Parkinson's disease (PD) is a common neurodegenerative disorder mainly related to mitochondrial dysfunction of dopaminergic neurons in the midbrain substantia nigra. This study aimed to investigate the effects of exercise preconditioning on motor deficits and mitochondrial function in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Eight-week-old male C57BL/6J mice were randomly divided into four groups: sedentary + saline (SS), sedentary + MPTP (SM), exercise + saline (ES), and exercise + MPTP (EM) groups. Mice in the ES and EM groups received 4 weeks of treadmill training, and then SM and EM groups were treated with MPTP for 5 days. Motor function was assessed by behavioral tests, and morphological and functional changes in dopaminergic neurons and mitochondria in the substantia nigra of the midbrain were evaluated using immunohistochemistry, Western blot, and transmission electron microscopy technology. The results showed that, compared with the SM group, the EM group exhibited significantly improved motor ability, up-regulated protein expression levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the midbrain, and down-regulated protein expression of α-synuclein (α-Syn) in the mitochondria of substantia nigra. Compared with the SM group, the EM group showed up-regulated protein expression levels of mitochondrial fusion proteins, including optical atrophy protein 1 (OPA1) and mitofusin 2 (MFN2), and biogenesis-related proteins, including peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), while the protein expression levels of dynamin-related protein 1 (DRP1) and mitochondrial fission protein 1 (FIS1) were significantly down-regulated. Compared with the SM group, the EM group showed significantly reduced damage to substantia nigra mitochondria, restored mitochondrial membrane potential and ATP production, and decreased levels of reactive oxygen species (ROS). These results suggest that 4-week treadmill pre-training can alleviate MPTP-induced motor impairments in PD mice by improving mitochondrial function, providing a theoretical basis for early exercise-based prevention of PD.
Animals ; Male ; Physical Conditioning, Animal/physiology* ; Mice ; Mice, Inbred C57BL ; Mitochondria/physiology* ; Dopaminergic Neurons ; MPTP Poisoning/physiopathology* ; Substantia Nigra ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

As an environmental risk factor, psychological stress may trigger the onset or accelerate the progression of Parkinson's disease (PD). Here, we evaluated the effects of acute restraint stress on striatal dopaminergic terminals and the brain metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been widely used for creating a mouse model of PD. Exposure to 2 h of restraint stress immediately after injection of a low dose of MPTP caused a severe loss of striatal dopaminergic terminals as indicated by decreases in the dopamine transporter protein and dopamine levels compared with MPTP administration alone. Both striatal 1-methyl-4-phenylpyridinium ion (MPP) and MPTP concentrations were significantly increased by the application of restraint stress. Striatal monoamine oxidase-B, which catalyzes the oxidation of MPTP to MPP, was not changed by the restraint stress. Our results indicate that the enhanced striatal dopaminergic terminal loss in the stressed mice is associated with an increase in the transport of neurotoxin into the brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; metabolism ; 1-Methyl-4-phenylpyridinium ; metabolism ; Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; MPTP Poisoning ; chemically induced ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurotoxins ; metabolism ; Restraint, Physical ; Stress, Psychological ; metabolism

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Female ; MPTP Poisoning ; drug therapy ; pathology ; physiopathology ; Male ; Materia Medica ; therapeutic use ; Mice ; Mice, Inbred C57BL ; Microglia ; drug effects ; pathology ; Parkinson Disease, Secondary ; chemically induced ; drug therapy ; physiopathology ; Scorpion Venoms ; chemistry

OBJECTIVETo investigate the toxic effect of environmental neurotoxin MPP+ to C. elegans and identify the mechanisms that cause the toxicity.

METHODSHuman alpha-synuclein transgenic C. elegans was used as the animal model, the toxic effect of MPP+ to dopamine (DA) neurons and the lifespan of worms was tested. The worms were feed with OP50 to determine whether ATP increase can rescue the worm from toxicity. ATP level and aberrant protein accumulation were analyzed in the MPP+ treated worms with or without OP50 addition.

RESULTSWe found that MPP+ induced DA cell death and worm lethality, which could be prevented by OP50 treatment. OP50 exerted the protective effect by up-regulating ATP level, even though it also induced accumulation of alpha-synuclein. Despite the undefined role of protein aggregation to the cell death, our results showed that the toxicity of MPP+ was mainly caused by the ATP depletion in the alpha-synuclein transgenic C. elegans.

CONCLUSIONMPP+ could induce DA neuronal death and worm lethality in alpha-synuclein transgenic C. elegans; Compared with the aggregation of alpha-synuclein, the major cause of MPP+ toxicity appeared due to ATP depletion.

1-Methyl-4-phenylpyridinium ; toxicity ; Adenosine Triphosphate ; deficiency ; metabolism ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins ; drug effects ; metabolism ; Cell Death ; Disease Models, Animal ; Dopamine ; metabolism ; Herbicides ; toxicity ; Humans ; MPTP Poisoning ; metabolism ; mortality ; Neurons ; drug effects ; metabolism ; alpha-Synuclein ; drug effects ; genetics ; metabolism

Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, intraperitoneal, i.p.) twice daily for 6 days enhanced the rotation induced by apomorphine from 341 turns/hour at the beginning to 755 turns/hr at the end. At the same time, the response to selective D2 agonist quinpirole (0.26 mg/kg, i.p.) was also enhanced from 203 to 555 turns/hr. Extracellular single unit recording revealed no significant difference in the basal firing rates of substantia nigra pars reticulata (SNr) neurons between the ipsilateral and contralateral side of the 6-OHDA lesion regardless of the repeated administrations of apomorphine. In SNr of the lesion side, the units with burst firing pattern were found more frequently after repeated administrations of apomorphine and the suppressive effect of quinpirole on the firing rate was enhanced. These findings suggest that the increased percentage of the burst units is the important electrophysiological change in the development of enhanced response to selective D2 agonist.
Animal ; Apomorphine/*pharmacology ; Dopamine Agonists/*pharmacology ; MPTP Poisoning/physiopathology ; Male ; Oxidopamine/toxicity ; Parkinsonian Disorders/*physiopathology ; Quinpirole/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D2/*drug effects ; Substantia Nigra/*drug effects/physiology