dihydroergotoxine and Parkinson-Disease--Secondary

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on respiratory chain features were studied in synaptic and non-synaptic mitochondrial populations from cerebral cortex and hippocampus of Macaca Fascicularis (Cynomolgus monkey). Enzymatic activity, cytochrome a + a3 content and turnover numbers of Complex IV, contents of Coenzyme Q10, of hydroperoxides and membrane fluidity were assessed in non-synaptic "perikaryal" and intra-synaptic "light" and "heavy" mitochondria isolated: (a) from the dopaminergic ascending terminal areas of cerebral cortex of monkeys treated p.o. with dihydroergocriptine at the dose of 2, 6 or 20 mg/kg/day for 52 weeks; (b) from the dopaminergic terminal areas of hippocampus of monkeys treated p.o. with dihydroergocriptine at the dose of 12 mg/kg/day before and during the induction of a Parkinson's-like syndrome by MPTP administration (i.v., 0.3 mg/kg/day for 5 days). Dihydroergocriptine administration moderately increased both cytochrome oxidase activity and cytochrome a + a3 content in "light" intra-synaptic mitochondria and hydroperoxides/CoQ10 ratio in all the types of mitochondria, as a consequence of the enhanced energy metabolism. The Parkinson's-like syndrome by MPTP changed the biochemical investigated parameters, affecting both directly the respiratory chain structures, i.e. by respiratory chain complexes inhibition and indirectly, i.e. by free radical mediated damages. MPTP administration negatively influenced Complex IV activity and Turnover Number of intra-synaptic mitochondria, without affecting the total cytochrome a + a3 amount. In all types of mitochondria and particularly on the "light" intra-synaptic ones, MPTP-induced lesion enhanced hydroperoxides/Coenzyme Q10 molar ratio due to the fall in Coenzyme Q10 levels and the concomitant increase in hydroperoxides. Dihydroergocriptine treatment appeared to be effective in MPTP-treated animals in improving those mitochondrial features that probably suffered free radical insults.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Cerebral Cortex; Dihydroergotoxine; Electron Transport Complex IV; Energy Metabolism; Hippocampus; Macaca fascicularis; Male; Mitochondria; Neuroprotective Agents; Parkinson Disease, Secondary; Peroxides; Ubiquinone

alpha-Dihydroergocryptine (alpha-DHEC) is a well known dopaminergic agent successfully employed in the treatment of Parkinson's disease. alpha-DHEC showed a neuroprotective activity against total cerebral ischemia induced by MgCl2 in mice and histocytic anoxia by NaCN in mice and rats. Moreover the drug promoted the recovery of locomotor activity in rats after cerebral ischemic damage and protected mice against convulsions induced by intracerebroventricular injections of NMDA and glutamate. alpha-DHEC showed a protective activity on neuronal degeneration induced by MPTP in monkeys, as evaluated through animal's behaviour and morphological-cytochemical changes in the substantia nigra, suggesting a preservative effect on neuronal morphology and brain architecture. In the MPTP-treated monkeys, the alpha-DHEC administration induced a restoration of the unstimulated MDA values to control levels. The neuroprotective activity of alpha-DHEC is related to its peculiar activity on antioxidative enzymes of GSH system and to reduction of lipid-peroxide-induced cellular degeneration.

Topics: Animals; Brain Ischemia; Constriction; Dihydroergotoxine; Disease Models, Animal; Hypoxia, Brain; Injections, Intraventricular; Macaca fascicularis; Male; Mice; Mice, Inbred ICR; Motor Activity; Neuroprotective Agents; Parkinson Disease, Secondary; Rats; Seizures

Monkeys, intravenously administered with MPTP at the dose of 0.3 mg/kg for 5 consecutive days, develop a severe Parkinson-like syndrome. Cholinergic enzyme activities are increased in the internal segment of the globus pallidus (GPi) and into a lesser extent in the external globus pallidus (GPe). Cholinergic activities are not significantly affected in the caudate and putamen nor in the frontal, parietotemporal, occipital cortices and in the cerebellum. The treatment of the animals twice daily for 2 weeks with dihydro-alpha-ergocryptine (DEK) starting 5 days before the first MPTP administration counteracts the neurotoxin-induced alteration in the internal pallidum and ameliorates some motor related parkinsonian symptoms.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acetylcholinesterase; Animals; Brain; Choline O-Acetyltransferase; Dihydroergotoxine; Globus Pallidus; Macaca fascicularis; Male; Motor Activity; MPTP Poisoning; Organ Specificity; Parkinson Disease, Secondary; Posture; Pyruvate Dehydrogenase Complex; Time Factors; Tremor

The maximal rates (Vmax) of some enzyme activities related to synaptosomal energy metabolism were studied in different types of synaptosomes from cerebellar cortex of Macaca Fascicularis (Cynomolgus monkey). Different synaptosomal populations, namely "large" and "small" synaptosomes, were isolated from the anterior lobule of the cerebellar cortex of monkeys treated p.o. with dihydroergocriptine at the dose of 12 mg/kg/day before and during the induction of a Parkinson's-like syndrome by MPTP administration (i.v., 0.3 mg/kg/day for 5 days). The enzymes were chosen according to their regulatory role and as markers of the following metabolic pathways: (a) glycolysis ((hexokinase, phosphofructokinase, lactate dehydrogenase), (b) Krebs' (TCA) cycle (citrate synthase, malate dehydrogenase), (c) amino acid, glutamate metabolism (glutamate dehydrogenase, glutamate-pyruvate- and glutamate-oxaloacetate-transaminases), (d) acetylcholine catabolism (acetylcholinesterase) and (e) ATPases, i.e. Na(+)-K(+)-ATPase, Mg(2+)-ATP synthetase, Mg(2+)-ATPase, Ca(2+)-Mg(2+)-ATPase and Ca(2+)-ATPase Low and High affinity for Ca2+. The MPTP administration modified the activities of citrate synthase, malate dehydrogenase, Na(+)-K(+)-ATPase, acetylcholinesterase and glutamate-oxaloacetate transaminase only on selected types of synaptosomes. Pharmacological treatment by dihydroergocriptine was able to recovery at the steady-state levels the activities of these enzymes, thus demonstrating a partial protective effect on these biochemical parameters.

Topics: Acetylcholine; Adenosine Triphosphatases; Amino Acids; Animals; Cerebellar Cortex; Citric Acid Cycle; Dihydroergotoxine; Energy Metabolism; Glycolysis; Macaca fascicularis; Male; Mitochondria; MPTP Poisoning; Parkinson Disease, Secondary; Synaptosomes

The effects of the Parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were evaluated in four different monkey brain areas (frontal and occipital cortex, caudate putamen, substantia nigra). The basal and stimulated lipid peroxidation and the reduced glutathione (GSH) concentration were evaluated in three groups of male Macaca fascicularis monkeys (6 animals/group): (a) controls; (b) MPTP-treated animals; (c) animals treated with MPTP and alpha-dihydroergocryptine (DEK; ergot alkaloid characterized by a dopaminergic agonist action). In MPTP-treated animals the GSH concentration was unchanged or decreased in a non-significant way in the frontal and occipital cortex, and in substantia nigra. The basal thiobabituric acid reactive substance (TBARS) concentrations were significantly higher in the caudate putamen and substantia nigra of MPTP-treated animals. In the MPTP-treated monkeys the DEK administration induced a restoration of basal TBARS values to nearly normal ones. By incubating tissue from different brain areas with FeSO4 plus ascorbic acid, the stimulation of lipid peroxidation decreased the TBARS production in the substantia nigra of the MPTP-treated animals. These results, taken together, may indicate that an increased lipid peroxidation could possibly play a role in producing the Parkinson-like syndrome by MPTP and that a free radical excess could be responsible for the degeneration of the substantia nigra. The treatment with an ergot alkaloid (i.e., alpha-dihydroergocryptine) partially antagonizes the MPTP-induced increase in basal TBARS concentration in caudate putamen.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Ascorbic Acid; Brain; Caudate Nucleus; Dihydroergotoxine; Ferrous Compounds; Frontal Lobe; Glutathione; Lipid Peroxidation; Macaca fascicularis; Male; Occipital Lobe; Oxidation-Reduction; Parkinson Disease, Secondary; Putamen; Substantia Nigra; Thiobarbituric Acid Reactive Substances

The maximal rates (Vmax) of some mitochondrial enzyme activities related to energy transduction (citrate synthase, succinate dehydrogenase, malate dehydrogenase, NADH-cytochrome c reductase, cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase, glutamate-pyruvate- and glutamate-oxaloacetate- transaminases) were evaluated in non-synaptic ("free") and intrasynaptic "light" and "heavy" mitochondria from hippocampus of Macaca fascicularis (Cynomolgus monkey). The different mitochondrial populations were isolated from the hippocampus of monkeys treated p.o. with dihydroergocryptine at a dose of 12 mg/kg/day before and during the induction of a Parkinson's-like syndrome by MPTP administration (i.v., 0.3 mg/kg/day for 5 days). The MPTP administration modified the activity of some enzymes related to the metabolism of glutamate and the activity of succinate dehydrogenase on selected types of mitochondria. Pharmacological treatment by dihydroergocryptine promoted return to the steady-state levels of most enzymes, demonstrating a protective effect on these biochemical parameters.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Amino Acids; Animals; Dihydroergotoxine; Energy Metabolism; Hippocampus; Macaca fascicularis; Male; Mitochondria; MPTP Poisoning; Parkinson Disease, Secondary; Synaptosomes