piperidines and nalmefene

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.

Topics: Acute Disease; Adult; Aged; Animals; Antioxidants; Calcium Channel Blockers; Chlormethiazole; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Excitatory Amino Acid Antagonists; Excitatory Amino Acids; Forecasting; GABA Modulators; Guanidines; Humans; Imidazoles; Middle Aged; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Pipecolic Acids; Piperidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Stroke; Thiazoles

Oral administration of the opioid antagonist nalmefene alone (up to 20 mg/kg) failed to show a significant effect on acute food intake in mice. However, combined oral dosing of nalmefene and subthreshold doses of AM251, a cannabinoid CB1 receptor inverse agonist, led to a significant reduction in food intake in both lean and diet-induced obese (DIO) mice. Furthermore, the anorectic effect of a high dose of AM251 was further enhanced when co-administered with nalmefene. The results support a synergistic interaction between opioid and cannabinoid systems in regulating feeding behavior.

Topics: Animals; Appetite Regulation; Body Weight; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Dose-Response Relationship, Drug; Drug Synergism; Homeostasis; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Obesity; Opioid Peptides; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1