dizocilpine-maleate and aptiganel

Although caffeinol (a combination of a low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action.. We used an in vivo excitotoxicity model based on intracortical infusion of N-methyl-D-aspartate (NMDA) and a model of reversible focal ischemia to demonstrate NMDA receptor inhibition as a potential mechanism of caffeinol anti-ischemic activity.. Caffeinol reduced the size of excitotoxic lesion, and substitution of ethanol in caffeinol with the NMDA antagonists CNS-1102 and MK-801 but not with MgSO(4) produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as caffeinol. This NMDA receptor antagonist and caffeine combination demonstrated a long window of opportunity, activity in spontaneously hypertensive rats, and, unlike caffeinol, was fully effective in animals chronically pretreated with ethanol.. Our study suggests that antiexcitotoxic properties may underlie some of the anti-ischemic effect of caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new use of NMDA-based pharmacology in the treatment of stroke.

Topics: Animals; Brain Ischemia; Caffeine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Ethanol; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Guanidines; Male; N-Methylaspartate; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Phosphodiesterase Inhibitors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Time Factors; Treatment Outcome

Prevention of the immediate excitotoxic phase occurring in response to spinal cord injury (SCI) is a major issue to reduce the neuronal damage responsible for any ensuing motor deficits. The present study evaluated the neuroprotective efficacy of three noncompetitive NMDA receptor antagonists: Gacyclidine (GK-11), a new compound, Dizocilpine (MK-801), and Cerestat (CNS-1102) in a rat spinal cord contusion model. To mimic human SCI, a standardized model of rat spinal cord closed contusion in which animals spontaneously and progressively recover from the induced paraplegia was employed. Such model, characterized by a slow recovery of hindlimb locomotor function enables easy quantification of the neuroprotection at both the behavioral and cellular level. The animals were treated intravenously with the respective drugs 10 min after the spinal contusion. The dose range study suggested that 1 mg/kg of Gacyclidine was the most effective dose to promote functional recovery in reducing by half the time needed to reach full locomotor recovery. Racemate and enantiomers of Gacyclidine showed similar neuroprotective effects, but treatment with the enantiomers were not as efficacious in promoting full functional recovery. Similarly, a prolonged treatment with the racemate was not as efficious as a single dose, suggesting that a prolonged blockade of the amino-excitatory neurotransmission may be deleterious. Finally, Dizocilpine and Cerestat treatments induced only a partial and delayed neuroprotective effect compared to Gacyclidine. Neuroprotection characterized by a reduction of the cystic cavity and of the astrogliosis was observed with all treatments. As Gacyclidine is already in clinical trials, the present findings suggest the premise that it is a promising agent for limiting the initial neuronal damage induced by CNS trauma leading to better functional recovery.

Topics: Animals; Astrocytes; Cyclohexanes; Cyclohexenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Female; Gliosis; Guanidines; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Stereoisomerism