Mitochondrial Dysfunction in the Striatum of Aged Chronic Mouse Model of Parkinson's Disease

Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (MPD). Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine (DA) deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4) and adenosine 5′-diphosphate-stimulated (state 3) respiration and a fall in adenosine triphosphate level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs

Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration

<p>Abstract</p> <p>Background</p> <p>Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg) and probenecid (250 mg/kg) over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD), which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits.</p> <p>Results</p> <p>We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8–12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and amphetamine-stimulated locomotor activity were not altered when compared to the sedentary chronic MPD animals.</p> <p>Conclusion</p> <p>This study indicates that in spite of the drastic loss of dopaminergic neurons and depletion of dopamine in the severe chronic MPD, endurance exercise training effectively reverses the Parkinson's like behavioral deficits related to regular movement, balance and gait performance.</p

The Report of the 2012-2013 Research and Graduate Affairs Committee

The RGA Committee met on October 29-30, 2012, in Crystal City, VA. The Committee corresponded via e-mail throughout the year, and had a conference call on June 13, 2013. The charge for the RGA Committee was to develop strategies on how to get our members to the right tables and at the right time for advancing pharmacy research and graduate education

Report of the 2011-2012 AACP Special Advisory Committee on Research and Graduate Education

According to the Bylaws of the American Association of Colleges of Pharmacy (AACP), the Research and Graduate Affairs Committee (RGAC) shall provide assistance to the Association in developing its research, graduate education, and scholarship agenda. This assistance may include facilitating colleges and schools in formulating and advancing legislative and regulatory initiatives, and nurturing collaborative activities with organizations sharing an interest in issues related to the pharmaceutical sciences

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Copyright Role of Calmodulin-Dependent Phosphorylation in Chronic Sulpiride-Induced Striatal Dopamine Receptor Supersensitivity&apos;

ABSTRACT In the present study we investigated several pharmacological and biochemical parameters in stnatal preparations of rats which were treated chronically with a selective D2 receptor antagonist

The Effect of Conduction Exercise and Self-Acupressure in Treatment of Parkinson’s Disease: A Pilot Study

Introduction. Parkinson’s disease cannot be well treated by conventional medication. Acupuncture and Tai Chi are proven to be effective in relieving symptoms of Parkinson’s disease. Traditional Chinese medicine exercises may prove to be an effective complementary therapy. Objective. To evaluate the efficacy and safety of conduction exercise and self-acupressure in treating Parkinson’s disease. Method. This study is an accessor- and data analyzer-blind, add-on, randomized, controlled, pilot clinical study. In the treatment group, they were taught to practice conduction exercise and self-acupressure for 8 weeks. No additional treatment was given in the control group. Assessments were done at week 4 and week 8 of the treatment period. The primary outcomes are the total score and domain scores of the Chinese version of 39-item Parkinson’s Disease Questionnaire. The secondary outcomes are the total score and domain scores of a custom-designed questionnaire, which is a short form of Nonmotor Symptom Scale. Results. 22 patients in the treatment group and 14 in the control group continued to the treatment phase. Patients in the treatment group displayed improvement trends in primary and secondary outcomes. Improvements were significant in two areas of a custom-designed questionnaire: total score (p=0.014) and domain score of gastrointestinal tract (p=0.004). No severe adverse events were reported. Conclusion. Conduction exercise and self-acupressure were well accepted by and feasible for Parkinson’s disease patients. The data generated can be used for the planning of future studies. The exercise regime can be promoted as a home-based, self-practice therapy for Parkinson’s disease patients, due to its safety, low cost, and convenience in implementation. This study is registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-17011987, on 14 July 2017)

Neuroprotective Effect of Long-term NDI1 Gene Expression in a Chronic Mouse Model of Parkinson Disorder

Previously, we showed that the internal rotenone-insensitive nicotinamide adenine dinucleotide (NADH)-quinone oxidoreductase (NDI1) gene from Saccharomyces cerevisiae (baker's yeast) can be successfully inserted into the mitochondria of mice and rats and the expressed enzyme was found to be fully functional. In this study, we investigated the ability of the Ndi1 enzyme to protect the dopaminergic neurons in a chronic mouse model of Parkinson disorder. After expression of the NDI1 gene in the unilateral substantia nigra of male C57BL/6 mice for 8 months, a chronic Parkinsonian model was created by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with probenecid and evaluated using neurochemical and behavioral responses 1–4 weeks post-MPTP/probenecid injection. We showed that expression of Ndi1 was able to significantly prevent the loss of dopamine and tyrosine hydroxylase as well as the dopaminergic transporters in the striatum of the chronic Parkinsonian mice. Behavioral assessment based on a methamphetamine-induced rotation test and spontaneous swing test further supported neurological preservation in the NDI1-treated Parkinsonian mice. The data presented in this study demonstrate a protective effect of the NDI1 gene in dopaminergic neurons, suggesting its therapeutic potential for Parkinson-like disorders