Ayu Trisnawati, Anasrulloh Anasrulloh, Sri Budhi Rianawati, Husnul Khotimah, Mulyohadi Ali, Budi Susetya
  MNJ, pp. 5-13  


Background: Parkinson disease is characterized with deposition of Lewy Bodies containing α–synuclein happened due to the effect of chronic neuroinflammation that causes the death of dopaminergic neurons through oxidative stress processes, so it involves the response of Nuclear factor erythroid 2-like 2 (Nrf2). Centella asiatica  (C.asiatica) contains antioxidant effect, inhibits the aggregation of α–synuclein and improves the locomotor on Parkinson-model animals so it needs to compare to the standard medication.
Objective: To compare the C. asiatica extract and Pramipexole to the zebrafish Parkinson model by determining the locomotor activity, α–synuclein expression, and Nrf2.
Methods: This study used six groups of zebrafish: negative control, rotenone rotenone [5 μg/L], pramipexole1, 2, 3 (rotenone + pramipexole [3,5] ng/mL, [7] ng/mL, [14] ng/mL), and C. asiatica
(rotenone + C. asiatica [10] μg/mL). The observations of locomotor activity of day 0, 14, and 28 were continued to the α–synuclein immunohistochemical examination, and Nrf2 on the midbrain area.
Results: There are significant differences in locomotor activity on day 28 among the C. asiatica group with rotenone (p<0,05), while there are no significant differences among the C. asiatica group with pramipexole [7] ng/mL and [14] ng/mL (p>0,05). α–synuclein expression of the C. asiatica group is the lowest and significantly different from all groups (p<0,05), while Nr2 had no significant differences (p>0,05).
Conclusion: C. asiatica extract [10] μg/mL is equal to pramipexole [7] ng/mL and [14] ng/mL in improving locomotor activity, but C. asiatica extract holds excellence as it decreases α–synuclein expression better than pramipexole, while Nrf2 expression shows no differences.


Centella asiatica; locomotor activity; α–synuclein; Nrf2; Parkinson disease; zebrafish

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Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. McGraw-Hill; 2005

PERDOSSI. Gangguan gerak. Kelompok Studi Gangguan Gerak Persatuan Dokter Spesialis Saraf Indonesia, editor. Jakarta; 2013

Ropper AH, Samuels MA, Klein JP. Adams and Victor’s Principles of Neurology. 10th ed. McGrawHill Education; 2014

Narayan S, Liew Z, Paul K, Lee P, Sinsheimer JS, Bronstein JM, et al. Household organophosphorus pesticide use and parkinson’s disease. International Journal of Epidemiology; 2013.42;1476–85. DOI: 10.1093/ije/dyt170

Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron; 2003.39:889–909 DOI:

Howells DW, Porritt MJ, Wong JYF, Batchelor PE, Kalnins R. Reduced bdnf mrna expression in the parkinson’s disease substantia nigra. Experimental Neurology; 2000;135:127–35. DOI: 10.1006/exnr.2000.7483

Baquet ZC, Bickford PC, Jones KR. Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci The Journal of Neuroscience; 2005.25(26):6251–9. DOI: 10.1523/JNEUROSCI.4601-04.2005

Greenamyre JT, Sherer TB, Betarbet R, Panov AV. Complex i and parkinson’s disease. IUBMB Life; 2001.52:135–41

Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, et al. Mechanism of toxicity in rotenone models of parkinson’s disease. J Neurosci The Journal of Neuroscience; 2003.23(34):10756–64

Keane PC, Kurzawa M, Blain PG, Morris CM. Mitochondrial dysfunct ion in parkinson’s disease. 2011;2011(Figure 1)

Betarbet R, Canet-Avilesb RM, Sherera TB, Mastroberardinoa PG, McLendonb C, Kima J-H, et al. Intersecting pathways to neurodegeneration in parkinson’s disease: effects of the pesticide rotenone on dj-1, α-synuclein, and the ubiquitin-proteasome system. Neurobiol Dis; 2006.22(2):404–20. DOI: 10.1016/j.nbd.2005.12.003

Blesa J, Phani S, Jackson-lewis V, Przedborski S. Classic and new animal models of parkinson’s disease. Journal of Biomedicine and Biotechnology; 2012;2012. DOI: 10.1155/2012/845618

Charbel E-H M, Rusnak M, Hailu A, Sidhu A, Fricke S. NIH Public Access. 2012;209(1):224–33

Martel S, Y.Keow J, Ekker M. Rotenone neurotoxicity causes dopamine neuron loss in zebrafish. University of Ottawa Journal of Medicine; 2015.5(2). DOI:

Chaves RS, Melo TQ, Martins SA, Ferrari MFR. Protein aggregation containing beta-amyloid, alphasynuclein and hyperphosphorylated tau in cultured cells of the hippocampus, substantia nigra and locus coeruleus after rotenone exposure. BMC Neuroscience; 2010.11. DOI: 10.1186/1471-2202-11144

Rahayu M, Kurniawan SN, Anggraini DJ. The effect of beta glucan of saccharomyces cerevisae on the increase of the number of brain cells in substantia nigra brain of parkinson’s wistar strain rat (rattus norvegicus) model induced with rotenone. Malang Neurology Journal; 2015.3:17–22. DOI:

Gunawan G, Dalhar M, Kurniawan SN. Parkinson and stem cell therapy. Malang Neurology Journal; 2017.3:39–46. DOI:

Brooks D. Dopamine agonists: their role in the treatment of parkinson’s disease. Journal Neurology Neurosurgery Psychiatry; 2000.68:685–90. DOI: 10.1136/jnnp.68.6.685

Ishibashi K, Ishii K, Oda K, Mizusawa H, Ishiwata K. Binding of pramipexole to extrastriatal dopamine d 2/d 3 receptors in the human brain: a positron emission tomography study using 11 c-flb 457. PLoS One; 2011.6(3):5–10. DOI: 10.1371/journal.pone.0017723

The Parkinson Study Group. Pramipexole vs levodopa as initial treatment for parkinson disease. J Am Med Assoc; 2015.61(July 2004):1044–54. DOI: 10.1001/archneur.61.7.1044

Ling ZD, Robie HC, Tong CW, Carvey PM. Both the antioxidant and d 3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures 1. Neurol Experimental Study; 1999.289(1):202–10. PubMed:

Le WD, Jankovic J, Xie W, Appel SH. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection. journal of neural transmission; 2000.107:1165–73. DOI: 10.1007/s007020070030

Ferrari-toninelli G, Maccarinelli G, Uberti D, Buerger E, Memo M. Mitochondria-targeted antioxidant effects of s ( - ) and r ( + ) pramipexole; 2010.1–6. DOI: 10.1186/1471-2210-10-2

Imamura K, Takeshima T, Nakaso K, Ito S, Nakashima K. Pramipexole has astrocyte-mediated neuroprotective effects against lactacystin toxicity. Neuroscience Letters; 2008.440:97–102. DOI: 10.1016/j.neulet.2008.05.067

Cuadrado A, Moreno-murciano P. The transcription factor nrf2 as a new therapeutic target in parkinson’s disease. Inf UK Journal Expert Opinion on Therapeutic Targets; 2009.319–29. DOI: 10.1517/13543780802716501

Kim W, Kim J, Veriansyah B, Kim J, Lee Y, Oh S, et al. The journal of supercritical fluids extraction of bioactive components from centella asiatica using subcritical water; 2009.48:211–6. DOI: 10.1016/j.supflu.2008.11.007

Hashim P, Sidek H, Helan MHM, Sabery A, Palanisamy UD, Ilham M. Triterpene composition and bioactivities of centella asiatica. Molecules; 2011.1310–22. DOI: 10.3390/molecules16021310

Brinkhaus B, Lindner M, Schupp D, Hahn EG. Chemical, the pharmacological and clinical profile of the east asian medical plant centella asiatica. Phytomedicine; 2000.7(5). PubMed:

Hussin M, Hamid AA, Mohamad S, Saari N, Bakar F, Dek SP. Modulation of lipid metabolism by centella asiatica in oxidative stress rats. J FOOD Sci; 2009.74(2):72–8. DOI: 10.1111/j.17503841.2009.01045.x

Haleagrahara N, Ponnusamy K. Neuroprotective effect of centella asiatica extract (cae) on experimentally induced parkinsonism in aged Sprague-Dawley rats. J Toxicol Sci; 2010.35(1):41–7. PubMed:

Siddique YH, Naz F, Jyoti S, Fatima A, Khanam S, Ali F, et al. Effect of centella asiatica leaf extract on the dietary supplementation in transgenic drosophila model of parkinson’ s disease. Hindawi Publ Corp; 2014. DOI: 10.1155/2014/262058

Zhao Y, Shu P, Zhang Y, Lin L, Zhou H, Xu Z, et al. Effect of centella asiatica on oxidative stress and lipid metabolism in hyperlipidemic animal models. Hindawi Publ Corp; 2014.2014. DOI: 10.1155/2014/154295

Khotimah H, Sumitro SB, Ali M, Widodo MA. Standardized centella asiatica increased brain-derived neurotrophic factor and decreased apoptosis of dopaminergic neuron in rotenone- induced zebrafish. GSTF J Psychology; 2015.2(1):22–7

Khotimah H, Ali M, Sumitro SB, Widodo MA. Decreasing a-synuclein aggregation by methanolic extract of centella asiatica in zebrafish parkinson’s model. Asian Pac J Trop Biomed. Elsevier (Singapore) Pte Ltd; 2015.5(11):948–54. DOI:

Hanum S, Widodo MA, Rahayu M. Pengaruh ekstrak c. asiatica (centella asiatica) terhadap ekspresi tirosin hidroksilase (th) serta aktivitas lokomotor ikan zebra (danio rerio) the effect of centella asiat ica’s extract towards the expression of tyrosine hydroxylase (th) and locomot. Jurnal Kedokteran Brawijaya; 2016.29(2):99–103

Gerlai R, Lahav M, Guo S, Rosenthal A. Drinks like a fish: zebrafish (danio rerio) as a behavior genetic model to study alcohol effects. Pharmacol Biochem Behav; 2001.67(2000):773–82

Xi Y, Noble S, Ekker M. Modeling neurodegeneration in zebrafish. Current Neurology and Neuroscience Reports; 2011.11(3):274–82. DOI: 10.1007/s11910011-0182-2

Gerlai R. Using zebrafish to unravel the genetics of complex brain disorders. Curr Top Behave Neurosci; 2012.12:3–24. DOI: 10.1007/7854_2011_180

Steele SL, Prykhozhij S V., Berman JN. Zebrafish as a model system for mitochondrial biology and diseases. Translational Research The Journal of Laboratory and Clinical Medicine. Mosby, Inc; 2014.163(2):79–98. DOI: 10.1016/j.trsl.2013.08.008

Bretaud S, Lee S, Guo S. Sensitivity of zebrafish to environmental toxins implicated in parkinson’s disease. Neurotoxicol Teratol; 2004.26:857–64. DOI: 10.1016/

Tierney KB. Behavioural assessments of neurotoxic effects and neurodegeneration in zebrafish ☆. Biochim Biophys Acta. Elsevier B.V.; 2011.1812(3):381–9. DOI: 10.1016/j.bbadis.2010.10.011

Panula P, Chen YC, Priyadarshini M, Kudo H, Semenova S, Sundvik M, et al. The comparative neuroanatomy and neurochemistry of zebrafish cns systems of relevance to human neuropsychiatric diseases. Neurobiology of Disease. Elsevier Inc.; 2010.40(1):46–57. DOI: 10.1016/j.nbd.2010.05.010

Khotimah H, Sumitro SB, Widodo MA. Zebrafish parkinson’s model : rotenone decrease motility, dopamine and increase α-synuclein aggregation and apoptosis of zebrafish. Int J PharmTech Res; 2015.8(4):614–21

Wrangel C Von, Schwabe K, John N, Krauss JK, Alam M. The rotenone-induced rat model of parkinson’s disease : behavioral and electrophysiological findings. behav brain res. Elsevier B.V.; 2015.279:52–61. DOI: 10.1016/j.bbr.2014.11.002

Xu C, Wang Q, Sun L, Li X, Deng J, Li L, et al. Asiaticoside: attenuation of neurotoxicity induced by mptp in a rat model of parkinsonism via maintaining redox balance and up-regulating the ratio of bcl-2/bax. Pharmacol Biochem Behav. Elsevier Inc.; 2012.100(3):413–8

Xu C, Qu R, Zhang J, Li L, Ma S. Fitoterapia neuroprotective effects of madecassoside in early stage of parkinson’s disease induced by mptp in rats. Fitoterapia. Elsevier B.V.; 2013.90:112–8

Chorfa A, Lazizzera C, Bétemps D, Morignat E, Dussurgey S, Andrieu T, et al. A variety of pesticides trigger in vitro α-synuclein accumulation, a key event in parkinson’s disease. Arch Toxicol; 2014.90(5):1279

Berrocal R, Vasudevaraju P, Satappa S. In vitro evidence that an aqueous extract of centella asiatica modulates α-synuclein aggregation dynamics. Journal of Alzheimer's Disease; 2014;39:457–65. DOI: 10.3233/JAD-131187

Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of parkinson’s disease. Annu Rev Neurosci; 2005;28:57–87. DOI: 10.1146/annurev.neuro.28.061604.135718

Lotharius J, Brundin P. Pathogenesis of parkinson’s disease: dopamine, vesicles and α-synuclein. Nature; 2002.3:932–42. DOI: 10.1038/nrn983

Yang Y, Jiang S, Yan J, Li Y, Xin Z, Lin Y, et al. Cytokine & growth factor reviews an overview of the molecular mechanisms and novel roles of nrf2 in neurodegenerative disorders. Cytokine Growth Factor Rev. Elsevier Ltd; 2016.26(1):47–57

Uruno A, Yagishita Y, Yamamoto M. The keap1 – nrf2 system and diabetes mellitus. Arch Biochem Biophys; 2014. DOI: 10.1016/

Zhimin Qi, Xinxin Ci, Jingbo Huang, Qinmei Liu, Qinlei Yu, Junfeng Zhou XD. Asiatic acid enhances nrf2 signaling to protect hepg2 cells from oxidative damage through akt and erk activation. Biomedicine & Pharmacotherapy; 2017.88:252–9. DOI: 10.1016/j.biopha.2017.01.067


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