Academic Journal
A refined chronic MPTP/probenecid model of Parkinson's disease in mature adult mice.
| Title: | A refined chronic MPTP/probenecid model of Parkinson's disease in mature adult mice. |
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| Authors: | Shen Z; School of Environment and Science, Griffith University, Brisbane 4111, Queensland, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane 4111, Queensland, Australia. Electronic address: zhiqiang.shen@griffithuni.edu.au., Garland B; School of Environment and Science, Griffith University, Brisbane 4111, Queensland, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane 4111, Queensland, Australia. Electronic address: ben.garland@griffithuni.edu.au., Mellick GD; School of Environment and Science, Griffith University, Brisbane 4111, Queensland, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane 4111, Queensland, Australia. Electronic address: g.mellick@griffith.edu.au., Ma L; School of Environment and Science, Griffith University, Brisbane 4111, Queensland, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane 4111, Queensland, Australia. Electronic address: linlin.ma@griffith.edu.au. |
| Source: | Experimental neurology [Exp Neurol] 2026 Aug; Vol. 402, pp. 115759. Date of Electronic Publication: 2026 Apr 04. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Orlando Fl : Academic Press Original Publication: New York. |
| MeSH Terms: | Probenecid*/toxicity , Probenecid*/administration & dosage , Parkinsonian Disorders*/pathology , Parkinsonian Disorders*/chemically induced , MPTP Poisoning*/pathology , Disease Models, Animal* , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine*, Motor Activity/drug effects ; Tyrosine 3-Monooxygenase/metabolism ; Substantia Nigra/pathology ; Animals ; Mice, Inbred C57BL ; Mice ; Male |
| Abstract: | Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons, leading to decreased dopamine levels and motor deficits. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is frequently used to induce dopaminergic neuron death in mouse models to mimic PD pathology. However, many acute/subacute protocols cause relatively rapid, sometimes partially reversible nigrostriatal injury, rather than slow, progressive neurodegeneration observed in idiopathic PD. While chronic MPTP regimens can better mimic disease progression, the high systemic toxicity of MPTP raises concerns about survival, particularly in mature or aged mice. In this study, we developed a refined chronic low-dose MPTP/probenecid regimen in mature adult C57BL/6 J mice comprising ten injections over five weeks. An initial challenge dose (25 mg/kg) excluded hypersensitive animals (four mice), allowing a subsequent reduced-dose maintenance regimen (20 mg/kg) to achieve 100% survival. Longitudinal assessment revealed a gradual phenotypic decline in treated animals. At two months post-treatment, MPTP/p mice exhibited fragmented locomotor activity, increased grooming, and impaired short-term spatial memory, which progressed to reduced motor endurance and postural instability by four months. Neuropathological evaluation confirmed significant loss of tyrosine hydroxylase-positive neurons and phosphorylated α-synuclein aggregation in the substantia nigra. Collectively, this optimized chronic MPTP/p protocol recapitulates the gradual emergence of motor, cognitive, and neuropathological hallmarks of PD, while maintaining animal survival rate necessary for longitudinal investigation. This model therefore offers a robust platform for therapeutic testing and is particularly well-suited for integration with gene knockout models to elucidate molecular mechanisms underlying PD. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Chronic regimen; MPTP; Mouse model; Parkinson's disease |
| Substance Nomenclature: | PO572Z7917 (Probenecid) 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) EC 1.14.16.2 (Tyrosine 3-Monooxygenase) |
| Entry Date(s): | Date Created: 20260406 Date Completed: 20260714 Latest Revision: 20260714 |
| Update Code: | 20260715 |
| DOI: | 10.1016/j.expneurol.2026.115759 |
| PMID: | 41941954 |
| Database: | MEDLINE |
| ISSN: | 1090-2430 |
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| DOI: | 10.1016/j.expneurol.2026.115759 |