Talipexole

Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole.[Pubmed:11301060]

Eur J Pharmacol. 2001 Apr 6;417(1-2):59-67.

Recently, it has been shown that release of cytochrome c from the mitochondria to the cytosol is required for activation of the caspase-3-dependent cascade in apoptosis, and also for alpha-synuclein aggregation. In the present study, we examined the effects of Talipexole and pramipexole on the release of cytochrome c and alpha-synuclein, their aggregations, and activation of caspases. Treatment of human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP(+), 1 mM) induced the first event, which was the release of cytochrome c from the organellar fraction to the cytosolic fraction, then came the DNA fragmentation, and caused the last event, which was the accumulation of alpha-synuclein protein in the cytosolic fraction. Talipexole and pramipexole at low concentration (0.1-1 mM) significantly inhibited the accumulation of cytochrome c or alpha-synuclein in the cytosolic fraction. These drugs at high concentration (3-10 mM) inhibited in vitro aggregation of cytochrome c by hydrogen peroxide or that of alpha-synuclein by cytochrome c and hydrogen peroxide. In addition, in vitro activation of caspase-3 induced by cytochrome c and/or dATP was also inhibited by drugs at high concentration (5-10 mM). These results suggest that Talipexole and pramipexole may have protective effects against the neurodegeneration, which is induced by intracellular accumulation of cytochrome c and alpha-synuclein.

Pharmacokinetic profile of talipexole in healthy volunteers is not altered when it is co-administered with Madopar (co-beneldopa).[Pubmed:19646081]

J Clin Pharm Ther. 2009 Jun;34(3):345-54.

OBJECTIVES: To investigate the pharmacokinetics of Talipexole hydrochloride tablets and the potential influence of Madopar (benserazide and levodopa combination; co-beneldopa) tablets on Talipexole's pharmacokinetics when the two tablets are co-administered orally to healthy Chinese volunteers. METHODS: A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure Talipexole concentration in human plasma in an open-label, randomized, two-way crossover, single-dose study, with 1-week washout period. Healthy Chinese volunteers were randomized to receive Talipexole tablets either alone or together with Madopar tablets by oral administration after an overnight fast. Serial blood samples were collected for a period of 36 h after the administration. Pharmacokinetic parameters C(max), t(max), t(1/2z), mean residence time (MRT), AUC(0-tau), AUC(0-infinity), CL(z)/F and V(z)/F were determined under the non-compartmental model. Pharmacokinetic values of Talipexole administered alone to the subjects were compared with those administered simultaneously with Madopar to determine whether or not the differences were statistically significant. RESULTS: The subjects experienced mild gastrointestinal irritation when Talipexole was administered alone as well as together with Madopar. For Talipexole hydrochloride, there were no significant differences in the pharmacokinetic values between the two administrations. No pharmacokinetic differences based on gender were observed either. CONCLUSION: A single oral dose of Madopar co-administered with Talipexole does not significantly change Talipexole's pharmacokinetics in human.

The neuroprotective effect of talipexole from paraquat-induced cell death in dopaminergic neuronal cells.[Pubmed:20673835]

Neurotoxicology. 2010 Dec;31(6):701-8.

Talipexole is a non-ergot dopamine (DA) agonist that has been used in the treatment of Parkinson's disease. In the present study, we examined the effect of Talipexole on paraquat (PQ)-induced N27 cell death and the intracellular pathways involved in this effect. Pretreatment of N27 cells with Talipexole (1mM) resulted in significant protection against paraquat-induced cell death. In N27 cells, Talipexole inhibited paraquat-induced apoptotic hallmarks such as cytochrome c release, caspase-3 activation, chromatin condensation and externalization of phosphatidilserine. Talipexole pretreatment prevents the reduction in the anti-apoptotic Bcl-x(L) protein and increases in the pro-apoptotic form of Bak and p-Bad, both induced by PQ. Finally, we also observed that Talipexole abrogates the activation of cell death pathways JNK1/2 and p38 produced by PQ, and increases the phosphorylated (active) forms of the pro-survival pathways ERK1/2 and Akt. These results reveal that Talipexole exerts a neuroprotective effect in a mesencephalic cell line exposed to the neurotoxin PQ, which is related to the etiology of Parkinson's disease.

Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors.[Pubmed:12649387]

J Pharmacol Exp Ther. 2003 Apr;305(1):338-46.

In a dialysis procedure not requiring perfusate addition of acetylcholinesterase inhibitors to "boost" basal levels of acetylcholine (ACh), the influence of the antiparkinson agent piribedil upon levels of ACh in frontal cortex and dorsal hippocampus of freely moving rats was compared with those of other antiparkinson drugs and selective ligands at alpha(2)-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of alpha(2A)-ARs upon cholinergic transmission, the alpha(2)-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential alpha(2A)-AR agonist guanabenz reduced levels of ACh. They were elevated by the antagonists 2(2-methoxy-1,4 benzodioxan-2-yl)-2-imidazoline HCl (RX821002) and atipamezole and by the preferential alpha(2A)-AR antagonist 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole (BRL44008). In contrast, trans-2,3,9,13b-tetrahydro-1,2-dimethyl-1H-dibenz[c,f]imidazo[1,5-a]azepine (BRL41992) and prazosin, preferential alpha(2B/2C)-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at alpha(2)-ARs, dose dependently increased extracellular levels of ACh. This action was absent upon pretreatment with a maximally effective dose of RX821002. On the other hand, a further dopaminergic agonist and antiparkinson agent, Talipexole, which possesses agonist properties at alpha(2)-ARs, dose dependently reduced levels of ACh. This action was also blocked by RX821002. In contrast to piribedil and Talipexole, quinelorane, which interacts with dopaminergic receptors but not alpha(2)-ARs, failed to affect ACh levels. Finally, in analogy to the frontal cortex, piribedil likewise elicited a dose-dependent increase in extracellular levels of ACh in the dorsal hippocampus. In conclusion, in distinction to Talipexole and quinelorane, and reflecting its antagonist properties at alpha(2A)-ARs, piribedil reinforces cholinergic transmission in the frontal cortex and dorsal hippocampus of freely moving rats. These actions may be related to its facilitatory influence upon cognitive function.