New genetic and environmental studies of Parkinson's disease have revealed early problems in synaptic function and connectivity indicating that axonal impairment may be an important hallmark in this disorder. Since many studies suggest that axonal dysfunction precedes cell body loss, it is critical to target axons with treatments aimed at preserving "connectivity" as well as to develop and verify "biomarkers" with which to assess disease progression and drug efficacy.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Axons ; Disease Progression ; Mitochondria ; Parkinson Disease ; Wallerian Degeneration

The electrophysiological effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP), a chemical inducer of Parkinsonism in man and monkey, on the pigmented rabbit retina were determined under acute conditions. The amplitude of the b-wave of the rabbit electroretinogram was affected, but both the implirit time and half-amplitude duration of it werenot. The amplitude of the photopic b-wave was increased by 72.9 +/- 32.1% 5hours after the intravenous injection of NMPTP (P[t] < 0.05), whereas that of the scotopic b-wave was decreased by 31.2 +/- 6.4% 4hours after injection (P[t] < 0.05). The above results suggest or support that: 1, the dopaminergic amacrine cells are related to the modulation of the b-wave of the rabbit electroretinogram. 2. during light adaptation, the dopaminergic amacrine cells uncouple the rod and cone systems in the inner plexiform layer and are involved in functions of the rod system. 3. the hypothesis that the funrtion of tyrosine hydroxylase may be affected by NMPTP.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Electrophysiology ; *Electroretinography ; Pyridines/*pharmacology ; Rabbits ; Retina/cytology/*drug effects

The effect of MPTP on catecholamine neurons in young (4-6 weeks) and aging (10-12 months) C57BL/6 mice was studied using immunocytochemical techniques. Both groups of mice received 4 repeated dosages of 10mg/kg of MPTP given 12 hours apart. We compared the number of tyrosine hydroxylase (TH)-positive cell bodies using immunocytochemical technique in substantia nigra (SN), ventral tegmental area(VTA) and locus ceruleus (LC) 7 days after the last injection of MPTP. There was a significant decrease in the number of TH-positive cell bodies in the SN of young mice, but not in VTA or LC. In aging mice, there was a significant decrease in the number of TH-positive cell bodies in VTA as well as in SN. It is concluded that aging mice are more sensitive to MPTP and show more widespread damage in the catecholamine neurons than young mice, suggesting that MPTP-treated aging mice provide a more useful model for studing anatomical characteristics of Parkinson's disease than young mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine* ; Aging* ; Animals ; Brain* ; Locus Coeruleus ; Mice* ; Neurons ; Parkinson Disease ; Substantia Nigra ; Tyrosine 3-Monooxygenase

The antioxidant effects of HS-1580 derived from Brown seaweeds in comparison with NOS inhibitor, L-NAME, were tested in the Parkinson's disease animal model. C57BL/6 mice were implanted with osmotic pump containing vehicle, HS-1580 or L-NAME intraperitoneally 2 days before MPTP injection. The Parkinson's animal model were prepared by intraperitonal injection of MPTP (20 mg/kg, 4 times with 2 hours intervals in a ay).The mice were perfused with Zamboni fixative 2 days or 7days after MPTP injection. The 30 micrometer cryostat section were immunostained with free-floating method. Rabbit anti-tyrosine hydroxylase (TH)and rat anti-mouse MAC-1 were used as the primary antibodies. The following results were obtained. The number of TH-immunoreactive (ir)neurons in substantia nigra (SN)and the relative density of TH-ir axon terminals in striatum were decreased by MPTP injection. But the ecrease was significantly attenuated with 10%HS-1580 or L-NAME (50 mg/kg)pretreatment before MPTP injection. MAC-1-ir activated microglia were observed in substantia nigra 2 days after MPTP injection. Activated microglia were showed as thickened processes with round cell bodies. The morphological changes of MAC-1-ir activated microglia were inhibited by HS-15980 or L-NAME pretreatment before MPTP injction. Above results mean that the damage of nigrostriatal dopaminergic system was rescued by pretreatment of HS-1580 or L-NAME in MPTP-induced Parkinson's disease animal model.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals* ; Antibodies ; Antioxidants ; Mice ; Microglia ; Models, Animal* ; NG-Nitroarginine Methyl Ester ; Parkinson Disease* ; Presynaptic Terminals ; Rats ; Specific Gravity ; Substantia Nigra

Epidemiological studies of Parkinson disease (PD) have found an inverse correlation between cigarette smoking and the risk of developing PD, which suggests that nicotine has a protective effect. Results from animal models of PD are conflicting, raising questions about a protective potential of nicotine. In this study, mice were pretreated with low-dose nicotine before MPTP administration, and examined to determine a neuroprotective potential of nicotine. The schedule of nicotine administration was selected to simulate the future human trials using this putative neuroprotective agent. Male C57Bl/6 mice were pretreated with nicotine for 5 days (0.2 mg/kg/d, i.p.). After the 5-day-pretreatment with nicotine only, nicotine and MPTP (30 mg/kg/d, i.p.) were co-administered for 1 to 5 consecutive days. The total dose of nicotine, 0.2 mg/kg/d for 6 to 10 days, is the lowest one ever studied. Tyrosine hydroxylase (TH) immunohistochemical staining of the nigral sections was performed. Over the experimental period, there was a significant reduction in the TH-positive cells. In the nicotine-MPTP group, the degree of TH neuron depletion was reduced at days 4 and 5 of co-administration. These findings suggest that the nicotinic neurotransmission on the dopaminergic neurons are promising targets for neuroprotective therapy of PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Appointments and Schedules ; Dopaminergic Neurons ; Humans ; Male ; Mice ; Models, Animal ; Neurons ; Nicotine ; Parkinson Disease ; Smoking ; Synaptic Transmission ; Tyrosine 3-Monooxygenase

Destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a common pathophysiology of Parkinson's disease (PD). Characteristics of PD patients include bradykinesia, muscle rigidity, tremor at rest and disturbances in balance. For about four decades, PD animal models have been produced by toxin-induced or gene-modified techniques. However, in mice, none of the gene-modified models showed all 4 major criteria of PD. Moreover, distinguishing between PD model pigs and normal pigs has not been well established. Therefore, we planned to produce a pig model for PD by chronic subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), neurotoxin. Changes in behavioral patterns of pigs were thoroughly evaluated and a new motor scoring system was established for this porcine model that was based on the Unified Parkinson's Disease Rating Scale (UPDRS) in human PD patients. In summary, this motor scoring system could be helpful to analyze the porcine PD model and to confirm the pathology prior to further examinations, such as positron emission tomography-computed tomography (PET-CT), which is expensive, and invasive immunohistochemistry (IHC) of the brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine* ; Animals ; Brain ; Dopaminergic Neurons ; Electrons ; Humans ; Hypokinesia ; Immunohistochemistry ; Injections, Subcutaneous* ; Mice ; Models, Animal ; Muscle Rigidity ; Parkinson Disease* ; Pathology ; Substantia Nigra ; Swine ; Tremor

The effects of 1-methyl-4-phenyl-1, 2. 3, 6-tetrahydropyridine (MPTP) on behavioral and histochemical changes were investigated in C57BL/6 mice. For immunocytochemis try, one group of mice received a dose of 2X30mg/kg of MPTP given 12hours apart and the other group 30mg/kg/day of MPTP for 7days. Locomotor activit,v was measured during 120minutes after a single injection of 30mg/kg of MPTP. We compared the numbers of tyrosine hydroxylase (TH)-positive cell bodies using immunocytochemical technique in the substantia nigra, ventral tegmental area and locus ceruleus 10 days after the last injection of MPTP. There was a significant decrease in locomotor activity during 100minutes after injection of MPTP and the number of TH-positive cell bodies in the substantia nigra of the mice which received the dose of 30mg/kg/day for 7 days, but not in the ventral tegmental area or the locus ceruleus. But 30mg/kg of MPTP given 12 hours apart failed to produce a significant decrease in the number of TH-positive cell bodies in any three catecholamine nuclei examined. It is concluded that MPTP-treated C57BL/6 mice provide a useful model for studying characteristics of Parkinson's disease and the dose of 30mg/kg/day for 7 days is more effective in the animal model for Parkinson s disease in C57BL/6 mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Locus Coeruleus ; Mice* ; Models, Animal ; Motor Activity ; Parkinson Disease* ; Substantia Nigra ; Tyrosine 3-Monooxygenase ; Ventral Tegmental Area

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rodents was investigated by measuring the locomotor activity and the changes of brain biogenic amines in MPTP-treated C57BL/6 mice. The mice showed a typical curved spine posture 24 hours after MPTP treatment. Total locomotor activity was reduced and the ratios of stereotyped activity/total locomotor activity were increased 24 hours after MPTP treatment. However no significant changes were observed 7 days after MPTP treatment. MPTP-induced changes of biogenic amines were evident only in corpus striatum, not in frontal lobe, midbrain and hippocampus; the levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by 94%, 76.3% and 60.2% after 24 hours, and 81.9%, 61.3% and 26.1% after 6 days compared to control values respectively. The ratios of DOPAC/dopamine, HVA/dopamine and HVA/DOPAC were increased 24 hours and 7 day after MPTP treatment compared to control valuse in corpus striatum, but the degree of the 7 days was less than the 24 hours. The ratios of 5-HIAA/5-HT were incresed 24 hours and 7 days after MPTP treatment in corpus striatum, but there were no significant changes in the levels of 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxtryptamine (5-HT). In conclusion, MPTP produced parkinsonism-like behavioral and biochemical changes in C57BL/ 6 mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine* ; Animals ; Biogenic Amines* ; Brain ; Corpus Striatum ; Dopamine ; Frontal Lobe ; Hippocampus ; Homovanillic Acid ; Mesencephalon ; Mice* ; Motor Activity* ; Posture ; Rodentia ; Spine

α-Synuclein (α-Syn) has a critical role in microglia-mediated neuroinflammation, which leads to the development of Parkinson's disease (PD). Recent studies have shown that bee venom (BV) has beneficial effects on PD symptoms in human patients or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin-induced PD mice. This study investigated whether treatment with BV-derived phospholipase A2 (bvPLA2) would improve the motor dysfunction and pathological features of PD in human A53T α-Syn mutant transgenic (A53T Tg) mice. The motor dysfunction of A53T Tg mice was assessed using the pole test. The levels of α-Syn, microglia and the M1/M2 phenotype in the spinal cord were evaluated by immunofluorescence. bvPLA2 treatment significantly ameliorated motor dysfunction in A53T Tg mice. In addition, bvPLA2 significantly reduced the expression of α-Syn, the activation and numbers of microglia, and the ratio of M1/M2 in A53T Tg mice. These results suggest that bvPLA2 could be a promising treatment option for PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; alpha-Synuclein* ; Animals ; Bee Venoms* ; Bees* ; Fluorescent Antibody Technique ; Humans ; Mice ; Mice, Transgenic* ; Microglia* ; Parkinson Disease* ; Phenotype ; Phospholipases A2* ; Phospholipases* ; Spinal Cord

The protective efficacy of a silkworm extract (SE) on N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism and its possible mechanisms were studied in C57BL/6 mice. Mice were administrated intraperitoneally with SE (20 mg/kg/day) for 15 days and MPTP (10 mg/kg/day) was administrated subcutaneously into the mice for the first 6 consecutive days 1 hour before SE treatment. All animals were sacrificed 24 hours after the last SE treatment. Then the parameters related to general toxicity and neurobiochemical markers, such as the dopamine level and the activities of monoamine oxidase (MAO)-B, were measured in various regions of the brain. Treatment of mice with SE effectively attenuated the MPTP-induced decline of striatal dopamine level. MAO-B activity in SE-pretreated mice was inhibited in whole brain, cerebellum and substantia nigra. These results suggest that SE plays an effective role in attenuating MPTP-induced neurotoxicity in animal model. These neuroprotective effects of SE are likely the result from the inhibitory effect on MAO-B activity in mouse brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Bombyx ; Brain ; Cerebellum ; Dopamine ; Mice ; Models, Animal ; Monoamine Oxidase ; Neuroprotective Agents ; Parkinsonian Disorders ; Substantia Nigra