Abstract
Pramipexole (PPX) is a full intrinsic activity, direct-acting dopamine (DA) agonist possessing 7-fold higher affinity for D3 than for D2 receptors. It also is a potent antioxidant. PPX was previously shown to be neuroprotective because it dose dependently attenuated the DA neuron loss produced by levodopa in mesencephalic cultures. Several different drugs with properties similar to PPX were studied here to better understand the mechanism or mechanisms responsible for this neuroprotective effect. The D3-preferring agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D3 antagonist U99194, respectively, increased and decreased the neuroprotective effects of PPX in a dose-dependent fashion. Addition of the selective D2agonist U95666 or the D2/D3 antagonists domperidone or raclopride did not affect PPX’s neuroprotective effect. Interestingly, 7-OH-DPAT by itself did not attenuate the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was combined with a low dose of the antioxidants U101033E or α-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed when the D3-preferring agonist PD128,907 was studied. In addition, media conditioned by exposure of mesencephalic cultures incubated with all D3-preferring agonists studied was shown to enhance the growth of DA neurons in freshly harvested recipient cultures implicating a D3-mediated trophic activity in the neuroprotective effect. These data suggest that PPX’s neuroprotective actions in the levodopa toxicity model are a consequence of its combined actions as a D3 receptor agonist and an antioxidant.
Footnotes
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Send reprint requests to: Paul M. Carvey, Ph.D, Department of Pharmacology, Rush-Presbyterian-St. Luke’s Medical Center, 2242 West Harrison St., Suite 260, Chicago, IL 60612. E-mail:pcarvey{at}rush.edu
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↵1 This work was supported by National Institute of Neurological Disorders and Stroke Grant NS33174 and a grant from the Pharmacia and Upjohn Co.
- Abbreviations:
- CM
- complete media
- DA
- dopamine
- DM
- defined media
- DMEM
- Dulbecco’s modified Eagle’s medium
- MPP+
- 1-methyl-4-phenylpyridinium
- PC
- plate control
- 7-OH-DPAT
- 7-hydroxy-diphenylaminotetralin
- PD
- Parkinson’s disease
- PD128
- 907, (+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)-benzpyrano-(4,3b)-1,4-oxasin-9-ol
- PPX
- pramipexole
- RMT
- rostral mesencephalic tegmentum
- TH
- tyrosine hydroxylase
- THir
- TH immunoreactive
- U101033E
- pyrrolopyrimidine lipid peroxidation inhibitor (lazeroid compound)
- U95666
- (R)-5,6-diydro-5-(methylamino)-4H-imidazo-(4,5,1-ij)-quinolin-2(1H)-one monohydrochloride
- U99194
- 5,6-dimethoxy-N,N-dipropyl-2-indanamine monochloride
- Received June 24, 1998.
- Accepted November 11, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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