Skip to main content
SpringerLink
Log in

High-Frequency Repetitive Transcranial Magnetic Stimulation Regulates Astrocyte Activation by Modulating the Endocannabinoid System in Parkinson’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Reactive astrogliosis and the over-production of proinflammatory factors are key pathogenetic processes in Parkinson’s disease (PD). Repetitive transcranial magnetic stimulation (rTMS), a promising noninvasive technique in treating PD, has been shown to alleviate neuroinflammation. However, high-frequency (HF) and low-frequency (LF) rTMS, which one produces better therapeutic and anti-inflammatory effects, and the underlying mechanism have yet to be determined. The efficacies of HF, LF, and sham rTMS on the survival of dopaminergic (DA) neurons, improvement of motor function, and downregulation of proinflammatory factors were compared in 6-hydroxydopamine (6-OHDA) rat model. Then we investigated the role of endocannabinoid (eCB) system in the inhibition of astrocyte activation between HF vs LF rTMS. The results showed that HF rTMS daily for 4 weeks produced stronger anti-inflammatory and neuroprotective effects. ECB receptor 2 (CB2R) but not receptor 1 (CB1R) expressions were substantially elevated in the GFAP-positive reactive astrocytes of the rat brains with 6-OHDA or LPS insults. Increased anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were also observed. Interestingly, the elevated CB2R, AEA and 2-AG, and the increased GFAP expression could be all significantly suppressed by HF rTMS, but not by LF rTMS. This effect was also confirmed in cell culture. Of note, selective agonism of CB2R was able to reverse HF rTMS-mediated activation of extracellular regulated kinase1/2 (Erk1/2) and suppression of GFAP expression, while selective antagonism of CB2R sustained these effects. This study indicates that the modulation of eCB/CB2R is a potential mechanism for the greater effectiveness of HF rTMS on the inhibition of astrogliosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

The original contributions presented in the study are included in the article/Supplementary material; further inquiries can be directed to the corresponding authors.

References

  1. Fahn S (2018) The 200-year journey of Parkinson disease: reflecting on the past and looking towards the future. Parkinsonism Relat D 46:1–5. https://doi.org/10.1016/j.parkreldis.2017.07.020

    Article  Google Scholar 

  2. Bastide MF, Meissner WG, Picconi B, Fasano S, Fernagut PO, Feyder M, Francardo V, Alcacer C et al (2015) Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol 132:96–168. https://doi.org/10.1016/j.pneurobio.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  3. Umemura A, Oyama G, Shimo Y, Nakajima M, Nakajima A, Jo T, Sekimoto S, Ito M et al (2016) Current topics in deep brain stimulation for Parkinson disease. Neurol Med Chir (Tokyo) 56(10):613–625. https://doi.org/10.2176/nmc.ra.2016-0021

    Article  Google Scholar 

  4. Kalia LV, Lang AE (2015) Parkinson’s disease. The Lancet 386(9996):896–912. https://doi.org/10.1016/S0140-6736(14)61393-3

    Article  CAS  Google Scholar 

  5. Kim DR, Pesiridou A, O’Reardon JP (2009) Transcranial magnetic stimulation in the treatment of psychiatric disorders. Curr Psychiatry Rep 11(6):447–452. https://doi.org/10.1007/s11920-009-0068-z

    Article  PubMed  Google Scholar 

  6. Sun X, Long H, Zhao C, Duan Q, Zhu H, Chen C, Sun W, Ju F et al (2019) Analgesia-enhancing effects of repetitive transcranial magnetic stimulation on neuropathic pain after spinal cord injury: an fNIRS study. Restor Neurol Neuros 37(5):497–507. https://doi.org/10.3233/RNN-190934

    Article  CAS  Google Scholar 

  7. Long H, Wang H, Zhao C, Duan Q, Feng F, Hui N, Mao L, Liu H et al (2018) Effects of combining high- and low-frequency repetitive transcranial magnetic stimulation on upper limb hemiparesis in the early phase of stroke. Restor Neurol Neuros 36(1):21–30. https://doi.org/10.3233/RNN-170733

    Article  Google Scholar 

  8. Lee JY, Park HJ, Kim JH, Cho BP, Cho S, Kim SH (2015) Effects of low- and high-frequency repetitive magnetic stimulation on neuronal cell proliferation and growth factor expression: a preliminary report. Neurosci Lett 604:167–172. https://doi.org/10.1016/j.neulet.2015.07.038

    Article  CAS  PubMed  Google Scholar 

  9. Li S, Jiao R, Zhou X, Chen S (2020) Motor recovery and antidepressant effects of repetitive transcranial magnetic stimulation on Parkinson disease. Medicine 99(18):e19642. https://doi.org/10.1097/MD.0000000000019642

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kam TI, Hinkle JT, Dawson TM, Dawson VL (2020) Microglia and astrocyte dysfunction in Parkinson’s disease. Neurobiol Dis 144:105028. https://doi.org/10.1016/j.nbd.2020.105028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74(12):995–1002. https://doi.org/10.1212/WNL.0b013e3181d5a4a3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang X, Song L, Liu Z (2010) The effect of repetitive transcranial magnetic stimulation on a model rat of Parkinson’s disease. NeuroReport 21(4):268–272. https://doi.org/10.1097/WNR.0b013e328335b411

    Article  PubMed  Google Scholar 

  13. Ba M, Ma G, Ren C, Sun X, Kong M (2017) Repetitive transcranial magnetic stimulation for treatment of lactacystin-induced Parkinsonian rat model. Oncotarget 8(31):50921–50929. https://doi.org/10.18632/oncotarget.17285

  14. Aftanas LI, Gevorgyan MM, Zhanaeva SY, Dzemidovich SS, Kulikova KI, Al Perina EL, Danilenko KV, Idova GV (2018) Therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on neuroinflammation and neuroplasticity in patients with Parkinson’s disease: a placebo-controlled study. B Exp Biol Med+ 165(2):195–199. https://doi.org/10.1007/s10517-018-4128-4

  15. More SV, Choi DK (2015) Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol Neurodegener 10:17. https://doi.org/10.1186/s13024-015-0012-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. García C, Palomo-Garo C, García-Arencibia M, Ramos JA, Pertwee RG, Fernández-Ruiz J (2011) Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease. Brit J Pharmacol 163(7):1495–1506. https://doi.org/10.1111/j.1476-5381.2011.01278.x

    Article  CAS  Google Scholar 

  17. Gómez-Gálvez Y, Palomo-Garo C, Fernández-Ruiz J, García C (2016) Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 64:200–208. https://doi.org/10.1016/j.pnpbp.2015.03.017

    Article  CAS  PubMed  Google Scholar 

  18. Concannon RM, Okine BN, Finn DP, Dowd E (2015) Differential upregulation of the cannabinoid CB2 receptor in neurotoxic and inflammation-driven rat models of Parkinson’s disease. Exp Neurol 269:133–141. https://doi.org/10.1016/j.expneurol.2015.04.007

    Article  CAS  PubMed  Google Scholar 

  19. Concannon RM, Okine BN, Finn DP, Dowd E (2016) Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson’s disease. Exp Neurol 283(Pt A):204–212. https://doi.org/10.1016/j.expneurol.2016.06.014

    Article  CAS  PubMed  Google Scholar 

  20. Esposito G, Iuvone T, Savani C, Scuderi C, De Filippis D, Papa M, Di Marzo V, Steardo L (2007) Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: in vitro and in vivo evidence. J Pharmacol Exp Ther 322(3):1144–1152. https://doi.org/10.1124/jpet.107.121566

    Article  CAS  PubMed  Google Scholar 

  21. Xue SS, Zhou CH, Xue F, Peng ZW, Wang HN (2017) Effect of repetitive magnetic stimulation on the expression of endocannabinoid system related genes in cultured neuron. Brain Stimul 10:399

    Article  Google Scholar 

  22. Wang H, Wang L, Zhang R, Chen Y, Liu L, Gao F, Nie H, Hou W et al (2014) Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system. J Psychiatr Res 51:79–87. https://doi.org/10.1016/j.jpsychires.2014.01.004

    Article  PubMed  Google Scholar 

  23. Lazary J, Elemery M, Dome P, Kiss S, Gonda X, Tombor L, Pogany L, Becskereki G et al (2021) Peripheral endocannabinoid serum level in association with repetitive transcranial magnetic stimulation (rTMS) treatment in patients with major depressive disorder. Sci Rep 11(1):8867. https://doi.org/10.1038/s41598-021-87840-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun XL, Chen BY, Zhao HK, Cheng YY, Zheng MH, Duan L, Jiang W, Chen LW (2016) Gas1 up-regulation is inducible and contributes to cell apoptosis in reactive astrocytes in the substantia nigra of LPS and MPTP models. J Neuroinflammation 13(1):180. https://doi.org/10.1186/s12974-016-0643-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xia Y, Chen B, Sun X, Duan L, Gao G, Wang J, Yung K, Chen L (2013) Presence of proNGF-sortilin signaling complex in nigral dopamine neurons and its variation in relation to aging, lactacystin and 6-OHDA insults. Int J Mol Sci 14(7):14085–14104. https://doi.org/10.3390/ijms140714085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Su RJ, Zhen JL, Wang W, Zhang JL, Zheng Y, Wang XM (2018) Time-course behavioral features are correlated with Parkinson’s disease associated pathology in a 6-hydroxydopamine hemiparkinsonian rat model. Mol Med Rep 17(2):3356–3363. https://doi.org/10.3892/mmr.2017.8277

    Article  CAS  PubMed  Google Scholar 

  27. Lee JY, Kim SH, Ko AR, Lee JS, Yu JH, Seo JH, Cho BP, Cho SR (2013) Therapeutic effects of repetitive transcranial magnetic stimulation in an animal model of Parkinson’s disease. Brain Res 1537:290–302. https://doi.org/10.1016/j.brainres.2013.08.051

    Article  CAS  PubMed  Google Scholar 

  28. Galland F, Seady M, Taday J, Smaili SS, Goncalves CA, Leite MC (2019) Astrocyte culture models: molecular and function characterization of primary culture, immortalized astrocytes and C6 glioma cells. Neurochem Int 131:104538. https://doi.org/10.1016/j.neuint.2019.104538

    Article  CAS  PubMed  Google Scholar 

  29. Fang G, Wang Y (2018) Effects of rTMS on hippocampal endocannabinoids and depressive-like behaviors in adolescent rats. Neurochem Res 43(9):1756–1765. https://doi.org/10.1007/s11064-018-2591-y

    Article  CAS  PubMed  Google Scholar 

  30. Li X, Xu H, Lei T, Yang Y, Jing D, Dai S, Luo P, Xu Q (2017) A pulsed electromagnetic field protects against glutamate-induced excitotoxicity by modulating the endocannabinoid system in HT22 cells. Front Neurosci-Switz 11.https://doi.org/10.3389/fnins.2017.00042

  31. Nadella R, Voutilainen MH, Saarma M, Gonzalez-Barrios JA, Leon-Chavez BA, Jimenez JM, Jimenez SH, Escobedo L et al (2014) Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. J Neuroinflammation 11:209. https://doi.org/10.1186/s12974-014-0209-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. https://doi.org/10.1016/S1474-4422(09)70062-6

    Article  CAS  PubMed  Google Scholar 

  33. Ma D, Jin S, Li E, Doi Y, Parajuli B, Noda M, Sonobe Y, Mizuno T et al (2013) The neurotoxic effect of astrocytes activated with toll-like receptor ligands. J Neuroimmunol 254(1–2):10–18. https://doi.org/10.1016/j.jneuroim.2012.08.010

  34. Liu B (2006) Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease. Aaps J 8(3):606–621. https://doi.org/10.1208/aapsj080369

    Article  CAS  Google Scholar 

  35. Sun X, Chen B, Duan L, Xia Y, Luo Z, Wang J, Rao Z, Chen L (2014) The proform of glia cell line-derived neurotrophic factor: a potentially biologically active protein. Mol Neurobiol 49(1):234–250. https://doi.org/10.1007/s12035-013-8515-6

    Article  CAS  PubMed  Google Scholar 

  36. Yang X, Li Y, Chen L, Xu M, Wu J, Zhang P, Nel D, Sun B (2020) Protective effect of hydroxysafflor yellow A on dopaminergic neurons against 6-hydroxydopamine, activating anti-apoptotic and anti-neuroinflammatory pathways. Pharm Biol 58(1):686–694. https://doi.org/10.1080/13880209.2020.1784237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li ZJ, Wu Q, Yi CJ (2015) Clinical efficacy of istradefylline versus rTMS on Parkinson’s disease in a randomized clinical trial. Curr Med Res Opin 31(11):2055–2058. https://doi.org/10.1185/03007995.2015.1086994

    Article  CAS  PubMed  Google Scholar 

  38. Khedr EM, Al-Fawal B, Abdel WA, Saber M, Hasan AM, Bassiony A, Nasr EA, Rothwell JC (2019) The effect of 20 Hz versus 1 Hz repetitive transcranial magnetic stimulation on motor dysfunction in Parkinson’s disease: which is more beneficial? J Parkinsons Dis 9(2):379–387. https://doi.org/10.3233/JPD-181540

    Article  PubMed  Google Scholar 

  39. Ba M, Kong M, Guan L, Yi M, Zhang H (2016) Repetitive transcranial magnetic stimulation (rTMS) improves behavioral and biochemical deficits in levodopa-induced dyskinetic rats model. Oncotarget 7(37):58802–58812. https://doi.org/10.18632/oncotarget.11587

  40. Filipovic SR, Rothwell JC, Bhatia K (2010) Low-frequency repetitive transcranial magnetic stimulation and off-phase motor symptoms in Parkinson’s disease. J Neurol Sci 291(1–2):1–4. https://doi.org/10.1016/j.jns.2010.01.017

    Article  PubMed  Google Scholar 

  41. Benninger DH, Berman BD, Houdayer E, Pal N, Luckenbaugh DA, Schneider L, Miranda S, Hallett M (2011) Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. Neurology 76(7):601–609. https://doi.org/10.1212/WNL.0b013e31820ce6bb

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bartels AL, Leenders KL (2007) Neuroinflammation in the pathophysiology of Parkinson’s disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET. Movement Disord 22(13):1852–1856. https://doi.org/10.1002/mds.21552

    Article  PubMed  Google Scholar 

  43. Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28(1):39–45. https://doi.org/10.1016/j.tips.2006.11.001

    Article  CAS  PubMed  Google Scholar 

  44. Ternianov A, Pérez-Ortiz JM, Solesio ME, García-Gutiérrez MS, Ortega-álvaro A, Navarrete F, Leiva C, Galindo MF et al (2012) Overexpression of CB2 cannabinoid receptors results in neuroprotection against behavioral and neurochemical alterations induced by intracaudate administration of 6-hydroxydopamine. Neurobiol Aging 33(2):421. https://doi.org/10.1016/j.neurobiolaging.2010.09.012

    Article  CAS  PubMed  Google Scholar 

  45. Pisani V, Moschella V, Bari M, Fezza F, Galati S, Bernardi G, Stanzione P, Pisani A et al (2010) Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson’s disease patients. Movement Disord 25(7):920–924. https://doi.org/10.1002/mds.23014

    Article  PubMed  Google Scholar 

  46. Medina-Fern Ndez FJ, Luque E, Aguilar-Luque M, Ag Era E, Feij OM, Garc A-Maceira FI, Escribano BAM, Pascual-Leone L, et al (2017) Transcranial magnetic stimulation modifies astrocytosis, cell density and lipopolysaccharide levels in experimental autoimmune encephalomyelitis. Life Sci 169:20–26. https://doi.org/10.1016/j.lfs.2016.11.011

    Article  CAS  Google Scholar 

  47. Kim JY, Choi G, Cho Y, Cho H, Hwang S, Ahn S (2013) Attenuation of spinal cord injury-induced astroglial and microglial activation by repetitive transcranial magnetic stimulation in rats. J Korean Med Sci 28(2):295. https://doi.org/10.3346/jkms.2013.28.2.295

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sasso V, Bisicchia E, Latini L, Ghiglieri V, Cacace F, Carola V, Molinari M, Viscomi MT (2016) Repetitive transcranial magnetic stimulation reduces remote apoptotic cell death and inflammation after focal brain injury. J Neuroinflammation 13(1):150. https://doi.org/10.1186/s12974-016-0616-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hong Y, Liu Q, Peng M, Bai M, Li J, Sun R, Guo H, Xu P et al (2020) High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. J Neuroinflamm 17(1). https://doi.org/10.1186/s12974-020-01747-y

  50. Price DA, Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, Strong R, Lutz B et al (2009) WIN55,212–2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur J Neurosci 29(11):2177–2186. https://doi.org/10.1111/j.1460-9568.2009.06764.x

    Article  PubMed  PubMed Central  Google Scholar 

  51. Garcia MC, Cinquina V, Palomo-Garo C, Rabano A, Fernandez-Ruiz J (2015) Identification of CB(2) receptors in human nigral neurons that degenerate in Parkinson’s disease. Neurosci Lett 587:1–4. https://doi.org/10.1016/j.neulet.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  52. Ribeiro R, Wen J, Li S, Zhang Y (2013) Involvement of ERK1/2, cPLA2 and NF-κB in microglia suppression by cannabinoid receptor agonists and antagonists. Prostag Oth Lipid M 100–101:1–14. https://doi.org/10.1016/j.prostaglandins.2012.11.003

    Article  CAS  Google Scholar 

  53. Dhopeshwarkar A, Mackie K (2014) CB2 cannabinoid receptors as a therapeutic target—what does the future hold? Mol Pharmacol 86(4):430–437. https://doi.org/10.1124/mol.114.094649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Koch G, Mori F, Codeca C, Kusayanagi H, Monteleone F, Buttari F, Fiore S, Bernardi G et al (2009) Cannabis-based treatment induces polarity-reversing plasticity assessed by theta burst stimulation in humans. Brain Stimul 2(4):229–233. https://doi.org/10.1016/j.brs.2009.03.001

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Boston Professional Group (BPG) Editing Service for the English language editing.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81802229, 82072534, 82071529), Young Elite Scientists Sponsorship Program by CAST (No. 2018QNRC001), Shaanxi Science Research Project (No. 2019JQ-043), and Shaanxi International Science and Technology Cooperation Project (No. 2020KW-050).

Author information

Author notes

  1. Xin Kang and Bing Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi, People’s Republic of China

    Xin Kang, Rui Zhao, Xiaobing Jiang, Jie Pang, Chenguang Zhao, Xiang Mou, Hua Yuan & Xiaolong Sun

  2. Department of Neurobiology, Institute of Neurosciences, Fourth Military Medical University, Xi’an, People’s Republic of China

    Xin Kang & Fang Gao

  3. Department of Orthopedics, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China

    Bing Zhang & Wanqing Du

  4. College of Life Sciences, Northwest University, Xi’an, People’s Republic of China

    Rui Zhao

  5. Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China

    Xuedong Liu & Ya Bai

Authors
  1. Xin Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanqing Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xuedong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ya Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaobing Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chenguang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiang Mou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hua Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaolong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xiaolong Sun, Hua Yuan, and Fang Gao participated in the whole design of this study. Xin Kang performed the animal model preparation, cell culture, western blot, MTT assay, and data analysis. Bing Zhang, Wanqing Du, and Rui Zhao participated in immunohistochemistry, cell culture, LC–MS/MS, and data analysis. Xuedong Liu and Ya Bai participated in rotation test. Xiaobing Jiang, Jie Pang, Chenguang Zhao, and Xiang Mou participated in rTMS, ELISA, and data analysis. Xiaolong Sun and Xin Kang wrote the draft and revised the whole manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Fang Gao, Hua Yuan or Xiaolong Sun.

Ethics declarations

Ethics Approval

The animal study was approved by the Committee of Animal Use for Research and Education of Fourth Military Medical University.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Fig. 1

Representative double-label immunostaining for GFAP/CB2R in the ipsilateral SN of 6-OHDA rat model at 5 wpi under sham, LF (1 Hz), and HF (10 Hz) rTMS. The positive cells are magnified in the inserts, and arrowheads point to representative double-labeled cells. SNpc, substantia nigra pars compacta; SNr, substantia nigra pars reticulate (PNG 2748 kb)

High resolution image (TIF 11048 kb)

Supplementary Fig. 2

Cell viability of the C6 astroglial cells with 10 μM 6-OHDA plus JWH015 (a) or AM630 (b) at increasing concentrations of 0, 0.01, 0.1, 1, 5, 10, 50, and 100 μM for 72 h (n = 5 samples). Data were analyzed by one-way ANOVA with Dunnett’s post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001 vs control (PNG 89 kb)

High resolution image (TIF 452 kb)

Supplementary Fig. 3

Effect of HF rTMS on cell viability of the 6-OHDA-induced C6 astroglial cells in the presence or absence of CB2-selective agonist JWH015, and CB2-selective antagonist AM630 (n = 5 samples). Data were analyzed by one-way ANOVA with Dunnett’s post hoc test. (PNG 32 kb)

High resolution image (TIF 84 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, X., Zhang, B., Du, W. et al. High-Frequency Repetitive Transcranial Magnetic Stimulation Regulates Astrocyte Activation by Modulating the Endocannabinoid System in Parkinson’s Disease. Mol Neurobiol 59, 5121–5134 (2022). https://doi.org/10.1007/s12035-022-02879-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02879-3

Keywords

Search

Navigation