Skip to main content

Advertisement

SpringerLink
Log in

A Disruption Mechanism of the Molecular Clock in a MPTP Mouse Model of Parkinson’s Disease

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP+) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP+-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

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

Similar content being viewed by others

References

  • Alfinito, P. D., Wang, S. P., Manzino, L., Rijhsinghani, S., Zeevalk, G. D., & Sonsalla, P. K. (2003). Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. Journal of Neuroscience, 23(34), 10982–10987.

    PubMed  CAS  Google Scholar 

  • Almirall, H., Bautista, V., Sanchez-Bahillo, A., & Trinidad-Herrero, M. (2001). Ultradian and circadian body temperature and activity rhythms in chronic MPTP treated monkeys. Neurophysiologie Clinique, 31(3), 161–170.

    Article  PubMed  CAS  Google Scholar 

  • Barcia, C., De Pablos, V., Bautista-Hernandez, V., Sanchez-Bahillo, A., Fernandez-Barreiro, A., Poza, M., et al. (2004). Measurement of motor disability in MPTP-treated macaques using a telemetry system for estimating circadian motor activity. Journal of Neuroscience Methods, 134(1), 59–64.

    Article  PubMed  CAS  Google Scholar 

  • Brooks, W. J., Jarvis, M. F., & Wagner, G. C. (1989). Astrocytes as a primary locus for the conversion MPTP into MPP+. Journal of Neural Transmission, 76(1), 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Bruguerolle, B. (2008). Clinical chronopharmacology in the elderly. Chronobiology International, 25(1), 1–15.

    Article  PubMed  Google Scholar 

  • Bruguerolle, B., & Simon, N. (2002). Biologic rhythms and Parkinson’s disease: A chronopharmacologic approach to considering fluctuations in function. Clinical Neuropharmacology, 25(4), 194–201.

    Article  PubMed  Google Scholar 

  • Cai, Y., Liu, S., Sothern, R. B., Xu, S., & Chan, P. (2010). Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease. European Journal of Neurology, 17(4), 550–554.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, M. Y., Bullock, C. M., Li, C., Lee, A. G., Bermak, J. C., Belluzzi, J., et al. (2002). Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature, 417(6887), 405–410.

    Article  PubMed  CAS  Google Scholar 

  • Chikahisa, S., Fujiki, N., Kitaoka, K., Shimizu, N., & Sei, H. (2009). Central AMPK contributes to sleep homeostasis in mice. Neuropharmacology, 57(4), 369–374.

    Article  PubMed  CAS  Google Scholar 

  • Choi, J. S., Park, C., & Jeong, J. W. (2010). AMP-activated protein kinase is activated in Parkinson’s disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Biochemical and Biophysical Research Communications, 391(1), 147–151.

    Article  PubMed  CAS  Google Scholar 

  • Ciruela, F., Gomez-Soler, M., Guidolin, D., Borroto-Escuela, D. O., Agnati, L. F., Fuxe, K., et al. (2011). Adenosine receptor containing oligomers: Their role in the control of dopamine and glutamate neurotransmission in the brain. Biochimica et Biophysica Acta, 1808(5), 1245–1255.

    Article  PubMed  CAS  Google Scholar 

  • Cunha, R. A. (2005). Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade. Purinergic Signaling, 1(2), 111–134.

    Article  CAS  Google Scholar 

  • Curtis, A. M., Cheng, Y., Kapoor, S., Reilly, D., Price, T. S., & Fitzgerald, G. A. (2007). Circadian variation of blood pressure and the vascular response to asynchronous stress. Proceedings of National Academy of Sciences USA, 104(9), 3450–3455.

    Article  CAS  Google Scholar 

  • Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: Mechanisms and models. Neuron, 39(6), 889–909.

    Article  PubMed  CAS  Google Scholar 

  • de Mendonca, A., Sebastiao, A. M., & Ribeiro, J. A. (2000). Adenosine: Does it have a neuroprotective role after all? Brain Research Reviews, 33(2–3), 258–274.

    Article  PubMed  Google Scholar 

  • Delle Donne, K. T., & Sonsalla, P. K. (1994). Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. Journal of Pharmacology and Experimental Therapeutics, 271(3), 1320–1326.

    PubMed  CAS  Google Scholar 

  • Eastman, C. I., Mistlberger, R. E., & Rechtschaffen, A. (1984). Suprachiasmatic nuclei lesions eliminate circadian temperature and sleep rhythms in the rat. Physiology & Behavior, 32(3), 357–368.

    Article  CAS  Google Scholar 

  • Etchegaray, J. P., Lee, C., Wade, P. A., & Reppert, S. M. (2003). Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature, 421(6919), 177–182.

    Article  PubMed  CAS  Google Scholar 

  • Fastbom, J., Pazos, A., & Palacios, J. M. (1987). The distribution of adenosine A1 receptors and 5′-nucleotidase in the brain of some commonly used experimental animals. Neuroscience, 22(3), 813–826.

    Article  PubMed  CAS  Google Scholar 

  • Fredholm, B. B., Abbracchio, M. P., Burnstock, G., Daly, J. W., Harden, T. K., Jacobson, K. A., et al. (1994). Nomenclature and classification of purinoceptors. Pharmacological Reviews, 46(2), 143–156.

    PubMed  CAS  Google Scholar 

  • Fredholm, B. B., Irenius, E., Kull, B., & Schulte, G. (2001). Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochemical Pharmacology, 61(4), 443–448.

    Article  PubMed  CAS  Google Scholar 

  • Gekakis, N., Staknis, D., Nguyen, H. B., Davis, F. C., Wilsbacher, L. D., King, D. P., et al. (1998). Role of the CLOCK protein in the mammalian circadian mechanism. Science, 280(5369), 1564–1569.

    Article  PubMed  CAS  Google Scholar 

  • Goldberg, N. R., Haack, A. K., Lim, N. S., Janson, O. K., & Meshul, C. K. (2011). Dopaminergic and behavioral correlates of progressive lesioning of the nigrostriatal pathway with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Neuroscience, 180, 256–271.

    Article  PubMed  CAS  Google Scholar 

  • Gordon, J. L. (1986). Extracellular ATP: Effects, sources and fate. Biochemical Journal, 233(2), 309–319.

    PubMed  CAS  Google Scholar 

  • Hartmann, A., Veldhuis, J. D., Deuschle, M., Standhardt, H., & Heuser, I. (1997). Twenty-four hour cortisol release profiles in patients with Alzheimer’s and Parkinson’s disease compared to normal controls: Ultradian secretory pulsatility and diurnal variation. Neurobiology of Aging, 18(3), 285–289.

    Article  PubMed  CAS  Google Scholar 

  • Hastings, M. H. (1997). Central clocking. Trends in Neurosciences, 20(10), 459–464.

    Article  PubMed  CAS  Google Scholar 

  • Hayashida, M., Fukuda, K., & Fukunaga, A. (2005). Clinical application of adenosine and ATP for pain control. Journal of Anesthesia, 19(3), 225–235.

    Article  PubMed  Google Scholar 

  • Isojima, Y., Okumura, N., & Nagai, K. (2003). Molecular mechanism of mammalian circadian clock. Journal of Biochemistry, 134(6), 777–784.

    Article  PubMed  CAS  Google Scholar 

  • Jackson-Lewis, V., & Przedborski, S. (2007). Protocol for the MPTP mouse model of Parkinson’s disease. Nature Protocols, 2(1), 141–151.

    Article  PubMed  CAS  Google Scholar 

  • Jin, X., Shearman, L. P., Weaver, D. R., Zylka, M. J., de Vries, G. J., & Reppert, S. M. (1999). A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell, 96(1), 57–68.

    Article  PubMed  CAS  Google Scholar 

  • Knutsson, A. (2003). Health disorders of shift workers. Occupational Medicine, 53(2), 103–108.

    Article  PubMed  Google Scholar 

  • Koyanagi, S., Kuramoto, Y., Nakagawa, H., Aramaki, H., Ohdo, S., Soeda, S., et al. (2003). A molecular mechanism regulating circadian expression of vascular endothelial growth factor in tumor cells. Cancer Research, 63(21), 7277–7283.

    PubMed  CAS  Google Scholar 

  • Kudo, T., Loh, D. H., Truong, D., Wu, Y., & Colwell, C. S. (2011). Circadian dysfunction in a mouse model of Parkinson’s disease. Experimental Neurology, 232(1), 66–75.

    Article  PubMed  Google Scholar 

  • Kuhn, K., Wellen, J., Link, N., Maskri, L., Lubbert, H., & Stichel, C. C. (2003). The mouse MPTP model: Gene expression changes in dopaminergic neurons. European Journal of Neuroscience, 17(1), 1–12.

    Article  PubMed  Google Scholar 

  • Kume, K., Zylka, M. J., Sriram, S., Shearman, L. P., Weaver, D. R., Jin, X., et al. (1999). mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell, 98(2), 193–205.

    Article  PubMed  CAS  Google Scholar 

  • Lamia, K. A., Sachdeva, U. M., DiTacchio, L., Williams, E. C., Alvarez, J. G., Egan, D. F., et al. (2009). AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science, 326(5951), 437–440.

    Article  PubMed  CAS  Google Scholar 

  • Lau, Y. S., & Mouradian, M. M. (1993). Protection against acute MPTP-induced dopamine depletion in mice by adenosine A1 agonist. Journal of Neurochemistry, 60(2), 768–771.

    Article  PubMed  CAS  Google Scholar 

  • Liu, S., Chen, X. M., Yoda, T., Nagashima, K., Fukuda, Y., & Kanosue, K. (2002). Involvement of the suprachiasmatic nucleus in body temperature modulation by food deprivation in rats. Brain Research, 929(1), 26–36.

    Article  PubMed  CAS  Google Scholar 

  • Maruyama, A., & Fujio, T. (2001). ATP production from adenine by a self-coupling enzymatic process: high-level accumulation under ammonium-limited conditions. Bioscience, Biotechnology, and Biochemistry, 65(3), 644–650.

    Article  PubMed  CAS  Google Scholar 

  • Matz, H., & Hertz, L. (1989). Adenosine metabolism in neurons and astrocytes in primary cultures. Journal of Neuroscience Research, 24(2), 260–267.

    Article  PubMed  CAS  Google Scholar 

  • Menza, M., Dobkin, R. D., Marin, H., & Bienfait, K. (2010). Sleep disturbances in Parkinson’s disease. Movement Disorders, 25(Suppl 1), S117–S122.

    Article  PubMed  Google Scholar 

  • Michel, P. P., Marien, M., Ruberg, M., Colpaert, F., & Agid, Y. (1999). Adenosine prevents the death of mesencephalic dopaminergic neurons by a mechanism that involves astrocytes. Journal of Neurochemistry, 72(5), 2074–2082.

    Article  PubMed  CAS  Google Scholar 

  • Mihaylova, M. M., & Shaw, R. J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biology, 13(9), 1016–1023.

    Article  PubMed  CAS  Google Scholar 

  • Miyasaki, J. M., Martin, W., Suchowersky, O., Weiner, W. J., & Lang, A. E. (2002). Practice parameter: initiation of treatment for Parkinson’s disease: An evidence-based review: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 58(1), 11–17.

    Article  PubMed  CAS  Google Scholar 

  • Monge, A., Viselli, F., Stocchi, F., Barbato, L., Bolner, A., Modugno, N., et al. (2004). Variation in the dopaminergic response during the day in Parkinson disease. Clinical Neuropharmacology, 27(3), 116–118.

    Article  PubMed  Google Scholar 

  • Monteleone, P., & Maj, M. (2008). The circadian basis of mood disorders: Recent developments and treatment implications. European Neuropsychopharmacology, 18(10), 701–711.

    Article  PubMed  CAS  Google Scholar 

  • Moore, R. Y., & Silver, R. (1998). Suprachiasmatic nucleus organization. Chronobiology International, 15(5), 475–487.

    Article  PubMed  CAS  Google Scholar 

  • Nagashima, K., Matsue, K., Konishi, M., Iidaka, C., Miyazaki, K., Ishida, N., et al. (2005). The involvement of Cry1 and Cry2 genes in the regulation of the circadian body temperature rhythm in mice. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 288(1), R329–R335.

    Article  PubMed  CAS  Google Scholar 

  • Ng, C. H., Guan, M. S., Koh, C., Ouyang, X., Yu, F., Tan, E. K., et al. (2012). AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in drosophila models of Parkinson’s disease. The Journal of Neuroscience, 32(41), 14311–14317.

    Article  PubMed  CAS  Google Scholar 

  • Ohdo, S., Koyanagi, S., Matsunaga, N., & Hamdan, A. (2011). Molecular basis of chronopharmaceutics. Journal of Pharmaceutical Sciences, 100(9), 3560–3576.

    Article  PubMed  CAS  Google Scholar 

  • Ohdo, S., Koyanagi, S., Suyama, H., Higuchi, S., & Aramaki, H. (2001). Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nature Medicine, 7(3), 356–360.

    Article  PubMed  CAS  Google Scholar 

  • Ongini, E., & Schubert, P. (1998). Neuroprotection induced by stimulating A1 or blocking A2A adenosine receptors: An apparent paradox. Drug Development Research, 45, 387–393.

    Article  CAS  Google Scholar 

  • Pahwa, R., Factor, S. A., Lyons, K. E., Ondo, W. G., Gronseth, G., Bronte-Stewart, H., et al. (2006). Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 66(7), 983–995.

    Article  PubMed  CAS  Google Scholar 

  • Ponsen, M. M., Stoffers, D., Booij, J., van Eck-Smit, B. L., Wolters, E. C., & Berendse, H. W. (2004). Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Annals of Neurology, 56(2), 173–181.

    Article  PubMed  Google Scholar 

  • Preitner, N., Damiola, F., Lopez-Molina, L., Zakany, J., Duboule, D., Albrecht, U., et al. (2002). The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell, 110(2), 251–260.

    Article  PubMed  CAS  Google Scholar 

  • Ransom, B. R., Kunis, D. M., Irwin, I., & Langston, J. W. (1987). Astrocytes convert the Parkinsonism inducing neurotoxin, MPTP, to its active metabolite, MPP+. Neuroscience Letters, 75(3), 323–328.

    Article  PubMed  CAS  Google Scholar 

  • Refinetti, R., Kaufman, C. M., & Menaker, M. (1994). Complete suprachiasmatic lesions eliminate circadian rhythmicity of body temperature and locomotor activity in golden hamsters. Journal of Comparative Physiology A, 175(2), 223–232.

    Article  CAS  Google Scholar 

  • Reichmann, H., Schneider, C., & Lohle, M. (2009). Non-motor features of Parkinson’s disease: Depression and dementia. Parkinsonism & Related Disorders, 15(Suppl 3), S87–S92.

    Article  Google Scholar 

  • Reppert, S. M., & Weaver, D. R. (2002). Coordination of circadian timing in mammals. Nature, 418(6901), 935–941.

    Article  PubMed  CAS  Google Scholar 

  • Ripperger, J. A., Shearman, L. P., Reppert, S. M., & Schibler, U. (2000). CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes & Development, 14(6), 679–689.

    CAS  Google Scholar 

  • Ronnett, G. V., Ramamurthy, S., Kleman, A. M., Landree, L. E., & Aja, S. (2009). AMPK in the brain: Its roles in energy balance and neuroprotection. Journal of Neurochemistry, 109(Suppl 1), 17–23.

    Article  PubMed  CAS  Google Scholar 

  • Rozas, G., Lopez-Martin, E., Guerra, M. J., & Labandeira-Garcia, J. L. (1998). The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism. Journal of Neuroscience Methods, 83(2), 165–175.

    Article  PubMed  CAS  Google Scholar 

  • Ruby, N. F., Dark, J., Burns, D. E., Heller, H. C., & Zucker, I. (2002). The suprachiasmatic nucleus is essential for circadian body temperature rhythms in hibernating ground squirrels. Journal of Neuroscience, 22(1), 357–364.

    PubMed  CAS  Google Scholar 

  • Rudolphi, K. A., Schubert, P., Parkinson, F. E., & Fredholm, B. B. (1992). Neuroprotective role of adenosine in cerebral ischaemia. Trends in Pharmacological Sciences, 13(12), 439–445.

    Article  PubMed  CAS  Google Scholar 

  • Sakamoto, K., Nagase, T., Fukui, H., Horikawa, K., Okada, T., Tanaka, H., et al. (1998). Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. Journal of Biological Chemistry, 273(42), 27039–27042.

    Article  PubMed  CAS  Google Scholar 

  • Sato, T. K., Yamada, R. G., Ukai, H., Baggs, J. E., Miraglia, L. J., Kobayashi, T. J., et al. (2006). Feedback repression is required for mammalian circadian clock function. Nature Genetics, 38(3), 312–319.

    Article  PubMed  CAS  Google Scholar 

  • Shinohara, A., Koyanagi, S., Hamdan, A. M., Matsunaga, N., Aramaki, H., & Ohdo, S. (2008). Dosing schedule-dependent change in the disruptive effects of interferon-alpha on the circadian clock function. Life Sciences, 83(15–16), 574–580.

    Article  PubMed  CAS  Google Scholar 

  • Smeyne, R. J., & Jackson-Lewis, V. (2005). The MPTP model of Parkinson’s disease. Molecular Brain Research, 134(1), 57–66.

    Article  PubMed  CAS  Google Scholar 

  • Stiasny-Kolster, K., Doerr, Y., Moller, J. C., Hoffken, H., Behr, T. M., Oertel, W. H., et al. (2005). Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain, 128, 126–137.

    Article  PubMed  CAS  Google Scholar 

  • Stiasny-Kolster, K., Mayer, G., Schafer, S., Moller, J. C., Heinzel-Gutenbrunner, M., & Oertel, W. H. (2007). The REM sleep behavior disorder screening questionnaire—A new diagnostic instrument. Movement Disorders, 22(16), 2386–2393.

    Article  PubMed  Google Scholar 

  • Takahashi, J. S., Hong, H. K., Ko, C. H., & McDearmon, E. L. (2008). The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nature Reviews Genetics, 9(10), 764–775.

    Article  PubMed  CAS  Google Scholar 

  • Terazono, H., Mutoh, T., Yamaguchi, S., Kobayashi, M., Akiyama, M., Udo, R., et al. (2003). Adrenergic regulation of clock gene expression in mouse liver. Proceedings of National Academy of Sciences USA, 100(11), 6795–6800.

    Article  CAS  Google Scholar 

  • Torres-Farfan, C., Abarzua-Catalan, L., Valenzuela, F. J., Mendez, N., Richter, H. G., Valenzuela, G. J., et al. (2009). Cryptochrome 2 expression level is critical for adrenocorticotropin stimulation of cortisol production in the capuchin monkey adrenal. Endocrinology, 150(6), 2717–2722.

    Article  PubMed  CAS  Google Scholar 

  • Ueda, H. R., Hayashi, S., Chen, W., Sano, M., Machida, M., Shigeyoshi, Y., et al. (2005). System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nature Genetics, 37(2), 187–192.

    Article  PubMed  CAS  Google Scholar 

  • Ukai-Tadenuma, M., Yamada, R. G., Xu, H., Ripperger, J. A., Liu, A. C., & Ueda, H. R. (2011). Delay in feedback repression by cryptochrome 1 is required for circadian clock function. Cell, 144(2), 268–281.

    Article  PubMed  CAS  Google Scholar 

  • Um, J. H., Pendergast, J. S., Springer, D. A., Foretz, M., Viollet, B., Brown, A., et al. (2011). AMPK regulates circadian rhythms in a tissue- and isoform-specific manner. PLoS One, 6(3), e18450.

    CAS  Google Scholar 

  • Um, J. H., Yang, S., Yamazaki, S., Kang, H., Viollet, B., Foretz, M., et al. (2007). Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. Journal of Biological Chemistry, 282(29), 20794–20798.

    Article  PubMed  CAS  Google Scholar 

  • Vieira, E., Nilsson, E. C., Nerstedt, A., Ormestad, M., Long, Y. C., Garcia-Roves, P. M., et al. (2008). Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle. American Journal of Physiology: Endocrinology and Metabolism, 295(5), E1032–E1037.

    Article  PubMed  CAS  Google Scholar 

  • Vingtdeux, V., Davies, P., Dickson, D. W., & Marambaud, P. (2011). AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies. Acta Neuropathologica, 121(3), 337–349.

    Article  PubMed  CAS  Google Scholar 

  • Wardas, J. (2002). Neuroprotective role of adenosine in the CNS. Polish Journal of Pharmacology, 54(4), 313–326.

    PubMed  CAS  Google Scholar 

  • Wu, Y., Li, X., Zhu, J. X., Xie, W., Le, W., Fan, Z., et al. (2011). Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neurosignals, 19(3), 163–174.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported partially by Grants-in-Aid for Scientific Research on Priority Areas “Cancer” (S.O. 20014016) from the Ministry of Education, Culture, Sport, Science and Technology of Japan; for Scientific Research (B) (S.O. 21390047); for Challenging Exploratory Research (S.O. 21659041); and for the Encouragement of Young Scientists (N.M. 20790137) from the Japan Society for the Promotion of Science.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Fukuoka, Higashi-ku, 812-8582, Japan

    Akane Hayashi, Naoya Matsunaga, Hiroyuki Okazaki, Keisuke Kakimoto, Yoshinori Kimura, Hiroki Azuma, Eriko Ikeda, Satoru Koyanagi & Shigehiro Ohdo

  2. Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Fukuoka, Higashi-ku, 812-8582, Japan

    Takeshi Shiba & Mayumi Yamato

  3. Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1, Maidashi, Fukuoka, Higashi-ku, 812-8582, Japan

    Takeshi Shiba, Mayumi Yamato & Ken-ichi Yamada

Authors
  1. Akane Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoya Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keisuke Kakimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshinori Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroki Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eriko Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takeshi Shiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mayumi Yamato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ken-ichi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Satoru Koyanagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shigehiro Ohdo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigehiro Ohdo.

Additional information

Akane Hayashi and Naoya Matsunaga contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hayashi, A., Matsunaga, N., Okazaki, H. et al. A Disruption Mechanism of the Molecular Clock in a MPTP Mouse Model of Parkinson’s Disease. Neuromol Med 15, 238–251 (2013). https://doi.org/10.1007/s12017-012-8214-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-012-8214-x

Keywords

Search

Navigation