Neuroprotective effects of pramipexole in young and aged MPTP-treated mice

doi:10.1016/S0006-8993(01)02466-0

Brain Research

Volume 905, Issues 1–2, 29 June 2001, Pages 44-53

https://doi.org/10.1016/S0006-8993(01)02466-0 Get rights and content

Abstract

This study examined the effect of pramipexole (PPX), a selective dopamine (DA) D₃/D₂ agonist, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to the nigrostriatal dopamine system in young (8-week-old) and aged (12-month-old) mice. Co-administration of PPX and MPTP to young or aged mice, followed by 2 or 14 days of additional PPX treatment, significantly attenuated MPTP-induced striatal DA loss. Pramipexole treatment also significantly attenuated the loss of tyrosine hydroxylase immunoreactive neurons (TH-IR) within the substantia nigra pars compacta (SNc) in both young and aged animals. Effects of PPX administration on dopaminergic cell survival were confirmed in Nissl-stained sections and by quantitation of retrogradely labeled Fluorogold-positive SNc neurons. Protective effects of PPX on striatal DA levels and SNc DA neuron survival were similar in young and aged animals, although the magnitude of these effects was significantly less in aged animals. These findings support the early initiation of PPX therapy in Parkinson’s disease patients.

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.

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Research reportNeuroprotective effects of pramipexole in young and aged MPTP-treated mice

Abstract

Introduction

Section snippets

MPTP/PPX administration

MPTP-induced DA depletion

Discussion

Acknowledgements

Eur. J. Pharmacol.

Neurobiol. Aging

Brain Res.

Biochem. Biophys. Res. Commun.

Jpn. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol. Mol. Pharmacol.

Life Sci.

Brain Res.

Eur. J. Pharmacol.

Neurosci. Lett.

Neuropharmacology

Brain Res.

FEBS Lett.

Brain Res.

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.

Research report
Neuroprotective effects of pramipexole in young and aged MPTP-treated mice