A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid

Abstract

Parkinson’s disease (PD) is characterized by non-motor symptoms as well as motor deficits. The non-motor symptoms rarely appear individually and occur simultaneously with motor deficits or independently. However, a comprehensive research on the non-motor symptoms using an experimental model of PD remains poorly understood. The aim of the current study is to establish a chronic mouse model of PD mimicking the comprehensive non-motor symptoms of human PD by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/p). The non-motor and motor symptoms were evaluated by performing buried food, short-term olfactory memory, hot plate, open field, tail suspension, Y maze, novel object recognition, bead expulsion, one-h stool collection, rotarod, rearing, catalepsy, and akinesia tests after 10 injections of MPTP/p into mice. The expression levels of α-synuclein, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) or DJ-1 were analyzed by Western blotting or immunostaining. MPTP/p-treated mice achieved to reproduce the key features of non-motor symptoms including olfactory deficit, thermal hyperalgesia, anxiety, depression, cognitive decline, and gastrointestinal dysfunction in addition to motor deficits. The MPTP/p-treated mice also showed the high levels of α-synuclein and low levels of TH and DJ-1 in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, or colon. In addition, the expression levels of phosphorylated-α-synuclein and GFAP were elevated in the striatum and substantia nigra in the MPTP/p-treated mice. Taken together, our study clarifies that the chronic MPTP/p-treated mice have a variety of non-motor dysfunctions as well as motor abnormalities by α-synuclein overexpression and dopaminergic depletion. Therefore, the study of comprehensive phenotypes of non-motor symptoms in one PD model would advance in-depth understandings of neuropathological alternations and contribute to future strategies for PD treatment.

The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease

“…The rotarod results showed that the GPR4 antagonist significantly prevented MPTP-induced motor deficits in mice. Cognitive impairments associated with spatial memory have been reported after the subchronic administration of MPTP in various studies [ 40 , 41 , 42 ]. To assess the impairment of spatial memory, we used the Y-maze test, which is widely used to assess MPTP-treated subchronic models of PD.…”

Animal models of Parkinson’s disease: a guide to selecting the optimal model for your research

“…Buhidma et al, have recently extensively reviewed the animal models of pain in PD [200]. Although a few individual studies have investigated nociceptive threshold changes in MPTP, reserpine, and LRRK2 models [201][202][203], findings are not always consistent [198]. The most well-characterised and Downloaded from http://portlandpress.com/neuronalsignal/article-pdf/doi/10.1042/NS20210026/924245/ns-2021-0026c.pdf by guest on 15 November 2021 consistent model for pain in PD is the 6-OHDA toxin model in rodents [200].…”

“…The repeated low-dose reserpine model in both mice and rats exhibits cognitive impairment, evidenced by a lack of novel object recognition [33,34]. A lot of the early pivotal studies using MPTP in NHPs showed that exposure to this toxin impacts cognitive function [143,185,[203][204][205][206]. Since then, rodent studies have reported similar deficits with MPTP as well as other toxins (paraquat, permethrin, 6-OHDA, rotenone and LPS) [53,114,[207][208][209].…”

Neuropsychiatric and Cognitive Deficits in Parkinson’s Disease and Their Modeling in Rodents

“…The clinical diagnosis is based on DSM V criteria [ 8 ], specific for each anxiety-related disorder, and completed by the Mini-Mental State Exam (MMSE). Few studies have used the Crown-Crisp Index, a specific test for phobic anxiety [ 21 ]. Some studies have focused on the link between anxiety and the subsequent risk of developing PD.…”

“…Some studies have focused on the link between anxiety and the subsequent risk of developing PD. Recent results suggest a greater prevalence of PD in the anxious population, independent of depression [ 10 , 21 ]. Several studies have shown that after diagnosis, 29% to 50% of PD patients present anxiety disorder and 20% of them present at least two anxiety diagnoses [ 10 , 22 ].…”