles of melatonin. The results also prove the existence of an ultradian rhythm of melatonin in most of the patients studied. The ultradian rhythm of melatonin in children was characterized by irregular interburst intervals, thus differing from the rhythm previously described in adults that had an almost constant pulse frequency. Moreover, the existence of low and high melatonin producers was revealed in the study, a feature unrelated to the cause of growth delay. The group of children with a GH deficit showed the lowest values of integrated melatonin production and of the area of peaks and troughs. These results prove that children exhibit an ultradian rhythm of melatonin like that in adults. Whereas it is not clear whether the episodic production of melatonin is required for its biological actions, the existence of irregular pulses may reflect endocrine influences at this age and/or the immaturity of the intrinsic pulse generator.
Adult↗
Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo.
Melatonin displays antioxidant and free radical scavenger properties. Due to its ability with which it enters cells, these protective effects are manifested in all subcellular compartments. Recent studies suggest a role for melatonin in mitochondrial metabolism. To study the effects of melatonin on this organelle we used ruthenium red to induce mitochondrial damage and oxidative stress. The results show that melatonin (10 mg/kg i.p.) can increase the activity of the mitochondrial respiratory complexes I and IV after its administration in vivo in a time-dependent manner; these changes correlate well with the half-life of the indole in plasma. Melatonin administration also prevented the decrease in the activity of complexes I and IV due to ruthenium red (60 microg/kg i.p.) administration. At this dose, ruthenium red did not induce lipid peroxidation but it significantly reduced the activity of the antioxidative enzyme glutathione peroxidase, an effect also counteracted by melatonin. These results suggest that melatonin modulates mitochondrial respiratory activity, an effect that may account for some of the protective properties of the indoleamine. The mitochondria-modulating role of melatonin may be of physiological significance since it seems that the indoleamine is concentrated into normal mitochondria. The data also support a pharmacological use of melatonin in drug-induced mitochondrial damage in vivo.
Animals↗
Effect of clonidine on plasma ACTH, cortisol and melatonin in children.
An interaction between melatonin and adrenocorticotropin (ACTH) seems to occur in humans and both hormones respond to beta-adrenergic stimulation. As in lower animal species, human pineal gland also contains alpha2-adrenergic receptors as does the hypothalamus-pituitary axis. In this study the response of the pineal gland and of the hypothalamus-pituitary-adrenal axis to alpha2-adrenergic stimulation was assessed. Twenty-nine children (21 males, mean age 11.2 +/- 0.6 yr and eight females, mean age 9.1 +/- 1.1 yr) from the University of Granada Hospital were studied. The children were diagnosed as having growth problems but with a normal response of growth hormone (GH) to clonidine test. Changes in plasma levels of ACTH, cortisol and melatonin were evaluated in these children after oral administration of the alpha2-adrenoceptor agonist clonidine (100 microg/m2) or a placebo. Plasma ACTH, cortisol and melatonin were measured before (basal) and at 30, 60 and 90 min after oral clonidine or placebo administration. Hormonal determinations were carried out by commercial radioimmunoassay kits, previously standardised in our laboratory. The results show a significant decrease in plasma ACTH, cortisol and melatonin 30 min after clonidine administration (P < 0.001), reaching lowest values at 90 min after the drug was administered. The reduction in the levels of these hormones is independent of their normal circadian decay since the control group showed a significantly different pattern of behaviour. These data support the existence of an inhibitory alpha2-adrenergic influence on both the pineal gland and the hypothalamus-pituitary-adrenal in children and further support the presence of alpha2-adrenoceptors in the human pineal gland.
Adrenergic alpha-Agonists↗
Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro.
Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.
Antioxidants↗
Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress.
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Animals↗
Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines.
We recently described that melatonin and some kynurenines modulate the N-methyl-D-aspartate-dependent excitatory response in rat striatal neurons, an effect that could be related to their inhibition of nNOS. In this report, we studied the effect of melatonin and these kynurenines on nNOS activity in both rat striatal homogenate and purified rat brain nNOS. In homogenates of rat striatum, melatonin inhibits nNOS activity, whereas synthetic kynurenines act in a structure-related manner. Kynurenines carrying an NH(2) group in their benzenic ring (NH(2)-kynurenines) inhibit nNOS activity more strongly than melatonin itself. However, kynurenines lacking the NH(2) group or with this group blocked do not affect enzyme activity. Kinetic analysis shows that melatonin and NH(2)-kynurenines behave as noncompetitive inhibitors of nNOS. Using purified rat brain nNOS, we show that the inhibitory effect of melatonin and NH(2)-kynurenines on the enzyme activity diminishes with increasing amounts of calmodulin in the incubation medium. However, changes in other nNOS cofactors such as FAD or H(4)-biopterin, do not modify the drugs' response. These data suggest that calmodulin may be involved in the nNOS inhibition by these compounds. Studies with urea-polyacrylamide gel electrophoresis further support an interaction between melatonin and NH(2)-kynurenines, but not kynurenines lacking the NH(2) group, with Ca(2+)-calmodulin yielding Ca(2+)-calmodulin-drug complexes that prevent nNOS activation. The results show that calmodulin is a target involved in the intracellular effects of melatonin and some melatonin-related kynurenines that may account, at least in part, for the neuroprotective properties of these compounds.
Animals↗
Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats.
We evaluated the role of melatonin in endotoxemia caused by lipopolysaccharide (LPS) in unanesthetized rats. The expression of inducible isoform of nitric oxide synthase (iNOS) and the increase in the oxidative stress seem to be responsible for the failure of lungs, liver, and kidneys in endotoxemia. Bacterial LPS (10 mg/kg b. w) was i.v. injected 6 h before rats were killed and melatonin (10-60 mg/kg b.w.) was i.p. injected before and/or after LPS. Endotoxemia was associated with a significant rise in the serum levels of aspartate and alanine aminotransferases, gamma-glutamyl-transferase, alkaline phosphatase, creatinine, urea, and uric acid, and hence liver and renal dysfunction. LPS also increased serum levels of cholesterol and triglycerides and reduced glucose levels. Melatonin administration counteracted these organ and metabolic alterations at doses ranging between 20 and 60 mg/kg b. w. Melatonin significantly decreased lung lipid peroxidation and counteracted the LPS-induced NO levels in lungs and liver. Our results also show an inhibition of iNOS activity in rat lungs by melatonin in a dose-dependent manner. Expression of iNOS mRNA in lungs and liver was significantly decreased by melatonin (60 mg/kg b. w., 58-65%). We conclude that melatonin inhibits NO production mainly by inhibition of iNOS expression. The inhibition of NO levels may account for the protection of the indoleamine against LPS-induced endotoxemia in rats.
Animals↗
Cartilage and serum levels of nitric oxide in patients with hip osteoarthritis.
OBJECTIVE: To assess whether nitric oxide (NO) is related to cartilage deterioration resulting from osteoarthritis, NO concentrations were analyzed in normal and deteriorated areas of cartilage obtained from femur heads of patients with primary hip osteoarthritis (HOA). METHODS: The concentration of NO in macroscopically deteriorated and non-deteriorated cartilage of femoral heads of patients with HOA at hip replacement surgery was analyzed spectrophotometrically. Serum NO levels were also determined in 16 ambulatory patients with hip OA and in healthy volunteers. RESULTS: NO levels of non-deteriorated areas of femoral head cartilage were significantly lower (3.82+/-1.30 micromol/l; mean +/- SD) than levels of deteriorated cartilage areas (11.07+/-6.48 micromol/l; p<0.01). The surgery HOA group showed serum NO levels (2.64+/-0.32 micromol/l; p<0.0001 vs. healthy group) similar to the ambulatory HOA group levels (2.56+/-0.56 micromol/l; p<0.0001 vs. healthy group). Serum NO concentrations in healthy volunteers were 1.37+/-0.55 micromol/l. CONCLUSION: This study shows increased NO levels in joint cartilage of patients with hip OA. This increase was not homogeneously distributed, but the higher NO levels were found in macroscopically deteriorated areas. The data also suggest that high NO serum levels found in patients with hip OA may be due to joint cartilage destruction.
Aged↗
Modulation of rat striatal glutamatergic response in search for new neuroprotective agents: evaluation of melatonin and some kynurenine derivatives.
Melatonin attenuates the excitatory response of striatal neurons to sensorimotor cortex (SMCx) stimulation, which may be the basis for its neuroprotective role. Searching for new compounds with melatonin-like properties, the effects of several kynurenine derivatives in the response of the rat striatum to SMCx stimulation were studied using electrophysiological and microiontophoretical techniques. Melatonin iontophoresis (-100 nA) significantly attenuated the striatal excitatory response in 89.4% of the recorded neurons, showing excitatory properties in the other 10.6%. Compound A [2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid] (-100 nA) displayed similar attenuating effects (86.7% of neurons inhibited vs. 13.3% excited). Compound B [2-acetamide-4-(2-amine-5-methoxyphenyl)-4-oxobutyric acid] (-100 nA) was more potent than melatonin itself to attenuate the excitatory response in 100% of the recorded neurons. Compound C [2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid] (-100 nA) significantly increased the excitatory response in 84.2% of the recorded neurons, showing attenuating effects on the other 15.8% of the neurons. Interestingly, compound C iontophoresis excited the neurons in which melatonin had attenuating properties, whereas it inhibited the neurons showing excitatory responses to melatonin. These data suggest melatonin inverse agonist properties for compound C. Also, the effects of compounds B and C appeared immediately after they were iontophoretized, whereas both melatonin and compound A onset latencies were longer (2-4 min). The lack of latency shown by these melatonin analogs points to the possibility that melatonin itself was metabolized before producing its effects on striatal neurons. The results show a family of structurally-related melatonin analogs that may open new perspectives in search for new neuroprotective agents, including its clinical potentiality.
Animals↗
Melatonin enhances tamoxifen's ability to prevent the reduction in microsomal membrane fluidity induced by lipid peroxidation.
The indoleamine melatonin and the synthetic antiestrogenic drug tamoxifen seem to have similar mechanisms in inhibiting the growth of estrogen receptor positive breast cancer cells. In this study, we compared the ability of these molecules, alone and in combination, in stabilizing microsomal membranes against free radical attack. Hepatic microsomes were obtained from male rats and incubated with or without tamoxifen (50-200 microM), melatonin (1 mM) or both; lipid peroxidation was induced by addition of FeCl3, NADPH and ADP. After oxidative damage, membrane fluidity, measured by fluorescence polarization techniques, decreased whereas malonaldehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations increased. Incubation of the microsomes with tamoxifen prior to exposure to free radical generating processes inhibited, in a dose-dependent manner, the increase in membrane rigidity and the rise in MDA + 4-HDA levels. When melatonin was added, the efficacy of tamoxifen in preventing membrane rigidity was enhanced. Thus, the IC50s for preventing membrane rigidity and for inhibiting lipid peroxidation obtained for tamoxifen in the presence of melatonin were lower than those obtained with tamoxifen alone. Moreover, tamoxifen (50-200 microM) in the presence of melatonin reduced basal membrane fluidity and MDA + 4-HDA levels in microsomes. These synergistic effects of tamoxifen and melatonin in stabilizing biological membranes may be important in protecting membranes from free radical damage.
Animals↗
Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives.
Tryptophan is mainly metabolized in the brain through methoxyindole and kynurenine pathways. The methoxyindole pathway produces (among other compounds) melatonin, which displays inhibitory effects on human and animal central nervous systems, including a significant attenuation of excitatory, glutamate-mediated responses. The kynurenine pathway produces kynurenines that interact with brain glutamate-mediated responses. Nitric oxide (NO) increases glutamate release, and melatonin and kynurenines may act via modification of NO synthesis. In the present study, the effects of melatonin and four synthetic kynurenines were studied on the activity of rat striatal nitric oxide synthase (NOS) and on the response of rat striatal neurons to sensorimotor cortex (SMCx) stimulation, a glutamate-mediated response. Melatonin inhibited both NOS activity and the striatal glutamate response, and these effects were dose-related. Compound A (2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid) did not inhibit NOS activity but inhibited the striatal response similarly to melatonin. Compound B (2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) was more potent than melatonin in inhibiting both NOS activity and the striatal response. Compound C (2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid) did not change NOS activity, but increased the striatal response. Compound D (2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) showed potent inhibitory effects on both NOS activity and striatal glutamate-mediated response. A structure-related effect of the kynurenine derivatives was observed, and those with an amino group in position 2 of the benzenic ring had more potent effects than melatonin itself in inhibiting striatal NOS activity and the response of striatal neurons to SMCx.
Animals↗
Melatonin interaction with magnesium and zinc in the response of the striatum to sensorimotor cortical stimulation in the rat.
The sensorimotor cortex (SMCx) sends numerous projections to the striatum. These projections are excitatory and glutamate mediated. Glutamatergic receptors, specifically those of NMDA type-receptors, are closely related to excitotoxicity. Thus, in some circumstances, an excess of Ca2+ influx through NMDA channels alters neuronal metabolism and may become lethal for the cell. Two other divalent cations, Mg2+ and Zn2+, have inhibitory effects on NMDA receptors. Magnesium ions exert a voltage-dependent block of the NMDA calcium channel, whereas zinc ions exert a voltage-independent NMDA block. In the present work, the effects of iontophoresis of Mg2+ and Zn2+ on the striatal response to SMCx stimulation were studied. Moreover melatonin, an indoleamine with anticonvulsant properties and inhibitory effects on the NMDA receptor, was also iontophorized alone or in combination with Mg2+ and Zn2+. Single pulse electrical stimulation of SMCx produced an excitatory response in the striatum. Iontophoresis of melatonin, Mg2+ and Zn2+ produced a potent attenuation of the excitatory response of the striatum to SMCx stimulation, although the latency of the effect of melatonin was longer than those of Mg2+ and Zn2+. When these cations were simultaneously ejected with melatonin, additive inhibitory effects were recorded. These observations suggest that the inhibitory effects produced by Mg2+ and Zn2+ and melatonin are produced via different processes, and thus the inhibitory role of melatonin on the NMDA receptor activity is exclusive of a direct action on the NMDA calcium channel.
Animals↗