Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg·d, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg·d), pramipexole (3 mg·kg·d), or medopar (100 mg·kg·d) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

The Pathology of Parkinson’s Disease and Potential Benefit of Dietary Polyphenols

“…MPTP causes an increase in α-synuclein, activation of astrocytes, and destruction of the blood–brain barrier. These changes, in turn, result in inflammation, oxidative stress, and decreased dopaminergic neurons, similar to what is seen in PD [ 88 ]. 6-hydroxydopamine (6-OHDA) is another popular chemical used in PD studies.…”

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

“…LY341495 amplified the reduction in DA level, up-regulated expression of glutamate and aggravated the performances in the rotarod test in sub-acute MPTP mice. LY354740 did not significantly improve locomotor function, influence dopamine and glutamate contents in subacute mice models, maybe because the lesions were not as severe enough to indicate apparent differences (Zhang et al, 2017). Meanwhile, LY354740 down-regulated the level of glutamate and improved locomotor function in acute-MPTP mice.…”

Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

“…This strain models early human Parkinson's disease, showing a gastrointestinal dysfunction without major central nervous system pathology [17,18]. Mice received intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Selleck Chemicals LLC, S4732) at 30 mg/kg/day (once daily for 5 successive days) [19][20][21], with or without IV injection of α-Syn at a dose of 5 mg/kg following each MPTP injection. Mice were sacrificed 12 h after the last injection.…”

“…We thus chose a model that features both microglial and α-syn pathology, in order to examine the potential immunomodulatory effects of monomeric α-syn in a situation where microglia become activated in an environment of pathological α-syn. We therefore turned to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model [19,20,43], in which microglial NADPH oxidase activity plays a critical role [44]. To accomplish this, we compared dbl-PAC-Tg(SNCAA53T);SNCA −/− animals injected with MPTP to those in which MPTP injection was accompanied by 5 mg/kg of α-Syn.…”