Sains Malaysiana 53(1)(2024): 49-61

http://doi.org/10.17576/jsm-2024-5301-05

MPTP- Induced BALB/C Mice Recapitulate Compensatory Parkinson’s-Like Motor Features

(MPTP- Mencit Aruhan BALB/C Merupakapitulasikan Pampasan Ciri Motor Seperti Parkinson)

MUSA MUSTAPHA^1,2, CHE NORMA MAT TAIB^1,*, SHARIDA FAKURAZI¹ & MOHAMAD ARIS MOHD MOKLAS¹

¹Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

²Department of Human Anatomy, Faculty of Basic Medical Sciences, College of Medical Sciences, Ahmadu Bello University, Zaria, Nigeria

Diserahkan: 2 Jun 2023/Diterima: 2 Januari 2024

Abstract

This study aimed to assess motor responses and associated pathological changes caused by MPTP neurotoxicity in Balb/c mice. Male mice (13 weeks old, 25-30 g) were divided into four groups and received intraperitoneal injections of normal saline or different doses of MPTP-HCl for five consecutive days. Body weight was monitored, and behavioral tests were conducted. Histological examination with H&E staining was performed on the striatum and substantia nigra. Contrary to expectations, MPTP-treated mice showed increased locomotor activity in the open field test, covering a greater distance and exhibiting more rearing compared to control mice (p<0.05). The catalepsy test also showed lower catalepsy scores in the MPTP-treated group (p<0.05). However, the pole test did not indicate the presence of MPTP-induced bradykinesia (p>0.05). Similarly, the traction and hang tests showed no significant effects of MPTP on motor balance or muscle strength (p>0.05). Among the MPTP-treated groups, the 30 mg/kg MPTP-HCl group displayed the most severe pathological changes, including reactive gliosis, as observed in histological examination. In conclusion, the subacute MPTP mouse model used in this study did not exhibit noticeable motor deficits or significant weight loss in Balb/c mice, possibly due to subthreshold dopamine depletion compensatory mechanisms. This model could provide valuable insights into the compensatory mechanisms involved in Parkinson's disease.

Keywords: Balb/c mice; MPTP; Parkinson's-like symptoms

Abstrak

Penyelidikan ini bertujuan untuk menilai respons motor dan perubahan patologi yang berkaitan disebabkan oleh neurotoksin MPTP pada model tikus Balb/c untuk penyakit Parkinson. Mencit jantan Balb/c berumur 13 minggu dan berat antara 25-30 g telah dibahagikan secara rawak kepada empat kumpulan. Mereka menerima suntikan intraperitoneal dengan larutan garam fisiologi 0.9% atau dos berbeza MPTP-HCl selama lima hari berturut-turut. Berat badan tikus dipantau dan ujian tingkah laku dilakukan. Setelah itu, pemeriksaan histologi menggunakan pewarnaan H&E dilakukan pada striatum dan substantia nigra. Berbeza dengan jangkaan, mencit yang diberikan MPTP menunjukkan aktiviti lokomotor yang meningkat dalam ujian lapangan terbuka, menempuh jarak yang lebih jauh dan menunjukkan lebih banyak gerakan memanjat berbanding dengan mencit kawalan (p<0.05). Ujian katalepsi juga menunjukkan skor katalepsi yang lebih rendah pada kumpulan yang diberikan MPTP (p<0.05). Walau bagaimanapun, ujian tiang tidak menunjukkan kehadiran bradikinesia yang disebabkan oleh MPTP (p>0.05). Begitu juga, ujian daya tarikan dan gantungan tidak menunjukkan kesan yang signifikan MPTP terhadap keseimbangan motor atau kekuatan otot mencit (p>0.05). Antara kumpulan yang diberikan MPTP, kumpulan MPTP-HCl dengan dos 30 mg/kg menunjukkan perubahan patologi yang paling teruk, termasuk hipokromasia dan gliosis yang teruk, seperti yang dilihat dalam pemeriksaan histologi. Secara kesimpulannya, model mencit MPTP subakut yang digunakan dalam kajian ini tidak menunjukkan ketidakupayaan motor yang ketara atau kehilangan berat badan yang signifikan pada mencit Balb/c. Ini mungkin disebabkan oleh mekanisme pampasan yang mengatasi penurunan dopamin melalui pemulihan dan mekanisme kelebihan. Model ini dapat memberikan pandangan yang berharga mengenai mekanisme pampasan yang terlibat dalam penyakit Parkinson.

Kata kunci:  Gejala seperti Parkinson; Mencit Balb/c; MPTP

RUJUKAN

Ali, S.J. & Rajini, P.S. 2016. Effect of monocrotophos, an organophosphorus insecticide, on the striatal dopaminergic system in a mouse model of Parkinson’s disease. Toxicology and Industrial Health 32(7): 1153-1165. doi.org/10.1177/0748233714547733

Bhaduri, B., Abhilash, P.L. & Alladi, P.A. 2018. Baseline striatal and nigral interneuronal protein levels in two distinct mice strains differ in accordance with their MPTP susceptibility. Journal of Chemical Neuroanatomy 91: 46-54. doi.org/10.1016/j.jchemneu.2018.04.005

Blesa, J. & Przedborski, S. 2014. Parkinson’s disease: Animal models and dopaminergic cell vulnerability. Frontiers in Neuroanatomy 8: 155. doi.org/10.3389/fnana.2014.00155

Blesa, J., Trigo-Damas, I., Dileone, M., Del Rey, N.L., Hernandez, L.F. & Obeso, J.A. 2017. Compensatory mechanisms in Parkinson's disease: Circuits adaptations and role in disease modification. Experimental Neurology 298: 148-161. doi.org/10.1016/j.expneurol.2017.10.002

Brooks, S.P. 2011. Neurological evaluation of movement disorders in mice. In Animal Models of Movement Disorders, Neuromethods, vol. 61, edited by Lane, E. & Dunnett, S. New Jersey: Humana Press. pp. 65-86. doi.org/10.1007/978-1-61779-298-4_5

Campolo, M., Casili, G., Biundo, F., Crupi, R., Cordaro, M., Cuzzocrea, S. & Esposito, E. 2017. The neuroprotective effect of dimethyl fumarate in an MPTP-mouse model of Parkinson's disease: Involvement of reactive oxygen species/nuclear factor-κB/nuclear transcription factor related to NF-E2. Antioxidants and Redox Signaling 27(8): 453-471. doi.org/10.1089/ars.2016.6800

Chen, L., Ding, Y., Cagniard, B., Van Laar, A.D., Mortimer, A., Chi, W., Hastings, T.G., Kang, U.J. & Zhuang, X. 2008. Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. Journal of Neuroscience 28(2): 425-433. doi.org/10.1523/JNEUROSCI.3602-07.2008

Garza-Ulloa, J. 2019. Update on Parkinson’s disease. American Journal of Biomedical Science and Research 2(6): 229-236. doi.org/10.34297/AJBSR.2019.02.000614

Gibrat, C., Saint‐Pierre, M., Bousquet, M., Lévesque, D., Rouillard, C. & Cicchetti, F. 2009 Differences between subacute and chronic MPTP mice models: Investigation of dopaminergic neuronal degeneration and α‐synuclein inclusions. Journal of Neurochemistry 109(5): 1469-1482. doi.org/10.1111/j.1471-4159.2009.06072.x

Hall, C.S. 1934. Emotional behavior in the rat. I. Defecation and urination as measures of individual differences in emotionality. Journal of Comparative Psychology 18(3): 385-403. doi.org/10.1037/h0071444

Huang, J. & Jiang, Q. 2019. Dexmedetomidine protects against neurological dysfunction in a mouse intracerebral hemorrhage model by inhibiting mitochondrial dysfunction-derived oxidative stress. Journal of Stroke and Cerebrovascular Diseases 28(5): 1281-1289. doi.org/10.1016/j.jstrokecerebrovasdis.2019.01.016

Hu, M., Li, F. & Wang, W. 2018. Vitexin protects dopaminergic neurons in MPTP-induced Parkinson’s disease through PI3K/Akt signaling pathway. Drug Design, Development and Therapy 12: 565-573. doi.org/10.2147/DDDT.S156920

Hu, D., Cui, Y. & Zhang, J. 2021. Nervonic acid amends motor disorder in a mouse model of Parkinson’s disease. Translational Neuroscience 12(1): 237-246. doi.org/10.1515/tnsci-2020-0171

Jackson-Lewis, V. & Przedborski, S. 2007. Protocol for the MPTP mouse model of Parkinson's disease. Nature Protocols 2(1): 141-151. doi.org/10.1038/nprot.2006.342

Jo, M.G., Ikram, M., Jo, M.H., Yoo, L., Chung, K.C., Nah, S.Y., Hwang, H., Rhim, H. & Kim, M.O. 2019. Gintonin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of α-synuclein via the Nrf2/HO-1 pathway. Molecular Neurobiology 56(1): 39-55. doi.org/10.1007/s12035-018-1020-1

Kistner, A., Lhommée, E. & Krack, P. 2014. Mechanisms of body weight fluctuations in Parkinson’s disease. Frontiers in Neurology 5: 84. doi.org/10.3389/fneur.2014.00084

Kozina, E.A., Khaindrava, V.G., Kudrin, V.S., Kucheryanu, V.G., Klodt, P.D., Bocharov, E.V., Raevskii, K.S., Kryzhanovskii, G.N. & Ugryumov, M.V. 2011. Experimental modeling of functional deficiency of the nigrostriatal dopaminergic system in mice. Neuroscience and Behavioral Physiology 41(7): 671-679. doi.org/10.1007/s11055-011-9471-0

Liu, Q., Zhu, D., Jiang, P., Tang, X., Lang, Q., Yu, Q., Zhang, S., Che, Y. & Feng, X. 2019. Resveratrol synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson disease in mice. Behavioural Brain Research 367: 10-18. doi.org/10.1016/j.bbr.2019.03.043

Luchtman, D.W., Shao, D.I. & Song, C. 2009. Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson's disease. Physiology and Behavior 98(1-2): 130-138. doi.org/10.1016/j.physbeh.2009.04.021

Mann, A. & Chesselet, M.F. 2015. Techniques for motor assessment in rodents. In Movement Disorders: Genetics and Models. 2nd ed., edited by LeDoux, M.S. Massachusetts: Academic Press. pp. 139-157. doi.org/10.1016/B978-0-12-405195-9.00008-1

Mustapha, M. & Mat Taib, C.N. 2021. MPTP-induced mouse model of Parkinson’s disease: A promising direction for therapeutic strategies. Bosnian Journal of Basic Medical Sciences 21(4): 422-433. doi.org/10.17305/bjbms.2020.5181

Nagarajan, S., Chellappan, D.R., Chinnaswamy, P. & Thulasingam, S. 2015. Ferulic acid pretreatment mitigates MPTP-induced motor impairment and histopathological alterations in C57BL/6 mice. Pharmaceutical Biology 53(11): 1591-1601. doi.org/10.3109/13880209.2014.993041

Obergasteiger, J., Frapporti, G., Pramstaller, P.P., Hicks, A.A. & Volta, M. 2018. A new hypothesis for Parkinson’s disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics. Molecular Neurodegeneration 13(1): 40. doi.org/10.1186/s13024-018-0273-5

Ogawa, N., Hirose, Y., Ohara, S., Ono, T. & Watanabe, Y. 1985. A simple quantitative bradykinesia test in MPTP-treated mice. Research Communications in Chemical Pathology and Pharmacology 50(3): 435-441.

Oliván, S., Calvo, A.C., Gasco, S., Muñoz, M.J., Zaragoza, P. & Osta, R. 2015. Time-point dependent activation of autophagy and the UPS in SOD1G93A mice skeletal muscle. PLoS ONE 10(8): e0134830. doi.org/10.1371/journal.pone.0134830

Paxinos, G. & Franklin, K.B. 2019. Paxinos and Franklin's the Mouse Brain in Stereotaxic Coordinates. 5th ed. Massachusetts: Academic Press.

Rai, S.N. & Singh, P. 2020. Advancement in the modelling and therapeutics of Parkinson’s disease. Journal of Chemical Neuroanatomy 104: 101752. doi.org/10.1016/j.jchemneu.2020.101752

Sanberg, P.R., Bunsey, M.D., Giordano, M. & Norman, A.B. 1988. The catalepsy test: its ups and downs. Behavioral Neuroscience 102(5): 748-759. doi.org/10.1037/0735-7044.102.5.748

Shi, X., Bai, H., Wang, J., Wang, J., Huang, L., He, M., Zheng, X., Duan, Z., Chen, D., Zhang, J., Chen, X. & Wang, J. 2021. Behavioral assessment of sensory, motor, emotion, and cognition in rodent models of intracerebral hemorrhage. Frontiers in Neurology 12: 667221. doi.org/10.3389/fneur.2021.667511

Sun, M.F., Zhu, Y.L., Zhou, Z.L., Jia, X.B., Xu, Y.D., Yang, Q., Cui, C. & Shen, Y.Q. 2018. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson ’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain, Behavior, and Immunity 70: 48-60. doi.org/10.1016/j.bbi.2018.02.005

Tatton, N.A. & Kish, S.J. 1997. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 77(4): 1037-1048. doi.org/10.1016/S0306-4522(96)00545-3

Voikar, V., Vasar, E. & Rauvala, H. 2004. Behavioral alterations induced by repeated testing in C57BL/6J and 129S2/Sv mice: Implications for phenotyping screens. Genes, Brain and Behavior 3(1): 27-38. doi.org/10.1046/j.1601-183X.2003.0044.x

Wile, D.J., Agarwal, P.A., Schulzer, M., Mak, E., Dinelle, K., Shahinfard, E., Vafai, N., Hasegawa, K., Zhang, J., McKenzie, J., Neilson, N., Strongosky, A., Uitti, R.J., Guttman, M., Zabetian, C.P., Ding, Y.S., Adam, M., Aasly, J., Wszolek, Z.K., Farrer, M., Sossi, V. & Stoessl, A.J. 2017. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: Cross-sectional studies. The Lancet Neurology 16(5): 351-359. doi.org/10.1016/S1474-4422(17)30056-X

Zeng, X.S., Geng, W.S. & Jia, J.J. 2018. Neurotoxin-induced animal models of Parkinson disease: Pathogenic mechanism and assessment. ASN Neuro 10: 1759091418777438. doi.org/10.1177/1759091418777438

Zhang, Q.S., Heng, Y., Mou, Z., Huang, J.Y., Yuan, Y.H. & Chen, N.H. 2017. Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease. Acta Pharmacologica Sinica 38(10): 1317-1328. doi.org/10.1038/aps.2017.49

*Pengarang untuk surat-menyurat; email: chenorma@upm.edu.my