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Neuroprotective effect of bee venom is mediated by reduced astrocyte activation in a subchronic MPTP-induced model of Parkinson’s disease

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Abstract

Bee venom (BV), also known as apitoxin, is widely used in traditional oriental medicine to treat immune-related diseases. Recent studies suggest that BV could be beneficial for the treatment of neurodegenerative diseases. Parkinson’s disease (PD) is the second most common neurodegenerative disease next to Alzheimer’s disease, and PD pathologies are closely associated with neuroinflammation. Previous studies have suggested the neuroprotective effects of BV in animal models of PD are due to the modulation of inflammation. However, the molecular mechanisms responsible for the anti-neuroinflammatory effect of BV have not been elucidated in astrocytes. Here, the authors investigated the neuroprotective effects of BV and pramipexole (PPX; a positive control) in a subchronic MPTP-induced murine PD model. Both BV and PPX prevented MPTP-induced impairments in motor performance and reduced dopaminergic neuron loss, and furthermore, these neuroprotective effects of BV and PPX were found to be associated with reduced astroglial activation in vivo PD model. However, in MPP+ treated primary cultured astrocytes, BV modulated astrocyte activation, whereas PPX did not, indicating that the neuroprotective effects of PPX were not mediated by neuroinflammation. These findings suggest that BV should be considered a potential therapeutic or preventive agent for PD and other neuroinflammatory associated disorders.

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References

  • Alvarez-Fischer D, Noelker C, Vulinovic F, Grunewald A, Chevarin C, Klein C, Oertel WH, Hirsch EC, Michel PP, Hartmann A (2013) Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model. PLoS One 8:e61700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson DW, Neavin T, Smith JA, Schneider JS (2001) Neuroprotective effects of pramipexole in young and aged MPTP-treated mice. Brain Res 905:44–53

    Article  CAS  PubMed  Google Scholar 

  • Bennett JP Jr, Piercey MF (1999) Pramipexole-a new dopamine agonist for the treatment of Parkinson’s disease. J Neurol Sci 163:25–31

    Article  CAS  PubMed  Google Scholar 

  • Blandini F, Armentero MT (2012) Animal models of Parkinson’s disease. FEBS J 279:1156–1166

    Article  CAS  PubMed  Google Scholar 

  • Borlongan CV, Koutouzis TK, Randall TS, Freeman TB, Cahill DW, Sanberg PR (1995) Systemic 3-nitropropionic acid: behavioral deficits and striatal damage in adult rats. Brain Res Bull 36:549–556

    Article  CAS  PubMed  Google Scholar 

  • Cho SY, Shim SR, Rhee HY, Park HJ, Jung WS, Moon SK, Park JM, Ko CN, Cho KH, Park SU (2012) Effectiveness of acupuncture and bee venom acupuncture in idiopathic Parkinson’s disease. Parkinsonism Relat Disord 18:948–952

    Article  PubMed  Google Scholar 

  • De Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group Neurology 54:S21–S23

    PubMed  Google Scholar 

  • Doo AR, Kim ST, Kim SN, Moon W, Yin CS, Chae Y, Park HK, Lee H, Park HJ (2010) Neuroprotective effects of bee venom pharmaceutical acupuncture in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Neurol Res 32(Suppl 1):88–91

    Article  PubMed  Google Scholar 

  • Herrero MT, Estrada C, Maatouk L, Vyas S (2015) Inflammation in Parkinson’s disease: role of glucocorticoids. Front Neuroanat 9:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Hong SJ, Rim GS, Yang HI, Yin CS, Koh HG, Jang MH, Kim CJ, Choe BK, Chung JH (2005) Bee venom induces apoptosis through caspase-3 activation in synovial fibroblasts of patients with rheumatoid arthritis. Toxicon 46:39–45

    Article  CAS  PubMed  Google Scholar 

  • Jang HS, Kim SK, Han JB, Ahn HJ, Bae H, Min BI (2005) Effects of bee venom on the pro-inflammatory responses in RAW264.7 macrophage cell line. J Ethnopharmacol 99:157–160

    Article  CAS  PubMed  Google Scholar 

  • Joyce JN, Woolsey C, Ryoo H, Borwege S, Hagner D (2004) Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson’s disease, and downregulates the dopamine transporter via the D3 receptor. BMC Biol 2:22

    Article  PubMed  PubMed Central  Google Scholar 

  • Khalil WK, Assaf N, Elshebiney SA, Salem NA (2015) Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis. Neurochem Int 80:79–86

    Article  CAS  PubMed  Google Scholar 

  • Kim JI, Yang EJ, Lee MS, Kim YS, Huh Y, Cho IH, Kang S, Koh HK (2011) Bee venom reduces neuroinflammation in the MPTP-induced model of Parkinson’s disease. Int J Neurosci 121:209–217

    Article  CAS  PubMed  Google Scholar 

  • Kopin IJ (1992) Features of the dopaminergic neurotoxin MPTP. Ann N Y Acad Sci 648:96–104

    Article  CAS  PubMed  Google Scholar 

  • Kwon YB, Lee HJ, Han HJ, Mar WC, Kang SK, Yoon OB, Beitz AJ, Lee JH (2002) The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sci 71:191–204

    Article  CAS  PubMed  Google Scholar 

  • Lee YJ, Han SB, Nam SY, Oh KW, Hong JT (2010) Inflammation and Alzheimer’s disease. Arch Pharm Res 33:1539–1556

    Article  CAS  PubMed  Google Scholar 

  • Lee SH, Kwon GS, Kang MS, Yoon HM, Kim CH (2012) Comparative study on the effects of bee venom pharmacopuncture according to the treatment method for knee osteoarthritis. J Pharmacopuncture 15:7–14

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SH, Choi SM, Yang EJ (2015) Bee venom acupuncture augments anti-inflammation in the peripheral organs of hSOD1G93A transgenic mice. Toxins (Basel) 7:2835–2844

    Article  CAS  Google Scholar 

  • Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Massano J, Bhatia KP (2012) Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2:a008870

    Article  PubMed  PubMed Central  Google Scholar 

  • Matysiak J, Schmelzer CE, Neubert RH, Kokot ZJ (2011) Characterization of honeybee venom by MALDI-TOF and nanoESI-QqTOF mass spectrometry. J Pharm Biomed Anal 54:273–278

    Article  CAS  PubMed  Google Scholar 

  • Mierau J, Schingnitz G (1992) Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist. Eur J Pharmacol 215:161–170

    Article  CAS  PubMed  Google Scholar 

  • Mirshafiey A (2007) Venom therapy in multiple sclerosis. Neuropharmacology 53:353–361

    Article  CAS  PubMed  Google Scholar 

  • Moon DO, Park SY, Lee KJ, Heo MS, Kim KC, Kim MO, Lee JD, Choi YH, Kim GY (2007) Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol 7:1092–1101

    Article  CAS  PubMed  Google Scholar 

  • Nisbet HO, Ozak A, Yardimci C, Nisbet C, Yarim M, Bayrak IK, Sirin YS (2012) Evaluation of bee venom and hyaluronic acid in the intra-articular treatment of osteoarthritis in an experimental rabbit model. Res Vet Sci 93:488–493

    Article  PubMed  Google Scholar 

  • Rascol O (2000) The pharmacological therapeutic management of levodopa-induced dyskinesias in patients with Parkinson’s disease. J Neurol 247(Suppl 2):II51–II57

    PubMed  Google Scholar 

  • Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH (1999) Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126:4017–4026

    CAS  PubMed  Google Scholar 

  • Schapira AH (2002a) Dopamine agonists and neuroprotection in Parkinson’s disease. Eur J Neurol 9(Suppl 3):7–14

    Article  PubMed  Google Scholar 

  • Schapira AH (2002b) Neuroprotection and dopamine agonists. Neurology 58:S9–S18

    Article  CAS  PubMed  Google Scholar 

  • Shin JY, Park HJ, Ahn YH, Lee PH (2009) Neuroprotective effect of L-dopa on dopaminergic neurons is comparable to pramipexol in MPTP-treated animal model of Parkinson’s disease: a direct comparison study. J Neurochem 111:1042–1050

    Article  CAS  PubMed  Google Scholar 

  • Silva J, Monge-Fuentes V, Gomes F, Lopes K, Dos Anjos L, Campos G, Arenas C, Biolchi A, Goncalves J, Galante P, Campos L, Mortari M (2015) Pharmacological alternatives for the treatment of neurodegenerative disorders: wasp and bee venoms and their components as new neuroactive tools. Toxins (Basel) 7:3179–3209

    Article  CAS  Google Scholar 

  • Somerfield SD, Brandwein S (1988) Bee venom and adjuvant arthritis. J Rheumatol 15:1878

    CAS  PubMed  Google Scholar 

  • Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT (2007) Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther 115:246–270

    Article  CAS  PubMed  Google Scholar 

  • Stern Y, Mayeux R, Rosen J, Ilson J (1983) Perceptual motor dysfunction in Parkinson’s disease: a deficit in sequential and predictive voluntary movement. J Neurol Neurosurg Psychiatry 46:145–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318:149–161

    Article  PubMed  Google Scholar 

  • Tufekci KU, Meuwissen R, Genc S, Genc K (2012) Inflammation in Parkinson’s disease. Adv Protein Chem Struct Biol 88:69–132

    Article  CAS  PubMed  Google Scholar 

  • Tzounopoulos T, Stackman R (2003) Enhancing synaptic plasticity and memory: a role for small-conductance Ca2+-activated K+ channels. Neuroscientist 9:434–439

    Article  CAS  PubMed  Google Scholar 

  • Vargas MR, Johnson JA (2010) Astrogliosis in amyotrophic lateral sclerosis: role and therapeutic potential of astrocytes. Neurotherapeutics 7:471–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Liu Y, Zhou J (2015) Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener 4:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang EJ, Jiang JH, Lee SM, Yang SC, Hwang HS, Lee MS, Choi SM (2010) Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. J Neuroinflamm 7:69

    Article  Google Scholar 

  • Yang EJ, Kim SH, Yang SC, Lee SM, Choi SM (2011) Melittin restores proteasome function in an animal model of ALS. J Neuroinflamm 8:69

    Article  CAS  Google Scholar 

  • Zhang F, Zhou H, Wilson BC, Shi JS, Hong JS, Gao HM (2012) Fluoxetine protects neurons against microglial activation-mediated neurotoxicity. Parkinsonism Relat Disord 18(Suppl 1):S213–S217

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by a 2-Year Research Grant of Pusan National University.

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Correspondence to Jaewon Lee.

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Mi Eun Kim and Joo Yeon Lee contributed equally to this work.

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Kim, M.E., Lee, J.Y., Lee, K.M. et al. Neuroprotective effect of bee venom is mediated by reduced astrocyte activation in a subchronic MPTP-induced model of Parkinson’s disease. Arch. Pharm. Res. 39, 1160–1170 (2016). https://doi.org/10.1007/s12272-016-0802-0

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  • DOI: https://doi.org/10.1007/s12272-016-0802-0

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