dihydroergotoxine and Nerve-Degeneration

Dihydroergocryptine is an ergot alkaloid endowed with pharmacological actions mainly related to its dopaminomimetic activity. Free radical formation and subsequent lipid peroxidation had been postulated to participate broadly to the pathogenesis of tissue injury, including the brain injury induced by hypoxia, ischemia or trauma, as well as in the physiopathology of chronic neurodegenerative diseases, such as Parkinson's disease. Here we report that dihydroergocryptine protects cultured rat cerebellar granule cells against age-dependent and glutamate-induced neurotoxicity. Dihydroergocryptine antagonizes in fact both the neuronal death produced by acute exposure to a toxic glutamate concentration as well as the normal age-dependent degeneration in culture, presumably by exerting a scavenger action. This effect does not seem mediated entirely by interactions with the dopamine D2 receptors. The neuroprotective action of dihydroergocryptine suggests a potential usefulness in halting the acute and chronic neurodegenerative diseases related to excitotoxic damage and free radical formation, including Parkinson's disease.

Topics: Animals; Cells, Cultured; Dihydroergotoxine; Dopamine Agonists; Free Radicals; Humans; Lipid Peroxidation; Nerve Degeneration; Neurons; Neuroprotective Agents

Dihydroergocryptine is a hydrogenated ergot derivative with pharmacological actions mainly related to its dopaminomimetic activity. Here we report that dihydroergocryptine can protect cultured rat cerebellar granule cells against glutamate-induced neurotoxicity, assessing cell viability with the fluorescein diacetate-propidium iodide technique. Dihydroergocryptine antagonized both the neuronal death produced by acute exposure to a toxic glutamate concentration as well as the normal age-dependent degeneration in culture. The effect of dihydroergocryptine might be mediated by a scavenger action as suggested by the fact that the compound in a concentration-dependent manner reduced the formation of intracellular peroxides produced in cerebellar granule cells by exposure to 100 microM glutamate. This action is apparently not mediated entirely by interactions with the dopamine D2 receptors. The neuroprotective action suggests that dihydroergocryptine might be a potential useful drug in the therapy and/or prophylaxis of acute and chronic neurodegenerative diseases related to excitotoxic damage.

Topics: Aging; Animals; Cell Survival; Cells, Cultured; Cerebellar Cortex; Dihydroergotoxine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fluoresceins; Glutamates; Glutamic Acid; Nerve Degeneration; Neurons; Peroxides; Propidium; Rats

The CA 1 neurons in the gerbil hippocampus exhibiting necrosis with delayed onset following 5 min ischemia were reduced markedly by the systemic administration of dihydroergotoxine mesylate (Hydergine; HYG). Immediately after 5 min of forebrain ischemia, the animals were injected intraperitoneally with HYG. Seven days after ischemia, perfusion-fixed brains were processed by conventional histology. The number of neurons per millimeter in the CA 1 pyramidal cell layer were calculated and they were labelled neuronal density. In the control group, the neuronal density was 66.03 +/- 7.37 (mean +/- SEM), in the vehicle group, it was 11.25 +/- 4.93. The neuronal density in the HYG group was 69.19 +/- 6.49. The difference in the neuronal density between the HYG group and the control group was not statistically significant. These data indicate that HYG protects on the CA 1 neurons, and this suggest that the suppression of adrenoceptors by this drugs may be the main mechanism of action. This morphologic outcome may explain the functional amelioration of mental impairment by HYG.

Topics: Animals; Brain Ischemia; Cell Survival; Dihydroergotoxine; Gerbillinae; Hippocampus; Male; Nerve Degeneration; Synaptic Transmission