A comparative analysis of the neuroprotective properties of competitive and uncompetitive n-methyl-d-aspartate receptor antagonists in vivo: Implications for the process of excitotoxic degeneration and its therapy

Massieu, Lourdes; Thedinga, Karen H.; McVey, Mary; Fagg, Graham E.

doi:10.1016/0306-4522(93)90305-y

Cited by 37 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MK-801 (2 mg/kg i.v. ), at a fully neuroprotective dose (Massieu et al, 1993), blocked SD triggering almost completely (Table 1) (Willette et al, 1994;Obrenovitch and Zilkha, 1996). Furthermore, compounds known not to inhibit SD generation when administered acutely in normal animals (sodium valproate and propranolol) (Ayata et al, 2006) were inactive.…”

Section: Discussionmentioning

confidence: 99%

Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Peeters

Gunthorpe²,

Strijbos³

et al. 2007

J Pharmacol Exp Ther

101

106

View full text Add to dashboard Cite

Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the Nmethyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) is implicated in the generation and propagation of SD has itself been available for more than 15 years. However, to date, there are no reports of NMDA-R antagonists being developed for migraine therapy. In this study, an uncompetitive, pan-NMDA-R blocker, memantine, approved for clinical use, and two antagonists with selectivity for NMDA-R containing the NR2B subunit, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (Ϯ)-(R*,S*)-␣-(4-hydroxyphenyl)-␤-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25-6981), were investigated to assess their protective effects against SD in the rat. Under isoflurane anesthesia, d.c. potential and the related cortical blood flow and partial pressure of O 2 (pO 2 ) were recorded simultaneously at separate cortical sites. Drugs (1, 3, and 10 mg/kg i.p.) were given 1 h or 30 min before KCl application to the brain surface. Core temperature and arterial pCO 2 , pO 2 , and pH measurements confirmed physiological stability. KCl induced 7.7 Ϯ 1.8 (mean Ϯ S.D.) SD events with d.c. amplitude of 14.9 Ϯ 2.8 mV.Memantine and CP-101,606 dose-dependently decreased SD event number (to 2.0 Ϯ 1.8 and 2.3 Ϯ 2.9, respectively) and SD amplitude at doses relevant for therapeutic use. Ro 25-6981 also decreased SD events significantly, but less effectively (to 4.5 Ϯ 1.6), without affecting amplitude. These results indicate that NR2B-containing NMDA receptors are key mediators of SD, and as such, memantine-and NR2B-selective antagonists may be useful new therapeutic agents for the treatment of migraine and other SD-related disorders (e.g., stroke and brain injury). Whether chronic, rather than acute, treatment may improve their efficacy remains to be determined.Spreading depression (SD) is a slowly (2-6 mm/min) propagating wave of transiently increased cerebral blood flow, suppressed cortical activity, and loss of membrane potential accompanied by major metabolic disturbance (for review, see Smith et al., 2006). SD can be induced in the brains of all animal species investigated, including human, using a variety of mechanical and chemical methods. Typically, in the anesthetized rat, the brain is surgically exposed using a small craniotomy, and SD is evoked by topical administration of KCl. SD can be detected via a reduction in d.c. amplitude using electrodes placed on the brain surface distant from the SD induction site. Associated changes in extracellular ion concentrations and cerebral blood flow can also be detected with appropriate probes. Changes in cerebral tissue water, This study was supported by Marie Curie Industry Host Fellowship QLG5-CT-2001-60018 and the Fonds Spécial de Recherche de l'Université Catholique de Louvain, Belgium) (to M.P.).

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Peeters

Gunthorpe²,

Strijbos³

et al. 2007

J Pharmacol Exp Ther

101

106

View full text Add to dashboard Cite

show abstract

“…Several source s of data support this hypothesis: (i) glutamate produces neurona l injury similar to that observed after cerebra l hypoxia-ischemia; (ii) elevated extracellu lar levels of glutamate and aspartate are present during cerebral ischemia; (iii) excitatory deafferentation results in improved neuronal survival; and (iv) NMDA receptor an-tagonists exhibit neurop rotective effects under a varie ty of experim ental conditions (1)(2)(3)(4). Although NMDA antagonists may be of therapeutic value in severa l forms of acute brain injury , the pharmacology of these compo unds is complex, and their effects on the developing anima l are not always pred ictable.…”

mentioning

confidence: 84%

Experimental Neuronal Injury in the Newborn Lamb: A Comparison of N-Methyl-D-Aspartic Acid Receptor Blockade and Nitric Oxide Synthesis Inhibition on Lesion Size and Cerebral Hyperemia

Taylor¹,

Trescher

Johnston³

et al. 1995

Pediatr Res

View full text Add to dashboard Cite

Vol. 38, No. 5, 1995 Printed in U.S.A.The purpose of this study was to compa re the effects of dizocilipine maleate (MK-801) and W -nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemod ynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 /Lmol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediatel y after intracerebral injection . Saline injection resulted in small lesions (mean volume; 13.6 :t 5 mrrr') without hyperemia. NMDA alone resulted in larger lesions (92.9 :t 24 mrrr') and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 :t 6 mm") and completely ablated cerebral hyperemia . Pretreatment with L-NAME showed no effect on lesion size (69.9 :t 20 mm") and hyperemia only in the ipsilateral hemisphere. Sonogr aphic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probab ly does not play a major part in NMDA-indu ced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection. (Pediatr Res 38: 644-651 , 1995) Abbr eviations NM DA, N-methyl-D-aspartic acid L-NAME, AP-nitro-L-arginine methyl ester MK-801, dizoci lipine maleate NO, nitric oxide CVR, cerebrovascula r resistance CBF, cerebral blood flow ANOVA, analysis of variance There is considerable evidence now suggesting that glutamate may mediate the neurotoxicity observe d in hypoxicischemic brain injury. Several source s of data support this hypothesis: (i) glutamate produces neurona l injury similar to that observed after cerebra l hypoxia-ischemia; (ii) elevated extracellu lar levels of glutamate and aspartate are present during cerebral ischemia; (iii) excitatory deafferentation results in improved neuronal survival; and (iv) NMDA receptor an-

show abstract

“…It has been suggested that neuroprotective doses of MK-801 (0.3-0.8 mg/kg; i.p.) block NMDA receptors in the brain, and these doses produce plasma concentrations within the range of NMDA receptor affinity (Gill et al, 1991;Massieu et al, 1993).…”

Section: Methodsmentioning

confidence: 99%

Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

Marvanová

Lakso

Wong

2004

Neuropsychopharmacol

View full text Add to dashboard Cite

In this study, we monitored gene expression profiles using cDNA microarrays after an acute systemic administration of the high affinity N-methyl-D-aspartate (NMDA) uncompetitive antagonist MK-801 (1 mg/kg; 4 h), and the clinically used moderate affinity antagonist memantine (25 mg/kg; 4 h) in adult rat brains. From a microarray containing 1090 known genes, 13 genes were regulated by both treatments of which 12 were upregulated and one was downregulated. In addition, 28 and 34 genes were regulated (X1.5-or p0.67-fold change) by either memantine or MK-801, respectively. Genes commonly regulated by both treatments and not previously reported were confirmed by in situ hybridization (ISH) and include regenerating liver inhibitory factor-1 (RL/IF-1), GDP-dissociation inhibitor 1 (GDI-1), neural visinin Ca 2 þ -binding protein 2 (NVP-2), neuromedin B receptor, and Na þ /K þ transporting ATPase 2b. ISH with memantine (5-50 mg/kg) revealed regulation of these genes in other cortical and hippocampal regions. RL/IF-1 induction occurred at 1 h and returned to basal levels by 8 h, consistent with the profile of an immediate early gene. Western blot analysis showed increases (B30-65%) in GDI-1 protein present in both cytosolic and membrane fractions that were significant in the 84-kDa Rab bound form, suggesting that memantine influences Ras-like GTPase function. Genes regulated by a 5 mg/kg dose of memantine might be important in its therapeutic effects. These findings increase the number of known, differentially altered genes after treatment of uncompetitive NMDA receptor antagonists and suggest broader actions of these agents than previously realized.

show abstract

A comparative analysis of the neuroprotective properties of competitive and uncompetitive n-methyl-d-aspartate receptor antagonists in vivo: Implications for the process of excitotoxic degeneration and its therapy

Cited by 37 publications

References 31 publications

Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Experimental Neuronal Injury in the Newborn Lamb: A Comparison of N-Methyl-D-Aspartic Acid Receptor Blockade and Nitric Oxide Synthesis Inhibition on Lesion Size and Cerebral Hyperemia

Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

Contact Info

Product

Resources

About