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2016 | 76 | 3 |

Tytuł artykułu

High-dose 1,25-dihydroxyvitamin D supplementation elongates the lifespan of Huntington’s disease transgenic mice

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Huntington’s disease is an autosomal dominant progressive neurodegenerative disease, which results in a decreased quality of life and an early death. A high prevalence of vitamin D deficiency was first described in a 2013 study in patients with manifest Huntington’s disease, where serum vitamin D level was found to be associated with motor capabilities of the patients. Objectives: Our objective was to investigate the effect of a high-dose vitamin D3 supplementation on a transgenic mouse model of Huntington’s disease. Methods: Our study was performed on N171-82Q Huntington’s disease transgenic mice in age- and gender-matched groups. We collected data on the motor state and survival of the mice. Results: The results demonstrate that though vitamin D3 had no effect on the motor performance of transgenic mice, but significantly increased the lifespan of transgenic animals (Kaplan-Meier survival curves: vehicle-supplemented group: 73 (67–94) days vs. vitamin D3-supplemented group: 101 (74–109) days, p=0.048 Mantel-Cox log rank test). Conclusions: Further investigations are needed to determine whether a neuroprotective or a general corroborative effect of vitamin D leads to the measured effect. Our findings support the potential influence of vitamin D deficiency on the disease course and propose that vitamin D may be an effective supplementary treatment to beneficially influence clinical features of Huntington’s disease.

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  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary
  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary
  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary
  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary
  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary
  • MTA-SZTE Neuroscience Research Group, Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary
  • Albert Szent-Gyorgyi Clinical Centre, Department of Neurology, University of Szeged, Szeged, Hungary


  • Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M, Sassone J, Ciammola A, Squitieri F, Beal  MF (2009) Impaired PGC-1α function in muscle in Huntington’s disease. Hum Mol Genet 18(16): 3048–3065.
  • Chaves M, Toral A, Bisonni A, Rojas JI, Fernández C, García Basalo MJ, Matusevich D, Cristiano E, Golimstok A (2014) Treatment with vitamin D and slowing of progression to severe stage of Alzheimer's disease. Vertex 25(114): 85–91.
  • Chel VG, Ooms ME, van der Bent J, Veldkamp F, Roos RA, Achterberg WP, Lips P (2013) High prevalence of vitamin D deficiency and insufficiency in patients with manifest Huntington disease: An explorative study. Dermatoendocrinol 5(3): 348–351.
  • Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7): 797–801.
  • Chiu CT, Liu GP, Leeds P, Chuang DM (2011) Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington’s Disease. Neuropsychopharmacology 36(12): 2406–2421.
  • Ciesielska A, Joniec I, Przybyłkowski A, Gromadzka G, Kurkowska-Jastrzebska I, Członkowska A, Członkowski A (2003) Dynamics of expression of the mRNA for cytokines and inducible nitric synthase in a murine model of the Parkinson’s disease. Acta Neurobiol Exp (Wars) 63(2): 117–126.
  • Deckel AW, Gordinier A, Nuttal D, Tang V, Kuwada C, Freitas R, Gary KA (2001) Reduced activity and protein expression of NOS in R6/2 HD transgenic mice: effects of L-NAME on symptom progression. Brain Res 919(1): 70–81.
  • Deckel AW, Tang V, Nuttal D, Gary K, Elder R (2002) Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice. Brain Res 939: 76–86.
  • DiCiero Miranda M, de Bruin VM, Vale MR, Viana G (2000) Lipid peroxidation and nitrite plus nitrate levels in brain tissue from patients with Alzheimer’s disease. Gerontology 46(4): 179–184.
  • Durk MR, Han K, Chow ECY, Ahrens R, Henderson JT, Fraser PE, Pang KS (2014) 1 alpha,25-Dihydroxyvitamin D-3 reduces cerebral amyloid-beta accumulation and improves cognition in mouse models of Alzheimer’s disease. J Neurosci 34(21): 7091–7101.
  • Dursun E, Gezen-Ak D, Yilmazer S (2013) A new mechanism for amyloid-β induction of iNOS: vitamin D-VDR pathway disruption. J Alzheimers Dis 36(3): 459–474.
  • Dusad A, Thiele GM, Klassen LW, Wang D, Duryee MJ, Mikuls TR, Staab EB, Wyatt TA, West WW, Reynolds SJ, Romberger DJ, Poole JA (2015) Vitamin D supplementation protects against bone loss following inhalant organic dust and lipopolysaccharide exposures in mice. Immunol Res 62(1): 46–59.
  • Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) Therapeutic effects of coenzyme Q(10) and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22(5): 1592–1599.
  • Fetahu IS, Höbaus J, Kállay E (2014) Vitamin D and the epigenome. Front Physiol 29(5): 164. Frank S, Jankovic J (2010) Advances in the Pharmacological Management of Huntington’s Disease. Drugs 70(5): 561–571.
  • Garcion E, Sindji L, Montero-Menei C, Andre C, Brachet P, Darcy F (1998) Expression of inducible nitric oxide synthase during rat brain inflammation: regulation by 1,25-dihydroxyvitamin D-3. Glia 22(3): 282–294.
  • Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D (2002) New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 13(3): 100–105.
  • Gardian G, Browne SE, Choi DK, Klivenyi P, Gregorio J, Kubilus JK, Ryu H, Langley B, Ratan RR, Ferrante RJ, Beal MF (2005) Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease. J Biol Chem 280(1): 556–563.
  • Gardian G, Yang L, Cleren C, Calingasan NY, Klivenyi P, Beal MF (2004) Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. Neuromolecular Med 5(3): 235–241.
  • Goodman AO, Barker RA (2011) Body composition in premanifest Huntington’s disease reveals lower bone density compared to controls. PLoS Curr 3: RRN1214. Killoran A, Biglan KM (2014) Current therapeutic options for Huntington’s disease: good clinical practice versus evidence-based approaches? Mov Disord 29(11): 1404–1413.
  • Kim JS RS, Yun I, Kim WJ, Lee KS, Park JW, Kim YI (2006) 1alpha,25-Dihydroxyvitamin D(3) Protects Dopaminergic Neurons in Rodent Models of Parkinson’s Disease through Inhibition of Microglial Activation. J Clin Neurol 2(4): 252–257.
  • Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PHM, Fried L, Kestenbaum BR, Kuller LH, Langa KM, Lopez OL, Kos K, Soni M, Llewellyn DJ (2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology 83(10): 920–928.
  • Łaczmański Ł, Jakubik M, Bednarek-Tupikowska G, Rymaszewska J, Słoka N, Lwow F (2015) Vitamin D receptor gene polymorphisms in Alzheimer’s disease patients. Exp Gerontol 69: 142–147.
  • Mehanna R, Scherzer CR, Ding H, Locascio JJ (2014) Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker study. Neurology 82(18): 1666–1666.
  • Milstien S, Sakai N, Brew BJ, Krieger C, Vickers JH, Saito K, Heyes MP (1994) Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J Neurochem 63(3): 1178–1180.
  • Nissou MF, Guttin A, Zenga C, Berger F, Issartel JP, Wion D (2014) Additional Clues for a Protective Role of Vitamin D in Neurodegenerative Diseases: 1,25-Dihydroxyvitamin D3 Triggers an Anti-Inflammatory Response in Brain Pericytes. J Alzheimers Dis 42(3): 789–799.
  • Pérez-De La Cruz V, González-Cortés C, Galván-Arzate S, Medina-Campos ON, Pérez-Severiano F, Ali SF, Pedraza-Chaverrí J, Santamaría A (2005) Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington’s disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III). Neuroscience 135(2): 463–474.
  • Pérez-Severiano F, Escalante B, Vergara P, Ríos C, Segovia J (2002) Age- -dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington’s disease mutation. Brain Res 951(1): 36–42.
  • Pickholtz I, Saadyan S, Keshet GI, Wang VS, Cohen R, Bouwman P, Jonkers J, Byers SW, Papa MZ, Yarden RI (2014) Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells. Oncotarget 5(23): 11827–11846.
  • Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8(3): 397–407.
  • Schmidt W, Wolf G, Calka J, Schmidt HH (1995) Evidence for bidirectional changes in nitric oxide synthase activity in the rat striatum after excitotoxically (quinolinic acid) induced degeneration. Neuroscience 67(2): 345–356.
  • Schulz JB, Matthews RT, Jenkins BG, Ferrante RJ, Siwek D, Henshaw DR, Cipolloni PB, Mecocci P, Kowall NW, Rosen BR, Beal MF (1995) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci 15(12): 8419–8429.
  • Szalardy L, Klivenyi P, Zadori D, Fulop F, Toldi J, Vecsei L (2012) Mitochondrial disturbances, tryptophan metabolites and neurodegeneration: medicinal chemistry aspects. Curr Med Chem 19(13): 1899–1920.
  • Torok R, Torok N, Szalardy L, Plangar I, Szolnoki Z, Somogyvari F, Vecsei L, Klivenyi P (2013) Association of vitamin D receptor gene polymorphisms and Parkinson’s disease in Hungarians. Neurosci Lett 551: 70–74.
  • Trześniewska K, Brzyska M, Elbaum D (2004) Neurodegenerative aspects of protein aggregation. Acta Neurobiol Exp (Wars) 64(1): 41–52.
  • Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y (2001) Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904(1): 67–75.
  • Zádori D, Geisz A, Vámos E, Vécsei L, Klivényi P (2009) Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington’s disease. Pharmacol Biochem Behav 94(1): 148–153.
  • Zádori D, Nyiri G, Szonyi A, Szatmári I, Fülöp F, Toldi J, Freund TF, Vécsei L, Klivényi P (2011) Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J Neural Transm (Vienna) 118(6): 865–875.
  • Ziemka-Nalecz M, Zalewska T (2014) Neuroprotective effects of histone deacetylase inhibitors in brain ischemia. Acta Neurobiol Exp (Wars) 74(4): 383–395.

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