| Objectives:To explore the neuroprotective effects and possible mechanisms of calcitriol in the acute1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice of Parkinson’s disease (PD).Methods:C57BL/6mice were divided into four groups, including Control group (saline+saline), Calcitriol group (calcitriol+saline), Model group (saline+MPTP) and Drug group (calcitriol+MPTP) with calcitriol-pre-treated. Mice received single intraperitoneal injection (i.p.) of saline or calcitriol (0.1μg/kg) daily for seven days and then four injections (i.p.) at2h intervals of MPTP (18mg/kg) to induce Parkinsonism. Effects of calcitriol on mice behavior, concentrations of the amino acid and monoamine neurotransmitters as well as dopaminergic neurodegeneration were evaluated by behavioral experiments (open field test, pole test and gait analysis), high performance liquid chromatography (HPLC) and immunofluorescence, respectively.Results:1. a. The numbers of crossed grids obtained at the1st,3rd,5th day after intraperitoneal injection of MPTP revealed a significant decrease for the Model group in comparison to itself before modeling, as well as upright times presented a significant reduction at the1st day until the7th day (P<0.01). For the Drug group, both of the values decreased at the1st and3rd day (P<0.01or P<0.05), but activity ability was still much better than mice in Model group (P<0.01) and could become normal at the5th day quickly.b. The inversion time of Model group achieved maximum change at the3rd day (P<0.01). The total time to climb down the pole of it markedly increased at the1st day (P<0.05) but decreased at the3rd day (P,0.01), followed by gradually restored to the former level. We failed to observe significant differences on both of them for the Drug group. c. A significant decrease was revealed on forelimb and hindlimb stride lengths for the Model group at the3rd and5th day after administration of MPTP (P<0.01or P<0.05). However, the stride lengths of mice in the Drug group did not change significantly, except the forelimb at the5th day (P<0.05).2. Aspartate (Asp), glutamate (Glu), glycine (Gly), taurine (Tau), γ-aminobutyric acid (GABA) in midbrain and Asp, Glu, Gly in striatum markedly increased after MPTP administration (P<0.05or P<0.01). The changes could be under control by calcitriol except Gly in midbrain and GABA in striatum.3. Concentrations of the monoamine neurotransmitters in striatum were significantly reduced by MPTP administration except5-hydroxyindole-3-acetic acid (5-HIAA) (P<0.05or P<0.01), while NE, DOPAC and DA consent in the calcitriol-treated mice presented a significant increase (P<0.05or P<0.01). DOPAC/DA ratio of the Model group (0.87) was significantly increased than those of Control (0.61) and Drug group (0.62)(P<0.01).4. There was a significant reduction in the number of TH-positive neurons in SNpc for the MPTP group compared with normal mice (50.83%of control, P<0.01).In mice receiving daily administration of calcitriol the number of TH-positive neurons was significantly higher than those in MPTP-induced animals (P<0.01).5. Neurotransmitters content and number of TH-positive neurons had no statistical difference between Control group and Calcitriol group.Conclusion:Calcitriol could significantly ameliorate the behavioral disorders such as reduction of spontaneous activity, slow movement, poor coordination and abnormal gait induced by toxicity of MPTP. What’s more, calcitriol could inhibit the increase of amino acid neurotransmitters content in midbrain and striatum, improve the sharp decrease of NE, DOPAC and DA in striatum, reduce DA metabolic rate, keep its stability balance and protect dopaminergicneuron from damage. The potential to improve symptoms and good neuroprotective effects prompt us that in-depth study of mechanism would be helpful to the development and application of new PD prevention or treatment drugs. |
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