Abstract
Background and aim
It has been reported that acupuncture at GB34 can enhance neurogenesis in the subventricular zone (SVZ) of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the signaling pathway that plays a critical role in neurogenesis needs to be established. Herein, we investigated the neurogenesis-promoting pathway mediated by acupuncture, focusing on extracellular signal-regulated kinase (ERK) signaling.
Experimental procedure
Male 10-week-old C57BL/6 mice were intraperitoneally injected with 30 mg/kg MPTP once daily for 5 days. Subsequently, mice were intraperitoneally injected with 50 mg/kg bromodeoxyuridine (BrdU), and electroacupuncture (EA) was performed at GB34 and BL60 for 3 weeks. The survival of dopaminergic neurons in the nigrostriatal pathway, cell proliferation in the SVZ, and expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated ERK (pERK) were evaluated.
Results and conclusion
MPTP induced dopaminergic neuronal death in the nigrostriatal pathway, and reduced the number of BrdU-positive and BrdU/doublecortin double-positive cells in the SVZ; these parameters were restored by EA. Moreover, EA prevented MPTP-induced reduction in striatal expression of BDNF and pERK. These results indicate that EA could prevent dopaminergic neuronal death in the nigrostriatal pathway and restore neurogenesis in the SVZ, which may be attributed to the activation of the BDNF-ERK pathway.
Keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acupuncture; Extracellular signal-regulated kinase; Neurogenesis; Parkinson's disease
Graphical abstract
Abbreviations
- BDNF
brain-derived neurotrophic factor
- EA
electroacupuncture
- ERK
extracellular signal-regulated kinase
- MA
manual acupuncture
- MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- PFA
paraformaldehyde
- PBS
phosphate-buffered saline
- PD
Parkinson's disease
- pAkt
phosphorylated Akt
- pERK
phosphorylated extracellular signal-regulated kinase
- RT
room temperature
- SN
substantia nigra
- SVZ
subventricular zone
- TH
tyrosine hydroxylase
- TrkB
tropomyosin-related kinase B
1. Introduction
Parkinson's disease (PD) is a neurodegenerative disorder that occurs with aging, especially in individuals aged over 65 years. The incidence of PD is approximately 1–2% of the total population, and the number of affected patients is rapidly increasing.1 Patients with PD exhibit gradual loss of dopaminergic neurons in the substantia nigra (SN) and dopamine content in the striatum, which is reportedly associated with the main motor symptoms of PD, such as rigidity, postural instability, akinesia, bradykinesia, and tremors.2 Although the etiology of PD remains unclear, several factors, including aging, inflammation, and oxidative stress, have been implicated.3
In the subventricular zone (SVZ) and subgranular zone of mammalian brains, new neurons are continually generated throughout life through a process called neurogenesis. As adult neurogenesis in the brain may function as an endogenous repair mechanism, neurodegenerative conditions such as PD, Alzheimer's disease, and stroke could be potentially treated by regulating adult endogenous neurogenesis.4 Moreover, non-motor symptoms of PD, including anxiety, depression, and hyposmia, have been associated with impaired neurogenesis.5 Therefore, recovery of neurogenesis could potentially alleviate symptoms in patients with PD.
Acupuncture has been used to treat various diseases in East Asia and is known to alleviate motor and non-motor symptoms in patients with PD.6 Animal studies have shown that acupuncture at GB34 can protect nigrostriatal dopaminergic neurons in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by suppressing neuroinflammation, oxidative stress, and gut microbial dysbiosis.7,8 Moreover, acupuncture at GB34 could restore defective neurogenesis in the SVZ of MPTP-treated mice.9 However, the mechanism remains poorly understood. In the present study, the neurogenesis-promoting mechanism of acupuncture was examined by focusing on the expression of brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) signaling in the MPTP mouse model of PD.
2. Methods
2.1. Animals and groups
This study was conducted with the approval of the Pusan National University Institutional Animal Care and Use Committee (Busan, Korea; approval number PNU-2019-2234), and the animals were handled in accordance with the current guidelines established by the committee. Ten-week-old male C57BL/6 mice, weighing 24–27 g, were purchased from Samtako Inc. (Osan, Korea) and housed at a standard temperature (22 ± 2 °C) under alternating 12 h light-dark cycles, with ad libitum access to food and water.
After one week adaptation period, mice were randomly assigned to four groups: the control group (n = 12), which would be injected with normal saline and would not receive electroacupuncture (EA) treatment; the MPTP group (n = 12), which would be injected with MPTP and would not receive EA treatment; the MPTP + EA group (n = 12), which would be injected with MPTP and would receive EA treatment; and the MPTP + sham group (n = 12), which would be injected with MPTP and would be inserted acupuncture needles without electrical stimulation.
2.2. MPTP and bromodeoxyuridine administration
Fig. 1 shows a schematic of the experimental procedures, and all experiments were performed on the indicated day. Except for the control group, mice were intraperitoneally injected with MPTP-HCl (30 mg/kg of free base; Sigma, St. Louis, MO, USA) in sterilized normal saline (vehicle) at 24 h intervals for 5 d. Control group mice were intraperitoneally administered the vehicle on the same schedule. Two hours after MPTP or vehicle injection, all animals were intraperitoneally injected with bromodeoxyuridine (BrdU; 50 mg/kg) to label proliferating cells. BrdU injection was administered for three weeks, with continuous daily injections for six consecutive days and one day off (Fig. 1).
Fig. 1.
Experimental procedure in the present study. BrdU, bromodeoxyuridine; EA, electroacupuncture; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
2.3. EA stimulation
EA stimulation was performed 2 h after the BrdU injection. Under isoflurane (JW Pharmaceutical, Seoul, Korea) anesthesia, two sterilized stainless steel needles (0.18 mm × 8 mm; Dongbang Acupuncture Inc., Boryeong, Korea) were inserted to a depth of approximately 2 mm in each leg, one at GB34 (Yangneungcheon in Korean, Yanglingquan in Chinese; on the fibular aspect of the leg, in the depression anterior and distal to the head of the fibula) and the other at BL60 (Gollyun in Korean, Kunlun in Chinese; on the posterolateral aspect of the ankle, in the depression between the prominence of the lateral malleolus and the calcaneal tendon). Electrodes were connected to the end of each needle. Mice in the MPTP + EA group received electrical stimulation using an A385 constant current stimulus isolator (WPI, Sarasota, FL, USA) at an intensity of 1.5 mA, frequency of 2 Hz, and pulse width of 100 ms for 20 min. For MPTP + sham group mice, acupuncture needles were inserted into the acupoints for 20 min without electrical stimulation.
2.4. Behavioral assessment
2.4.1. Pole test
The pole test was conducted 1 d before the first MPTP injection (day 0), 7 d after the first MPTP injection (day 7), and 21 d after the first MPTP injection (day 21). Mice (n = 6 per group) were positioned head-down near the top of a rough-surfaced wood pole (10 mm in diameter and 55 cm in height), and the time required to reach the floor was measured. The test was performed three times at 30 min intervals per day.
2.4.2. Rotarod test
The rotarod test was performed immediately after the pole test on days 0, 7, and 21, using a rotarod apparatus (Harvard Apparatus, Holliston, MA, USA). Mice (n = 6 per group) were placed on the rotating rod for three trials per day at a speed of 20 rpm; the time length for which the animal remained on the rod was measured. The cut-off time was 3 min. Prior to performing the test, mice were trained on the rod for three days at 10, 15, and 20 rpm.
2.5. Immunohistochemistry
On day 22 (one day after the last behavioral test), mice (n = 6 per group) were anesthetized with isoflurane and perfused with 4% paraformaldehyde (PFA) in 0.1 M phosphate buffer. The brain was harvested and fixed in 4% PFA for 48 h, washed in 0.1 M phosphate buffer, and immersed in 30% sucrose solution for storage at 4 °C prior to sectioning. Frozen sections were cut to a thickness of 30 μm using a Leica CM3050S cryostat (Leica Microsystems, Wetzlar, Germany).
The SN and striatal sections were incubated with 1% H2O2 in 0.05 M phosphate-buffered saline (PBS) for 15 min, followed by 0.3% Triton X-100 and 3% normal blocking serum in 0.05 M PBS at room temperature (RT) for 1 h. Then, sections were stained overnight at 4 °C using anti-tyrosine hydroxylase (TH; 1:1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA) as the primary antibody for dopaminergic neurons. Next, the sections were incubated with Vectastain Elite ABC reagent (Vector Laboratories Inc., Burlingame, CA, USA) at RT for 1 h, followed by incubation with a diaminobenzidine substrate kit (Vector Laboratories Inc.) for 5 min. Subsequently, tissues were mounted on gelatin-coated slides, air-dried, dehydrated, and covered with coverslips. Histological images were obtained using an Axio Scope A1 microscope (Carl ZEISS, Oberkochen, Germany) and an AxioCam ICc3 camera (Carl ZEISS). The survival of dopaminergic neurons was evaluated by the number of TH-positive neuronal cells in the SN and the mean value of optical density in the striatum using ImageJ (version 1.52p; NIH, Bethesda, MD, USA).
2.6. Immunofluorescence staining
Striatal sections were blocked with 10% normal serum blocking solution containing 3% (w/v) bovine serum albumin, 0.1% Triton X-100, and 0.05% Tween-20 for 2 h at RT to avoid non-specific staining. The sections were then incubated with rabbit primary antibody against doublecortin X (DCX; 1:200; Abcam, Cambridge, UK) and mouse monoclonal primary antibody against BrdU (1:200; Abcam) overnight at 4 °C, followed by anti-rabbit Alexa-488 IgG and anti-mouse Alexa Fluor 594 IgG (Molecular probes, OR, USA) for 1 h at RT. The stained sections were imaged with a LSM700 confocal microscope (Carl ZEISS). The number of BrdU-positive cells and BrdU/DCX double-stained cells in the SVZ were manually counted for each capture.
2.7. Western blotting
On day 22, mice (n = 6 per group) were euthanized, and striatal tissues were immediately collected and stored at −80 °C in a CLN-50U ultra-low temperature freezer (Nihon Freezer, Tokyo, Japan). Then, striatal tissues were lysed using RIPA lysis buffer (LPS Solution, Daejeon, Korea) containing 1 mM phenylmethanesulfonyl fluoride (Enzo Life Sciences, Farmingdale, NY, USA). Proteins (40 μg per lane) were separated by 1 or 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to 0.2 μm nitrocellulose blotting membranes (GE Healthcare UK Ltd, Little Chalfont, UK). Membranes were blocked with 5% bovine serum albumin in Tris-buffered saline containing 0.1% Tween-20 for 1 h at RT, followed by overnight incubation at 4 °C with primary antibodies against TH (1:1000; Santa Cruz Biotechnology), BDNF (1:500; Santa Cruz Biotechnology), ERK (1:1000; Cell Signaling Technology, Beverly, MA, USA), phosphorylated ERK (pERK; 1:1000; Cell Signaling Technology), Akt (1:1000; Cell Signaling Technology), phosphorylated Akt (pAkt; 1:1000; Cell Signaling Technology), or β-actin antibody (1:1000; Santa Cruz Biotechnology). The membranes were then incubated with secondary antibodies (Santa Cruz Biotechnology) for 1.5 h at RT. Protein bands were visualized using an enhanced chemiluminescence detection kit (Thermo Scientific, Rockford, IL, USA) and an Image Quant LAS 4000 imaging system (Fujifilm, Tokyo, Japan). Band intensities were quantified using the ImageJ software.
2.8. Statistical analysis
Behavioral tests are presented as the mean ± standard error of the mean and analyzed by two-way analysis of variance (ANOVA), followed by the Bonferroni post-hoc test. All data, except behavioral tests, are presented as the mean ± standard deviation and analyzed by one-way ANOVA, followed by Tukey's post-hoc test. All statistical analyses were performed using GraphPad Prism 5 for Windows (GraphPad Software Inc., La Jolla, CA, USA), and differences were considered statistically significant at p < 0.05.
3. Results
3.1. Effect of EA on MPTP-induced motor dysfunction
In the pole test, no significant differences were detected between days 0 and 7. On day 21, the time to reach the bottom was significantly longer in the MPTP group than in the control, MPTP + EA, and MPTP + sham groups (p < 0.05, p < 0.01, and p < 0.001, respectively; Fig. 2A).
Fig. 2.
Effect of EA at GB34 on MPTP-induced behavioral impairment in mice. Based on the results of the pole test (A) and rotarod test (B), EA at GB34 alleviates MPTP-induced motor dysfunction. Data values represent the mean ± standard error of the mean (n = 6 per group). ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus the control group; #p < 0.05, ##p < 0.01, and ###p < 0.001 versus the MPTP group. EA, electroacupuncture; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
In the rotarod test, no significant differences were observed on day 0. On day 7, the time spent on the cylinder was significantly shorter in the MPTP and MPTP + sham groups than in the control group (p < 0.001 and p < 0.001, respectively); this parameter did not significantly differ between the MPTP + EA and control groups. On day 21, the time spent on the cylinder was significantly shorter in the MPTP, MPTP + EA, and MPTP + sham groups than in the control group (p < 0.001 in each group), whereas this parameter was significantly longer in the MPTP + EA group than in the MPTP group (p < 0.05; Fig. 2B).
3.2. Effect of EA on MPTP-induced neuronal death
The neuroprotective effect of EA on MPTP-induced neuronal death was evaluated by measuring the number of TH-positive cells in the SN and optical density in the striatum. Considering TH-positive cells in the SN, the number of cells was significantly lower in the MPTP, MPTP + EA, and MPTP + sham groups than in the control group (p < 0.001, p < 0.01, and p < 0.001, respectively); however, the cell number was significantly higher in the MPTP + EA group than in the MPTP and MPTP + sham groups (p < 0.01, Fig. 3A and 3 B). The optical density in the striatum showed a similar trend. The density was significantly lower in the MPTP, MPTP + EA, and MPTP + sham groups than in the control group (p < 0.001 in each group); however, the density was significantly higher in the MPTP + EA group than in the MPTP and MPTP + sham groups (p < 0.05 and p < 0.01, respectively; Fig. 3A and 3C). Western blotting confirmed TH expression in the striatum, and a similar trend was observed on immunohistochemical examination (Fig. 3D and 3E).
Fig. 3.
Protective effect of EA at GB34 on MPTP-induced dopaminergic neuronal death in the SN and striatum. Images of TH-immunohistochemistry (A), quantitative graphs of TH-immunohistochemistry in the SN (B) and striatum (C), representative Western blot immunolabeling of TH in the striatum (D), and quantitative graphs of immunolabeling are presented. Scale bar indicates 200 μm. Data values represent the mean ± standard deviation (n = 6 per group). ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus the control group; #p < 0.05, and ##p < 0.01 versus the MPTP group; $p < 0.05, and $$p < 0.01 versus the MPTP + EA group. EA, electroacupuncture; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SN, substantia nigra; TH, tyrosine hydroxylase.
3.3. Effect of EA on promoting neurogenesis in the SVZ
The neurogenesis-promoting effect of EA was evaluated based on the number of BrdU-positive cells and BrdU/DCX double-immunoreactive cells. The number of BrdU-positive cells was significantly lower in the MPTP and MPTP + sham groups than in the control group (p < 0.001 and p < 0.01, respectively), whereas this number was significantly higher in the MPTP + EA and MPTP + sham groups than in the MPTP group (p < 0.001 and p < 0.01, respectively; Fig. 4A and 4B).
Fig. 4.
Effect of EA at GB34 on neurogenesis in the SVZ of MPTP-treated mice. Representative images of BrdU/DCX double-immunofluorescence staining (A), and quantitative graphs of BrdU-positive cells (B) and BrdU/DCX-stained cells (C) are presented. Scale bar indicates 20 μm. Data values represent the mean ± standard deviation (n = 6 per group). ∗∗p < 0.01 and ∗∗∗p < 0.001 versus the control group; #p < 0.05, ##p < 0.01, and ###p < 0.001 versus the MPTP group. BrdU, bromodeoxyuridine; DCX, doublecortin; EA, electroacupuncture; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SVZ, subventricular zone.
The number of BrdU/DCX double-immunoreactive cells was significantly lower in the MPTP, MPTP + EA, and MPTP + sham groups than in the control group (p < 0.001, p < 0.01, and p < 0.01, respectively), while this number was significantly higher in the MPTP + EA group than in the MPTP group (p < 0.05; Fig. 4A and 4C).
3.4. Effect of EA to activate BDNF-ERK signaling in the striatum
The BDNF level was significantly lower in the MPTP and MPTP + sham groups than in the control group (p < 0.05, in each group), while the level was significantly higher in the MPTP + EA group than in the MPTP and MPTP + sham groups (p < 0.01 and p < 0.05, respectively; Fig. 5A and 5B). The pERK/ERK ratio was significantly lower in the MPTP and MPTP + sham groups than in the control group (p < 0.05, in each group), while the ratio was significantly higher in the MPTP + EA group than in the MPTP and MPTP + sham groups (p < 0.01 in each group; Fig. 5A and 5C). Whereas the pAkt/Akt ratio was not significantly different among the groups (Fig. 5A and 5D).
Fig. 5.
Effect of EA at GB34 on BDNF/ERK signaling in the striatum of MPTP-treated mice. Representative images of BDNF, ERK, pERK, and β-actin western blotting (A) and quantitative graphs of the BDNF expression (B), pERK/ERK ratio (C), and pAkt/Akt ratio (D) are presented. Data values represent the mean ± standard deviation (n = 6 per group). ∗p < 0.05 versus the control group; ##p < 0.01 versus the MPTP group; $p < 0.05, and $$p < 0.01 versus the MPTP + EA group. BDNF, brain-derived neurotrophic factor; EA, electroacupuncture; ERK, extracellular signal-regulated kinase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; pAkt, phosphorylated Akt; pERK, phosphorylated ERK.
4. Discussion
In the present study, MPTP administration induced dopaminergic neuronal death in the nigrostriatal pathway and suppressed cell proliferation in the SVZ; these effects were alleviated by EA stimulation at GB34 and BL60. Moreover, EA stimulation alleviated MPTP-induced impairment of BDNF and ERK signaling.
In the EA procedure, two or more acupoints are typically selected, given that the cathode and anode must be connected to allow the flow of electric current. We used GB34 as the main acupoint and BL60 as an adjuvant acupoint for electrical stimulation. GB34 is a representative acupoint to demonstrate the neuroprotective effect in PD animal models.10 EA, as well as manual acupuncture (MA) at GB34, can prevent behavioral impairment and dopaminergic neuronal death in the nigrostriatal pathway of MPTP-treated mice and 6-hydroxydopamine-injected rats.7, 8, 9,11,12 Consistent with previous studies, this study demonstrated that EA at GB34 could suppress the MPTP-induced behavioral impairment and dopaminergic neuronal death, confirming that GB34 has a high potential to alleviate the PD symptoms and progression.
PD is a typical neurodegenerative disease, and some PD symptoms have been associated with neurogenesis impairment; therefore, restoring neurogenesis could potentially inhibit the progression of PD and alleviate the symptoms.5 BrdU, a thymidine analog, has been used to identify cell proliferation.13 DCX, a microtubule-associated protein, can be observed in newly generated neuroblasts and proliferating progenitor cells.13 Therefore, BrdU/DCX double-immunoreactive cells are regarded as proliferated immature neuronal cells or neuronal precursors.14 In the present study, EA at GB34 alleviated the reduction in BrdU-positive and BrdU/DCX double-immunoreactive cells, indicating the EA alleviates the MPTP-induced impairment of neuronal cell proliferation in the SVZ.
Diverse extrinsic and intrinsic factors can reportedly promote neurogenesis. BDNF is an important factor in the regulation of neurogenesis.15 The binding of BDNF to tropomyosin-related kinase B (TrkB) can activate neurogenesis-related pathways, including mitogen-activated protein kinase/ERK, phosphoinositide 3-kinase/Akt, and phospholipase C γ signaling pathways. Although all three pathways can regulate neuronal survival, they play distinct roles in neurogenesis. The mitogen-activated protein kinase/ERK pathway regulates differentiation and proliferation, while the phosphoinositide 3-kinase/Akt pathway regulates axonal and dendritic growth, and the phospholipase C γ pathway regulates synaptic plasticity.16 Interestingly, it has been reported that acupuncture at GB34 can regulate BDNF and TrkB expression. EA at GB34 reportedly increases BDNF expression in the SN of MPTP-treated mice, as well as in the spinal cord or neuropathic pain rat model, while MA at GB34 can enhance TrkB expression in the SN of a PD rat model.12,17,18 Moreover, some studies have shown that acupuncture at GB34 can modulate ERK signaling. MA at GB34 can activate the ERK signaling pathway in the skin of a mouse pain model and the SN of an MPTP-induced PD mouse model, and EA at GB34 can activate ERK signaling in the hippocampus of neuropathic pain rats, as well as stressed rats.19, 20, 21, 22 These results suggest that EA at GB34 can activate the BDNF/ERK signaling pathway.
The limitations of this study need to be addressed. First, sham EA (inserting acupuncture needles at the same acupoints without electrical stimulation) also affected behavioral test results and cell proliferation. Considering that MA at GB34 also affords a neuroprotective effect and alleviates MPTP-induced behavioral impairment, the effect could be attributed to the needle penetration of the skin at GB34.7, 8, 9,11 Second, BDNF activates various signaling pathways; however, we examined only ERK and Akt signaling, and other pathways including phospholipase C γ pathway were not investigated. Third, although EA at GB34 enhances BDNF/ERK signaling, there is insufficient evidence that the EA-induced activation of BDNF/ERK signaling actually promotes neurogenesis in the SVZ. Additional in-depth studies are required to confirm these limitations.
5. Conclusion
In the present study, EA at GB34 enhanced neurogenesis in the SVZ, as well as BDNF and pERK expression in the striatum, indicating that EA has the potential to promote neurogenesis in the SVZ by activating BDNF/ERK signaling.
Funding sources
This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by MSIT (NRF-2021R1A4A1025662 and NRF-2019R1A2C1085130).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Peer review under responsibility of The Center for Food and Biomolecules, National Taiwan University.
Contributor Information
Yukyoung Lee, Email: dalkis0815@gmail.com.
Hanul Lee, Email: ihv1432@naver.com.
Chang-Hwan Bae, Email: ssaybch@gmail.com.
Ji Eun Seo, Email: seoji0612@naver.com.
Hee-Young Kim, Email: kimhy@pusan.ac.kr.
Sungtae Koo, Email: stkoo@pusan.ac.kr.
Seungtae Kim, Email: kimst@pusan.ac.kr.
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