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].
Pramipexole has been shown to possess neuroprotective properties in vitro that are partly independent of its dopaminergic agonism. The site of neuroprotective action is still unknown. Using [(3)H]pramipexole, we show that the drug enters and accumulates in cells and mitochondria. Detoxification of reactive oxygen species (ROS) by pramipexole is shown in vitro and in vivo by evaluating mitochondrial ROS release and aconitase-2 activity, respectively. Pramipexole and its (+)-enantiomer SND919CL2X [low-affinity dopamine agonist; (+)2-amino-4,5,6,7-tetrahydro-6-l-propylamino-benzathiazole dihydrochloride] possess equipotent efficacy toward hydrogen peroxide and nitric oxide generated in vitro and inhibit cell death in glutathione-depleted neuroblastoma cells. IC(50) values ranged from 15 to 1000 microM, consistent with the reactivity of the respective radical and the compartmentalization of ROS generation and ROS detoxification. Finally, both compounds were tested in superoxide dismutase 1-G93A mice, a model of familial amyotrophic lateral sclerosis. SND919CL2X (100 mg/kg) prolongs survival time and preserves motor function in contrast to pramipexole (3 mg/kg), which shows an increase in running wheel activity before disease onset, presumably caused by the dopaminergic agonism. We conclude that both enantiomers, in addition to their dopaminergic activity, are able to confer neuroprotective effects by their ability to accumulate in brain, cells, and mitochondria where they detoxify ROS. However, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, because the high doses needed for antioxidative action in vitro are not accessible in vivo due to dopaminergic side effects. In contrast, SND919CL2X may represent the prototype of a mitochondria-targeted neuroprotectant because it has the same antioxidative properties without causing adverse effects.
Danzeisen
R
R
Department of Central Nervous System Research, Boehringer-Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany. lothar.kussmaul@bc.boehringer-ingelheim.com.
Schwalenstoecker
B
B
Gillardon
F
F
Buerger
E
E
Krzykalla
V
V
Klinder
K
K
Schild
L
L
Hengerer
B
B
Ludolph
A C
AC
Dorner-Ciossek
C
C
Kussmaul
L
L
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D052160:Benzothiazoles; D001923:Brain Chemistry / Q000187:drug effects; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003470:Culture Media; D018491:Dopamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000523:psychology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents; D016877:Oxidants / Q000494:pharmacology; D000077487:Pramipexole; D013237:Stereoisomerism; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D000072105:Superoxide Dismutase-1; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D000975:Antioxidants; D052160:Benzothiazoles; D003470:Culture Media; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D016877:Oxidants; D013844:Thiazoles; D000077487:Pramipexole; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000154:Aconitate Hydratase