nach oben

Erschienen in:

01.10.2008 | Original Paper

Neurotrophic effects of Cerebrolysin in the Mecp2^308/Y transgenic model of Rett syndrome

verfasst von: Edith Doppler, Edward Rockenstein, Kiren Ubhi, Chandra Inglis, Michael Mante, Anthony Adame, Leslie Crews, Monika Hitzl, Herbert Moessler, Eliezer Masliah

Erschienen in: Acta Neuropathologica | Ausgabe 4/2008

Einloggen, um Zugang zu erhalten

Abstract

Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG-binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neurotrophic peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2^308/Y mutant mice. Two sets of experiments were performed, the first with 4-month-old male Mecp2^308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1-month-old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2^308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2^308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2^308/Y mutant mice and suggests that CBL may have neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome.

Alvarez XA, Cacabelos R, Laredo M, Couceiro V, Sampedro C, Varela M et al (2006) A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Eur J Neurol 13:43–54. doi:10.1111/j.1468-1331.2006.01222.x PubMedCrossRef

Amir RE, Van den Veyver IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ et al (2000) Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol 47:670–679. doi:10.1002/1531-8249(200005)47:5<670::AID-ANA20>3.0.CO;2-FPubMedCrossRef

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedCrossRef

Armstrong D, Dunn JK, Antalffy B, Trivedi R (1995) Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol 54:195–201. doi:10.1097/00005072-199503000-00006 PubMedCrossRef

Armstrong DD (2005) Neuropathology of Rett syndrome. J Child Neurol 20:747–753PubMed

Armstrong DD, Dunn K, Antalffy B (1998) Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21. J Neuropathol Exp Neurol 57:1013–1017. doi:10.1097/00005072-199811000-00003 PubMedCrossRef

Belichenko PV, Hagberg B, Dahlstrom A (1997) Morphological study of neocortical areas in Rett syndrome. Acta Neuropathol 93:50–61. doi:10.1007/s004010050582 PubMedCrossRef

Bienvenu T, Carrie A, de Roux N, Vinet MC, Jonveaux P, Couvert P et al (2000) MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet 9:1377–1384. doi:10.1093/hmg/9.9.1377 PubMedCrossRef

Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331. doi:10.1038/85906 PubMedCrossRef

10.

Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ et al (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 94:5401–5404. doi:10.1073/pnas.94.10.5401 PubMedCrossRef

11.

Crawley JN (2000) What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Wiley, New York

12.

Fernagut PO, Diguet E, Jaber M, Bioulac B, Tison F (2002) Dopamine transporter knock-out mice are hypersensitive to 3-nitropropionic acid-induced striatal damage. Eur J NeuroSci 15:2053–2056. doi:10.1046/j.1460-9568.2002.02047.x PubMedCrossRef

13.

Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS et al (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 24:9434–9440. doi:10.1523/JNEUROSCI.3080-04.2004 PubMedCrossRef

14.

Francis-Turner L, Valouskova V (1996) Nerve growth factor and nootropic drug Cerebrolysin but not fibroblast growth factor can reduce spatial memory impairment elicited by fimbria-fornix transection: short-term study. Neurosci Lett 202:1–4. doi:10.1016/0304-3940(95)12240-0 CrossRef

15.

Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040. doi:10.1074/jbc.M210256200 PubMedCrossRef

16.

Gorbachevskaya N, Bashina V, Gratchev V, Iznak A (2001) Cerebrolysin therapy in Rett syndrome: clinical and EEG mapping study. Brain Dev 23(Suppl. 1):S90–S93. doi:10.1016/S0387-7604(01)00349-7 PubMedCrossRef

17.

Grove EA, Tole S (1999) Patterning events and specification signals in the developing hippocampus. Cereb Cortex 9:551–561. doi:10.1093/cercor/9.6.551 PubMedCrossRef

18.

Gschanes A, Windisch M (1999) Early postnatal treatment with peptide preparations influences spatial navigation of young and adult rats. Behav Brain Res 100:161–166. doi:10.1016/S0166-4328(98)00127-2 PubMedCrossRef

19.

Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326. doi:10.1038/85899 PubMedCrossRef

20.

Hagberg B (2002) Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev 8:61–65. doi:10.1002/mrdd.10020 PubMedCrossRef

21.

Haninec P, Dubovy P, Samal F, Houstava L, Stejskal L (2004) Reinnervation of the rat musculocutaneous nerve stump after its direct reconnection with the C5 spinal cord segment by the nerve graft following avulsion of the ventral spinal roots: a comparison of intrathecal administration of brain-derived neurotrophic factor and Cerebrolysin. Exp Brain Res 159:425–432. doi:10.1007/s00221-004-1969-z PubMedCrossRef

22.

Haninec P, Houst’ava L, Stejskal L, Dubovy P (2003) Rescue of rat spinal motoneurons from avulsion-induced cell death by intrathecal administration of IGF-I and Cerebrolysin. Ann Anat 185:233–238. doi:10.1016/S0940-9602(03)80030-4 PubMed

23.

Hartbauer M, Hutter-Paie B, Windisch M (2001) Effects of Cerebrolysin on the outgrowth and protection of processes of cultured brain neurons. J Neural Transm 108:581–592. doi:10.1007/s007020170058 PubMedCrossRef

24.

Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M (2001) Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm 108:459–473. doi:10.1007/s007020170067 PubMedCrossRef

25.

Hutter-Paier B, Fruhwirth M, Grygar E, Windisch M (1996) Cerebrolysin protects neurons from ischemia-induced loss of microtubule-associated protein 2. J Neural Transm Suppl 47:276PubMed

26.

Hutter-Paier B, Steiner E, Windisch M (1998) Cerebrolysin protects isolated cortical neurons from neurodegeneration after brief histotoxic hypoxia. J Neural Transm Suppl 53:351–361PubMed

27.

Hwang DY, Fleming SM, Ardayfio P, Moran-Gates T, Kim H, Tarazi FI et al (2005) 3, 4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J Neurosci 25:2132–2137. doi:10.1523/JNEUROSCI.3718-04.2005 PubMedCrossRef

28.

Jellinger KA (2003) Rett syndrome—an update. J Neural Transm 110:681–701. doi:10.1007/s00702-003-0822-z PubMedCrossRef

29.

Kaufmann WE, Naidu S, Budden S (1995) Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome. Neuropediatrics 26:109–113PubMedCrossRef

30.

Kaufmann WE, Taylor CV, Hohmann CF, Sanwal IB, Naidu S (1997) Abnormalities in neuronal maturation in Rett syndrome neocortex: preliminary molecular correlates. Eur Child Adolesc Psychiatry 6(Suppl. 1):75–77PubMed

31.

Kerr AM (1995) Early clinical signs in the Rett disorder. Neuropediatrics 26:67–71PubMed

32.

Kuczenski R, Everall IP, Crews L, Adame A, Grant I, Masliah E (2007) Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat. Exp Neurol 207:42–51. doi:10.1016/j.expneurol.2007.05.023 PubMedCrossRef

33.

Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F et al (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914. doi:10.1016/0092-8674(92)90610-O PubMedCrossRef

34.

Mallory M, Honer W, Hsu L, Johnson R, Rockenstein E, Masliah E (1999) In vitro synaptotrophic effects of Cerebrolysin in NT2 N cells. Acta Neuropathol 97:437–446. doi:10.1007/s004010051012 PubMedCrossRef

35.

Masliah E, Armasolo F, Veinbergs I, Mallory M, Samuel W (1999) Cerebrolysin ameliorates performance deficits, and neuronal damage in apolipoprotein E-deficient mice. Pharmacol Biochem Behav 62:239–245. doi:10.1016/S0091-3057(98)00144-0 PubMedCrossRef

36.

Matsuura K, Kabuto H, Makino H, Ogawa N (1997) Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 73:45–48. doi:10.1016/S0165-0270(96)02211-X PubMedCrossRef

37.

Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. doi:10.1093/nar/16.3.1215 PubMedCrossRef

38.

Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY (2005) Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 14:205–220. doi:10.1093/hmg/ddi016 PubMedCrossRef

39.

Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B et al (2006) Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 26:319–327. doi:10.1523/JNEUROSCI.2623-05.2006 PubMedCrossRef

40.

Muresanu DF, Alvarez XA, Moessler H, Buia M, Stan A, Pintea D et al (2008) A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration. J Neurol Sci 267:112–119. doi:10.1016/j.jns.2007.10.016 PubMedCrossRef

41.

Nan X, Campoy FJ, Bird A (1997) MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88:471–481. doi:10.1016/S0092-8674(00)81887-5 PubMedCrossRef

42.

Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389. doi:10.1038/30764 PubMedCrossRef

43.

Nan X, Tate P, Li E, Bird A (1996) DNA methylation specifies chromosomal localization of MeCP2. Mol Cell Biol 16:414–421PubMed

44.

Nomura Y, Segawa M, Higurashi M (1985) Rett syndrome—an early catecholamine and indolamine deficient disorder? Brain Dev 7:334–341PubMed

45.

Ogawa N, Hirose Y, Ohara S, Ono T, Watanabe Y (1985) A simple quantitative bradykinesia test in MPTP-treated mice. Res Commun Chem Pathol Pharmacol 50:435–441PubMed

46.

Ogawa N, Mizukawa K, Hirose Y, Kajita S, Ohara S, Watanabe Y (1987) MPTP-induced parkinsonian model in mice: biochemistry, pharmacology and behavior. Eur Neurol 26(Suppl. 1):16–23. doi:10.1159/000116351 PubMedCrossRef

47.

Percy AK, Zoghbi HY, Glaze DG (1987) Rett syndrome: discrimination of typical and variant forms. Brain Dev 9:458–461PubMed

48.

Poliakov GI (1961) Some results of research into the development of the neuronal structure of the cortical ends of the analyzers in man. J Comp Neurol 117:197–212. doi:10.1002/cne.901170206 PubMedCrossRef

49.

Reinprecht I, Gschanes A, Windisch M, Fachbach G (1999) Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 24-month-old rats. Histochem J 31:395–401. doi:10.1023/A:1003752208971 PubMedCrossRef

50.

Rockenstein E, Adame A, Mante M, Moessler H, Windisch M, Masliah E (2003) The neuroprotective effects of Cerebrolysin trade mark in a transgenic model of Alzheimer’s disease are associated with improved behavioral performance. J Neural Transm 110:1313–1327. doi:10.1007/s00702-003-0025-7 PubMedCrossRef

51.

Rockenstein E, Mallory M, Mante M, Alford M, Windisch M, Moessler H, et al (2002) Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer’s disease. J Neural Transm Suppl 62:327–336

52.

Rockenstein E, Mante M, Adame A, Crews L, Moessler H, Masliah E (2007) Effects of Cerebrolysintrade mark on neurogenesis in an APP transgenic model of Alzheimer’s disease. Acta Neuropathol 113:265–275. doi:10.1007/s00401-006-0166-5 PubMedCrossRef

53.

Rockenstein E, Torrance M, Mante M, Adame A, Paulino A, Rose JB et al (2006) Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease. J Neurosci Res 83:1252–1261. doi:10.1002/jnr.20818 PubMedCrossRef

54.

Rockenstein E, Torrance M, Mante M, Adame A, Paulino A, Rose JB, Crews L, Moessler H, Masliah E (2006) Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease. J Neurosci Res 83(7):1252-61.

55.

Satou T, Itoh T, Tamai Y, Ohde H, Anderson AJ, Hashimoto S (2000) Neurotrophic effects of FPF-1070 (Cerebrolysin) on cultured neurons from chicken embryo dorsal root ganglia, ciliary ganglia, and sympathetic trunks. J Neural Transm 107:1253–1262. doi:10.1007/s007020070015 PubMedCrossRef

56.

Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J et al (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243–254. doi:10.1016/S0896-6273(02)00768-7 PubMedCrossRef

57.

Shahbazian MD, Zoghbi HY (2002) Rett syndrome and MeCP2: linking epigenetics and neuronal function. Am J Hum Genet 71:1259–1272. doi:10.1086/345360 PubMedCrossRef

58.

Stearns NA, Schaevitz LR, Bowling H, Nag N, Berger UV, Berger-Sweeney J (2007) Behavioral and anatomical abnormalities in Mecp2 mutant mice: a model for Rett syndrome. Neuroscience 146:907–921. doi:10.1016/j.neuroscience.2007.02.009 PubMedCrossRef

59.

Takashima S, Ieshima A, Nakamura H, Becker LE (1989) Dendrites, dementia and the Down syndrome. Brain Dev 11:131–133PubMed

60.

Tole S, Christian C, Grove EA (1997) Early specification and autonomous development of cortical fields in the mouse hippocampus. Development 124:4959–4970PubMed

61.

Villard L, Kpebe A, Cardoso C, Chelly PJ, Tardieu PM, Fontes M (2000) Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 55:1188–1193PubMed

62.

Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE et al (1999) Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 65:1520–1529. doi:10.1086/302690 PubMedCrossRef

63.

Wei ZH, He QB, Wang H, Su BH, Chen HZ (2007) Meta-analysis: the efficacy of nootropic agent Cerebrolysin in the treatment of Alzheimer’s disease. J Neural Transm 114:629–634. doi:10.1007/s00702-007-0630-y PubMedCrossRef

64.

Windholz E, Gschanes A, Windisch M, Fachbach G (2000) Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 6-week-old rats. Histochem J 32:79–84. doi:10.1023/A:1004053809591 PubMedCrossRef

65.

Wronski R, Kronawetter S, Hutter-Paier B, Crailsheim K, Windisch M (2000) A brain derived peptide preparation reduces the translation dependent loss of a cytoskeletal protein in primary cultured chicken neurons. J Neural Transm Suppl 59:263–272PubMed

66.

Young JI, Zoghbi HY (2004) X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of rett syndrome. Am J Hum Genet 74:511–520. doi:10.1086/382228 PubMedCrossRef

Titel: Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome
verfasst von: Edith Doppler
Edward Rockenstein
Kiren Ubhi
Chandra Inglis
Michael Mante
Anthony Adame
Leslie Crews
Monika Hitzl
Herbert Moessler
Eliezer Masliah
Publikationsdatum: 01.10.2008
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 4/2008
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-008-0407-x

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2008

Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG)

Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex

The pathology of superficial siderosis of the central nervous system

Aldehyde fixation is not necessary for the formation of “dark” neurons

Accumulation of genomic aberrations during clinical progression of medulloblastoma