ergoline and Necrosis

To study if cabergoline, a long-lasting specific dopamine D2 receptor agonist, has neuroprotective effects against oxidative stress, we exposed (3 h) SH-SY5Y human neuroblastoma cells to tert-butylhydroperoxide (t-BOOH; 500 microM). t-BOOH caused a 42+/-4% neuronal death, which was prevented by cabergoline (2 h before) in a concentration-dependent manner (EC(50): 1.24 microM). This effect was not antagonised by haloperidol (concentration up to 10 microM), and was associated with an increased availability of intracellular GSH contents (+30+/-11%) and a decrease in the membrane lipid peroxidation (-23+/-9%). Our data suggest that cabergoline has neuroprotective effects useful for Parkinson's disease therapy.

Topics: Cabergoline; Cell Death; Cell Survival; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Free Radicals; Haloperidol; Humans; Lipid Peroxidation; Models, Neurological; Necrosis; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Receptors, Dopamine D2; tert-Butylhydroperoxide; Tumor Cells, Cultured

Ischemic necrosis resulting from vasospasm is a common complication in skin flap surgery, and serotonin released by traumatized platelets is likely to play an important role in the pathogenesis of skin vasospasm in flap surgery. We studied the pathogenic role of serotonin and its pharmacologic intervention thereof in skin flap ischemic necrosis in pigs. We observed that serotonin caused a concentration-dependent (10(-8)-10(-5) M) increase in perfusion pressure in isolated perfused pig skin flaps. This vasoconstrictive effect of serotonin was blocked by S1C/2-serotonergic receptor antagonists LY53857 (10(-5) M) and ketanserin (10(-5) M), but not by an alpha 1-adrenoceptor antagonist (prazosin 10(-5) M), or a thromboxane A2 (TxA2)/endoperoxide receptor antagonist (SQ30741 10(-5) M). The vasoconstrictive effect of serotonin was more pronounced (p < 0.05) in the presence of an endothelium-derived nitric oxide (NO) synthesis inhibitor [N omega-monomethyl-L-arginine (L-NA) or NG-nitro-L-arginine (L-NMMA) 10(-5) M] but not a cyclooxygenase inhibitor (indomethacin 10(-5) M). In in vivo studies, serotonin infusion (5 micrograms/kg/min intravenously, i.v.) significantly (p < 0.05) decreased pig random pattern skin flap capillary blood flow. This in vivo vascular effect was also completely blocked in pigs pretreated with LY53857 (0.4 mg/kg i.v.). In a separate experiment without serotonin infusion, i.v. prazosin (2-8 micrograms/kg), dazmegrel (2-6 mg/kg), or SQ30741 (2-4 mg/kg) had no significant effect on skin flap capillary blood flow as compared with control. On the other hand, i.v. sergolexole or LY53857 significantly (p < 0.05) increased skin flap capillary blood flow in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Animals; Arginine; Dose-Response Relationship, Drug; Ergolines; In Vitro Techniques; Ischemia; Ketanserin; Necrosis; omega-N-Methylarginine; Prostaglandin H2; Prostaglandins H; Regional Blood Flow; Serotonin; Serotonin Antagonists; Skin; Surgical Flaps; Swine; Thromboxane A2; Vasoconstriction

The purpose of this study was to examine the effects of blockade (sulpiride) and activation (quinpirole) of dopaminergic D2 (DA2) receptors on brain lesions subsequent to excessive activation of glutamate (GLU) receptors. Striatal lesions were produced by direct injection of quinolinic acid, an endogenous GLU receptor agonist. Sulpiride (100 mg kg-1 i.p., 30 min before quinolinic acid injection and 1 h after) significantly (p < or = 0.05) reduced the volume of the lesion by around 20%. Quinpirole (1.25 mg kg-1 i.p., 30 min before quinolinic acid injection) had no effect. The protective action of DA2 receptor blockade strongly suggests that quinolinic acid-induced excitotoxicity may be partly modulated by DA2 receptors.

Topics: Animals; Corpus Striatum; Dopamine Agents; Dopamine Antagonists; Ergolines; Male; Necrosis; Nerve Degeneration; Quinolinic Acid; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Glutamate; Sulpiride

Topics: Adrenergic alpha-Antagonists; Animals; Bromine; Drug Synergism; Ergolines; Ergoloid Mesylates; Heart Diseases; Necrosis; Nicotinic Acids; Phenylephrine; Rats; Theophylline