Research reportNeuroprotective effects of pramipexole in young and aged MPTP-treated mice
Introduction
Striatal dopamine (DA) depletion consequent to degeneration of substantia nigra pars compacta (SNc) neurons is associated with both idiopathic Parkinson’s disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. While the mechanisms that trigger neuronal degeneration in the SNc in idiopathic PD are still unknown, the mechanisms contributing to DA neuron degeneration following MPTP exposure are better defined [16], [35]. MPTP is converted to the methylpyridinium ion (MPP+) by monoamine oxidase-B primarily within glia, and actively taken up by dopaminergic (DAergic) neurons. Although additional factors have been hypothesized to play a role in the death of SNc neurons in PD [7], [11], [12], [34], [35], [37], accumulation of MPP+ in mitochondria leads to inhibition of complex 1 of the electron transport chain, impaired ATP synthesis, increased generation of free radicals, lipid peroxidation [11], [21], [36] and ultimately cell death.
While current PD therapies are designed primarily to improve symptoms, an additional goal of new PD therapies needs to be neuroprotection. Dopaminergic agonists (e.g. bromocriptine and pergolide), used as symptomatic therapy for PD, have been suggested to have neuroprotective properties in addition to their symptomatic effects [9], [10], [23], [25], [27], [32], [42]. Although most therapeutic effects of DA agonists are thought to be associated with postsynaptic receptor stimulation [25], recent evidence suggests that DA agonist effects may also be mediated at least in part through pre-synaptic stimulation of DA autoreceptors and intracellular sites within presynaptic DAergic neurons [27]. Potential neuroprotective effects of DA agonists on presynaptic neurons may involve altered control of DA metabolism, resulting in reduced oxidative stress [15], [41].
Pramipexole (PPX) {(−)-2-amino-4,5,6,7-tetrahydro-6-propylamino-bensthiazol dihydrochloride} is a high affinity, synthetic, non-ergoline DA agonist which preferentially binds to the D2 subfamily of DA receptors (D2, D3, and D4) [19]. Recent studies have identified a sevenfold greater affinity of PPX for binding to D3 receptors, both pre- and post-synaptically, when compared to its affinity for either D2 or D4 receptors [2], [19]. Similarly a greater affinity for binding to presynaptic D2 autoreceptors as opposed to post-synaptic D2 receptors has been identified. The clinical relevance of this binding specificity is not clear. The major concentration of D3 receptors is within the mesolimbic and mesocortical DAergic pathways (primarily associated with mood regulation), but D3 receptors have also been identified within the Islands of Calleja and the dorsal striatum [29]. Pramipexole has been shown to reduce the levels of extracellular DA in a dose-dependent manner [19] and appears to possess antioxidant properties [4], [5], [10], [32], [43]. Pramipexole can also protect against postischemic or metamphetamine-induced degeneration as well as MPTP, 6-hydroxydopamine and levodopa-induced toxicity and resultant nigral cell death [4], [10], [32], [40], [43].
In view of the putative neuroprotective effects of PPX reported elsewhere, the present study was designed to assess the neuroprotective potential of PPX on striatal DA levels and DA cell survival in the substantia nigra pars compacta (SNc) in young and aged MPTP-treated mice.
Section snippets
MPTP/PPX administration
All animals used in this study were cared for according to institutional and NIH animal care and use guidelines. Ninety young (8-week-old) and 22 aged (12-month-old) male C57Bl/6J mice (Taconic Animal Research, Germantown, NY) were used for this study.
Fifty-four 8-week-old animals received MPTP–HCl (Research Biochemical Inc., Natick, MA), dissolved in physiological saline and administered subcutaneously at a concentration of 20 mg/kg b.i.d. at 4-h intervals for five consecutive days. Thirty-six
MPTP-induced DA depletion
In mice that received MPTP and no PPX, significant reductions in striatal DA levels were observed. In young mice, striatal DA levels were depleted by 86±1% and 83±2% at 2 days (Table 1, Group 6) and 14 days (Table 1, Group 2), respectively, after cessation of MPTP administration. In aged mice, striatal DA levels were decreased by 87±2% at 14 days (Table 2, Group 12) after MPTP. MPTP also significantly decreased DOPAC levels and increased DOPAC/DA ratios (Table 1, Table 2).
Co-administration of
Discussion
Previous studies have suggested that the DA receptor agonist, PPX, may be neuroprotective against different types of damage [10], [13], [32], including that caused by MPTP [13], [41], [43]. It has also been suggested that PPX may reduce reactive oxygen species formed in DAergic terminal fields through DA auto-oxidation [24], as well as inhibit the formation of mitochondrial permeability transition pores after MPTP administration [5].
In the current study, co-administration of PPX and MPTP to
Acknowledgements
This research was supported by Pharmacia & Upjohn Inc.
References (43)
- et al.
Pramipexole, a dopamine D2 receptor agonist, decreases the extracellular concentration of dopamine in vivo
Eur. J. Pharmacol.
(1991) - et al.
Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats
Neurobiol. Aging
(1992) - et al.
Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons
Brain Res.
(1996) - et al.
1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles
Biochem. Biophys. Res. Commun.
(1990) - et al.
Inhibitory effects of talipexole and pramipexole on MPTP-induced dopamine reduction in the striatum of C57BL/6N mice
Jpn. J. Pharmacol.
(1997) - et al.
Partial purification of a pramipexole-induced trophic activity directed at dopamine neurons in ventral mesencephalic cultures
Brain Res.
(1998) - et al.
Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist
Eur. J. Pharmacol.
(1992) - et al.
Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors
Eur. J. Pharmacol. Mol. Pharmacol.
(1995) - et al.
Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
Life Sci.
(1985) - et al.
Differences in recovery patterns of striatal dopamine content, tyrosine hydroxylase activity and total biopterin content after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration: a comparison of young and older mice
Brain Res.
(1989)
Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia
Eur. J. Pharmacol.
High affinity binding for pramipexole, a dopamine D3 receptor ligand, in rat striatum
Neurosci. Lett.
Effects of age on GM1 ganglioside-induced recovery of concentrations of dopamine in the striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice
Neuropharmacology
Neuroprotective effects of the dopamine agonist pramipexole and bromocriptine in 3-acetylpyridine-treated rats
Brain Res.
Mechanisms of the neurotoxicity of MPTP
FEBS Lett.
Increase of bcl-2 protein in neuronal dendritic processes of cerebral cortex and hippocampus by the antiparkinsonian drugs, talipexole and pramipexole
Brain Res.
Pramipexole inhibits lipid peroxidation and reduces injury in the substantia nigra induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydroprysidine in C57BL/6 mice
Neurosci. Lett.
Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Proc. Natl. Acad. Sci. USA
Rat brain binding sites for pramipexole, a clinically useful D3-preferring dopamine agonist
Neurosci. Lett.
Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole
J. Neural Transm.
Pramipexole reduces reactive oxygen species production In Vivo and In Vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion
J. Neurochem.
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