dizocilpine-maleate and lubeluzole

The neuroprotective effects of a novel synthetic compound, M50463, have been determined by using embryonic rat neocortical neurons in various culture conditions. M50463 was initially characterized as a potent specific ligand for a voltage-dependent sodium channel by radioligand binding studies. In fact, M50463 inhibited neuronal cell death induced by veratrine and inhibited an increase of the intracellular calcium level in neurons evoked by veratrine. In addition to such expected effects, M50463 had the ability to prevent glutamate neurotoxicity, to promote the neuronal survival in serum-deprived medium and to prevent nitric oxide-induced neurotoxicity. These results suggested that M50463 is not a simple sodium channel blocker, but a neuroprotective agent which has some crucial mechanism of action on neuronal death occurring in various situations, and it is a novel, innovative candidate for neuroprotective therapy for various neurodegenerative disorders.

Topics: Acetylcysteine; Animals; Antihypertensive Agents; Batrachotoxins; Binding Sites; Binding, Competitive; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Cell Death; Cells, Cultured; Culture Media, Serum-Free; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fetus; Glutamic Acid; Indoles; Neurons; Neuroprotective Agents; Neurotoxins; Nicardipine; Nitroprusside; Piperidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Sodium Channels; Thiazoles; Veratrine; Vitamin E

Seizures are one of the most frequent complications after cerebral ischemia in patients. Up to now it is unknown which mechanisms are responsible for this. As shown previously photothrombotic infarction in rat neocortex leads to a sweeping suppression of GABAergic inhibition. In this study we investigated whether and to what extent epileptiform discharges can be observed in this ischemia model. In neocortical slices from lesioned animals we did not find spontaneous epileptic activity or paroxysmal depolarisation shifts. However, ipsi- and contralateral to a photothrombotic lesion the frequency of double and multiple discharges was markedly increased when compared to unlesioned controls. Surprisingly, neither the drug lubeluzole which was has been shown to prevent the GABAergic disinhibition observed after photothrombotic lesioning of rat neocortex, nor the prevention of spreading depressions by the NMDA-receptor antagonist MK-801 during lesion induction significantly affected the frequency of epileptiform discharges. This indicates that the epileptiform discharges are probably caused by functional alterations of glutamatergic receptors.

Topics: Animals; Cerebral Infarction; Dizocilpine Maleate; Electric Stimulation; Electrophysiology; Epilepsy; In Vitro Techniques; Intracranial Embolism and Thrombosis; Light; Male; Neocortex; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Reaction Time; Thiazoles

Focal cerebral lesions in the rat brain induced by photothrombosis cause hyperexcitability of the surrounding brain. This can be demonstrated in brain slices taken from animals several days after lesioning, by analysis of field potential responses to paired-pulse stimulation. We now investigated whether and how these remote effects of a cortical lesion can be modified pharmacologically. Application of the NMDA receptor antagonist, MK-801 ((+)-5-methyl-10, 11-dihydro-5H-dibnzo[a,d]cyclohepten-5,10-imine), was shown to block induction of immediate early genes and activation of astrocytes as evidenced by glial fibrillary acidic protein (GFAP) staining in the photothrombosis model. However, MK-801 did not affect the hyperexcitability that had been demonstrated by field potential recordings in brain slices. In another series of experiments, lubeluzole ((+)-(S)-4-(2-benzothiazolylmethylamino)-alpha-[(3,4-difluoroph enoxy) methyl]-1-piperidineethanol), which inhibits the glutamate-activated nitric oxide pathway as evidenced by down-regulation of intracellular cyclic GMP, was given immediately after induction of the insult. This reduced hyperexcitability as investigated 7 days later. In the light of these data one can suggest that a nitric oxide-cyclic GMP-related mechanism may be responsible for functional alterations in the surround of photothrombotic brain lesions.

Topics: Animals; Cerebral Cortex; Dermatitis, Phototoxic; Disease Models, Animal; Dizocilpine Maleate; Electrophysiology; Evoked Potentials; Excitatory Amino Acid Antagonists; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Thiazoles

Posttreatment with lubeluzole, the S-isomer of a novel 3,4-difluoro benzothiazole, potently rescued tactile/proprioceptive hindlimb placing reactions contralateral to unilateral thrombotic infarcts in the hindlimb area of the parietal sensorimotor neocortex of rats. Administered at 5 min postinfarct, a single i.v. bolus of lubeluzole was three times as potent as the racemate, whereas the R-isomer was inactive. Neurological protection was near-maximal for treatment delays through 1 hr postinfarct, but declined with longer delays. However, when administered at 6 hr, 1.25 mg/kg i.v. still protected 60% of infarcted rats. An i.v. bolus followed by a 1-hr i.v. infusion produced equieffective neurologic protection at both 6- and 3-hr delays. This optimal lubeluzole regimen, started at 5 min postinfarct, reduced infarct volume by 22 to 24% at 4 hr postinfarct and by 28% at 7 days postinfarct. Again, the R-isomer was inactive. Down-regulation of the glutamate-activated nitric oxide synthase pathway leading to neurotoxicity and neuronal death may constitute a neuroprotective mechanism of action for lubeluzole.

Topics: Animals; Brain; Cerebral Cortex; Cerebral Infarction; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Neuroprotective Agents; Nimodipine; Nitric Oxide Synthase; Photochemistry; Piperidines; Rats; Rats, Wistar; Stereoisomerism; Thiazoles