Review
Modeling PD pathogenesis in mice: Advantages of a chronic MPTP protocol

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Abstract

Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calcium-channel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

Introduction

Parkinson's disease (PD) is characterized by progressive loss of dopamine neurons and terminals from the nigrostriatal pathway and by a slow onset of motor symptoms. To provide an insight into the pathophysiological processes of this disease, animal models should mimic as many of the clinical features as possible. The loss of the dopaminergic pathway can be replicated in rodents using various surgical, toxic or genetic approaches. Over the past couple of decades, one neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has become a widely used method for modeling PD. However, for most MPTP models, the loss of dopamine is rapid and not progressive, and the motor disability is often difficult to demonstrate, especially when tested some time after toxin application [1]. A model that shows great promise, particularly in its progressive nature, involves the administration of MPTP and an adjuvant, probenecid (MPTP/p), that blocks the rapid clearance of the toxin and its metabolites [2]. Chronic MPTP/p treatment produces many of the pathological hallmarks and motor deficits of PD, making it an excellent choice for studies of pathogenesis, for testing neuroprotective therapies and developing biomarkers to detect the disease presymptomatically [3], [4]. This review covers the key features of this model and discusses its applicability to neuroprotective strategies.

Section snippets

Preparation of the chronic MPTP/p model

Male C57/bl mice, initially weighing 20–24 g, are injected with 10 doses of MPTP hydrochloride (25 mg/kg in saline, s.c.) and probenecid (250 mg/kg in Tris–HCl buffer) over 5 weeks at 3.5-day intervals. Control mice are injected with vehicle (saline or probenecid) in the same volume and on the same schedule. Three days before treatment, and each week thereafter, mice are tested for coordination and rigidity using the grid test [1], [3], [5]. Briefly, mice are placed in the center of a wire mesh

Dopamine loss, motor dysfunction, inflammation and inclusion formation

The chronic MPTP/p model shows a significant reduction in the number of neurons in the substantia nigra pars compacta (SNpc). Shortly after MPTP/p treatment, approximately 50% of dopamine neurons are lost, increasing to nearly 70% 3 weeks after toxin treatment (Table 1). Striatal dopamine levels are reduced by 90–93% within a week, and by 70–80% of the total at 3–24 weeks after MPTP/p treatment [4]. The low level of striatal dopamine is matched by a significant loss of TH-immunopositive fibers

Cell death in the MPTP/p model

MPTP intoxication rapidly and persistently depletes ATP and increases reactive oxygen and nitrogen species molecules that induce cell death pathways. In acute or subchronic MPTP models, less than half of the SNpc dopaminergic neurons are destroyed, whereas nigrostriatal degeneration with the chronic MPTP/p regimen is more extensive (Table 1[2]). This is because striatal dopamine depletion peaks within 24 h after a single dose of MPTP, but that loss is extended with MPTP/p, presumably due to the

Neuroprotection

Adult SNpc dopamine neurons are Ca2+-dependent autonomous pacemakers, the basal activity of which is driven by the relatively rare, voltage-dependent, L-type Ca2+ channel Cav1.3 [13]. Pacemaking elevates cytosolic Ca2+, and would therefore harm neurons that are energy-compromised through mitochondrial stress (as in PD [12], [14]). If the Ca2+ dependence of pacemaking could be changed, perhaps through the blockade of Cav1.3, some protection may be afforded to dopamine neurons. We conducted in

Conflict of interest

The authors have declared no conflicts of interest.

Role of the funding source

Funding was provided by the United States Army Medical Research and Material Command (grant number W81XWH-05-1-0580 to G.E.M.) and the NIH (grants NS41799 to G.E.M., and NS047085 to D.J.S.).

Acknowledgements

This article is based on a presentation given at the LIMPE Seminars 2007 'Experimental Models in Parkinson's Disease' held in September 2007 at the "Porto Conte Ricerche" Congress Center in Alghero, Sardinia, Italy. Technical assistance was provided by J. Jackolin, F. Jodelka, S. Blume, and Drs. M. Mo and P. Loomis.

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