dizocilpine-maleate and 5-(2-3-5-trichlorophenyl)pyrimidine-2-4-diamine-ethane-sulfonate

Neuronal death in neurodegenerative diseases may involve energy impairment leading to secondary excitotoxicity, and free radical generation. Potential therapies for the treatment of neurodegenerative diseases therefore include glutamate release blockers, excitatory amino acid receptor antagonists, agents that improve mitochondrial function, and free radical scavengers. In the present study we examined whether these strategies either alone or in combination had neuroprotective effects against striatal lesions produced by mitochondrial toxins. The glutamate release blockers lamotrigine and BW1003C87 significantly attenuated lesions produced by intrastriatal administration of 1-methyl-4-phenylpyridinium. Lamotrigine significantly attenuated lesions produced by systemic administration of 3-nitropropionic acid. Memantine, an N-methyl-D-aspartate antagonist, protected against malonate induced striatal lesions. We previously found that coenzyme Q10 and nicotinamide, and the free radical spin trap n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) dose-dependently protect against lesions produced by intrastriatal injection of malonate. In the present study we found that the combination of MK-801 (dizocipiline) with coenzyme Q10 exerted additive neuroprotective effects against malonate. Lamotrigine with coenzyme Q10 was more effective than coenzyme Q10 alone. The combination of nicotinamide with S-PBN was more effective than nicotinamide alone. These results provide further evidence that glutamate release inhibitors and N-acetyl-D-aspartate antagonists can protect against secondary excitotoxic lesions in vivo. Furthermore, they show that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. These findings suggest that combinations of therapies to improve mitochondrial function, to block excitotoxicity and to scavenge free radicals may be useful in treating neurodegenerative diseases.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Anticonvulsants; Coenzymes; Cyclic N-Oxides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Free Radicals; Lamotrigine; Male; Malonates; Memantine; Mitochondria; Nervous System Diseases; Neuroprotective Agents; Neurotoxins; Niacinamide; Nitro Compounds; Nitrogen Oxides; Propionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Spin Labels; Thallium; Triazines; Ubiquinone

The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], L-nitroarginine methyl ester [L-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored halothane-anesthetised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 microm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (L-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Benzofurans; Blood Pressure; Brain Ischemia; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Male; Microdialysis; Neurons; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyrimidines; Pyrrolidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors

Sound-induced seizures in genetically epilepsy-prone rats were used to compare the anticonvulsant effect of phenytoin and diazepam with compounds which decrease glutamatergic neurotransmission including excitatory amino acid antagonists acting at N-methyl-D-aspartate (NMDA) receptors: D(-)CPPene, CGP 37849 and MK 801 or at the glycine/NMDA site: ACPC (1-aminocyclopropane-dicarboxylic acid) (partial agonist) or non-NMDA receptors: NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline.Li) and GYKI 52466 (1-(aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepin e.HCl) or acting at sodium channels to decrease glutamate release: lamotrigine and BW 1003C87 (5(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate). ED50 values against clonic seizures (in mumol/kg at the time of peak anticonvulsant effect) were: phenytoin 30.5 (2 h), diazepam 0.5 (0.5 h), MK 801 0.01 (4 h), D(-)CPPene 1.9 (4 h), CGP 37849 2 (1 h), GYKI 52466 24 (0.25 h), NBQX 40 (0.5 h), ACPC 1053 (0.5 h), BW 1003C87 2.2 (1 h), lamotrigine 4.8 (4 h). BW 1003C87, lamotrigine, MK 801, phenytoin, diazepam and CGP 37849 had the most favourable therapeutic indices (rotarod locomotor deficit ED50/anticonvulsant ED50).

Topics: 2-Amino-5-phosphonovalerate; Acoustic Stimulation; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Female; Lamotrigine; Male; Motor Activity; Phenytoin; Pyrimidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors; Triazines

Excessive release of glutamate has been implicated in the pathogenesis of excitotoxic neurologic disorders, such as stroke. BW 1003C87, an inhibitor of glutamate release and a putative Na+ channel antagonist, reduced veratridine-stimulated, tetrodotoxin- and dizocilpine-sensitive toxicity (measured by lactate dehydrogenase efflux) in neuron-enriched cortical cultures (IC50 = 5 microM). In contrast, BW 1003C87 (300 microM) had no effect on toxicity induced by direct application of 1 mM glutamate or 1 mM N-methyl-D-aspartate, or by depolarization with 50 mM KCl. Glutamate release inhibitors such as BW 1003C87 may provide a novel approach to protection from excitotoxicity.

Topics: Animals; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Glutamates; Glutamic Acid; N-Methylaspartate; Neurons; Neurotoxins; Potassium Chloride; Pyrimidines; Rats; Rats, Sprague-Dawley; Sodium Channels; Tetrodotoxin; Veratridine