Electroacupuncture Promotes Recovery of Motor Function and Reduces Dopaminergic Neuron Degeneration in Rodent Models of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta in the brain, ultimately resulting in severe striatal dopamine deficiency and the development of primary motor symptoms (e.g., resting tremor, bradykinesia) in PD. Acupuncture has long been used in traditional Chinese medicine to treat PD for the control of tremor and pain. Accumulating evidence has shown that using electroacupuncture (EA) as a complementary therapy ameliorates motor symptoms of PD. However, the most appropriate timing for EA intervention and its effect on dopamine neuronal protection remain unclear. Thus, this study used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model (systemic-lesioned by intraperitoneal injection) and the 1-methyl-4-phenylpyridinium (MPP⁺)-lesioned rat model (unilateral-lesioned by intra-SN infusion) of PD, to explore the therapeutic effects and mechanisms of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints. We found that EA increased the latency to fall from the accelerating rotarod and improved striatal dopamine levels in the MPTP studies. In the MPP⁺ studies, EA inhibited apomorphine induced rotational behavior and locomotor activity, and demonstrated neuroprotective effects via the activation of survival pathways of Akt and brain-derived neurotrophic factor (BDNF) in the SN region. In conclusion, we observed that EA treatment reduces motor symptoms of PD and dopaminergic neurodegeneration in rodent models, whether EA is given as a pretreatment or after the initiation of disease symptoms. The results indicate that EA treatment may be an effective therapy for patients with PD.

Keywords: Parkinson’s disease; dopamine; electroacupuncture; motor function; neuroprotection.

Figure 1

Electroacupuncture (EA) reduced motor deficiency and dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice. Systemic MPTP injections (intraperitoneal; i.p., 10 mg/kg/day for three days) induced dopaminergic neuronal loss in the substantial nigra (SN) and striatal nerve terminal degeneration in both sides of the nigrostriatal dopaminergic pathway. (A) The experimental procedure of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints in MPTP mice; (B) Rotarod results on the last day (day 9) showed that MPTP treatment reduced the latency to fall as compared to baseline (before treatment) on day 1. EA stimulation at 50 Hz but not 0 Hz significantly increased the latency to fall in the rotarod test on day 9; (C) Dopamine content from both sides of the mouse brain showed that EA 50 Hz but not 0 Hz stimulation increased the striatal dopamine content as compared to MPTP-alone treated animals; (D) Immunohistochemistry (IHC) analysis of tyrosine hydroxylase levels in the SN also indicated that 50 Hz EA stimulation exerted neuroprotection in dopaminergic neuronal bodies. Scale bar = 300 μm. *, p < 0.05 compared with MPP⁺-treated group.

Figure 2

EA reduced motor deficiency in rats unilaterally lesioned with MPP⁺. Intracerebral injection of MPP⁺ (8 μg) into one side of substantia nigra (SN) induces dopaminergic neuronal death in the SN and depletes striatal dopamine. In this study, EA was applied to rats after MPP⁺ administration. (A) shows the experimental protocol of the rat study. Eight days after MPP⁺ administration, EA did not increase MPP⁺-induced body weight loss (B), but significantly reduced apomorphine-induced turning behavior (C) and locomotor activity, as assessed by both distance and velocity (D). The data indicate that 50 Hz EA stimulation at GB34 and LR3 acupoints after MPP⁺ administration reduced motor deficiency in rats unilaterally lesioned with MPP⁺. *, p < 0.05 compared with MPP⁺-treated group.

Figure 3

EA produces dopaminergic neuroprotection in rats unilaterally lesioned with MPP⁺. Immunostaining for tyrosine hydroxylase in the rat substantia nigra (SN) and striatum was performed eight days after MPP⁺ lesions. (A) shows EA 50 Hz stimulation repressed tyrosine hydroxylase (+) neuronal loss in the SN and induced dopaminergic terminal degeneration in the striatum. Scale bars = 200 μm (top) and 2 mm (bottom); (B) Unilateral MPP⁺ lesioning significantly reduced striatal dopamine content in the ipsilateral side of the injection as compared to the contralateral side (Figure 3B). *, p < 0.05 compared with contralateral side of MPP⁺; #, p < 0.05 compared with MPP⁺-treated group.

Figure 4

EA reduced MPP⁺-induced dopaminergic neuronal apoptosis by increasing BDNF (brain-derived neurotrophic factor) expression and further Akt phosphorylation in the rat substantia nigra. (A) Eight days after MPP⁺ administration, our Western blot results show that MPP⁺ treatment reduced tyrosine hydroxylase and Bcl-2 expression in the ipsilateral side of the rat substantia nigra (SN), but not in the contralateral side. EA stimulation (50 Hz) enhanced mature BDNF, tyrosine hydroxylase, and Bcl-2 expression in the MPP⁺-treated ipsilateral side; (B) EA enhanced the phosphorylation of Akt (phospho-Akt) but had no effect on Erk1/2 phosphorylation (phospho-Erk1/2) in the MPP⁺-treated ipsilateral side (Figure 4B). The data suggest that the way in which EA exerts dopaminergic neuroprotection in the unilateral MPP⁺-lesion model is by activating Akt phosphorylation and enhancing BDNF and Bcl-2 expression in the rat SN. * p < 0.05 compared with contralateral side of EA+MPP⁺ or ipsilateral side of EA+MPP⁺ group.