Release and aggregation of cytochrome c and α-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole

Antiparkinsonian Drugs and Their Neuroprotective Effects.

“…Interestingly, while pramipexole and talipexole (non-ergot D 2 -receptor agonists) inhibited the in vitro aggregation of asynuclein and cytochrome c, 82) they inhibited a-synuclein aggregation only at higher concentrations. Therefore, a usual clinical dose of pramipexole or talipexole can not be expected to inhibit a-synuclein aggregation.…”

“…87) At higher concentrations, pramipexole and talipexole inhibited the activation of caspase-9 and caspase-3 in similar manners and with similar potencies, suggesting that these drugs may also inhibit Apaf-1 at higher concentrations. 82) In addition, recent studies have suggested that ER stress-induced neurodegeneration may also play a role in the pathology of PD. 45,47,48) Therefore, drugs that inhibit the neuronal death induced by oxidative stress and/or ER stress should also be useful for treating parkinsonism.…”

$alpha;-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease

“…Here, the expression of DAT confers the selectivity of MPP þ toward SN [47], since this neurotoxin enters the dopaminergic neuron through DAT in an energydependent manner. Once in the cell, MPP þ inhibits complex I of the mitochondrial respiratory chain, releasing cytochrome c, which accelerates aggregation of a-synuclein [48], ultimately affecting the properties of a-synuclein (Fig. 2).…”

Targeted Antioxidative and Neuroprotective Properties of the Dopamine Agonist Pramipexole and Its Nondopaminergic Enantiomer SND919CL2x [(+)2-Amino-4,5,6,7-tetrahydro-6-lpropylamino-benzathiazole Dihydrochloride]

“…Several studies described an antioxidative action of the drug and/or a preservation of mitochondrial function, resulting in inhibition of cell death (Cassarino et al, 1998;Kitamura et al, 1998;Kakimura et al, 2001;Abramova et al, 2002;Gu et al, 2004). Because both enantiomers are lipophilic cations, it has been hypothesized (Abramova et al, 2002) that they might accumulate in mitochondria, as predicted for other lipophilic cations (Trapp and Horobin, 2005).…”