title: Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease.
abstract: BACKGROUND
  Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD.
  
  
  OBJECTIVE
  To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD.
  
  
  METHODS
  A chemical screen was performed in a mouse Hdh(Q111/Q111) striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HD mouse model.
  
  
  RESULTS
  We found that in striatal Hdh(Q111/Q111) cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HD mouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance.
  
  
  CONCLUSIONS
  These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD.
authors: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors: Melissa R
authors: MR
authors: Sarantos
authors: Theodora
authors: T
authors: Papanikolaou
authors: Lisa M
authors: LM
authors: Ellerby
authors: Robert E
authors: RE
authors: Hughes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006816:Huntington Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010918:Pizotyline / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D010918:Pizotyline
references: Pharmacol Biochem Behav. 2003 Jan;74(2):371-80
references: 12479957
references: Psychopharmacology (Berl). 1992;107(2-3):379-84
references: 1352056
references: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6809-14
references: 10829080
references: J Neurosci. 2010 Jan 6;30(1):316-24
references: 20053912
references: Brain Res. 2004 Sep 3;1019(1-2):246-54
references: 15306259
references: J Biol Chem. 2002 Feb 22;277(8):6703-7
references: 11733534
references: Hum Mol Genet. 2006 Jan 15;15(2):273-85
references: 16330479
references: J Biol Chem. 2010 Nov 26;285(48):37445-57
references: 20858895
references: Neurochem Int. 2010 Jan;56(2):208-12
references: 19852992
references: Exp Neurol. 2005 May;193(1):65-74
references: 15817265
references: Chem Biol. 2010 Nov 24;17(11):1189-200
references: 21095569
references: Pharmacol Biochem Behav. 2005 Oct;82(2):404-10
references: 16253319
references: Drugs. 2010 Mar 26;70(5):561-71
references: 20329804
references: Psychopharmacology (Berl). 1995 Oct;121(3):347-56
references: 8584617
references: Cell Mol Neurobiol. 2010 Oct;30(7):1107-15
references: 20644995
references: Neuroreport. 2000 Nov 27;11(17):3751-7
references: 11117485
references: J Pharmacol Exp Ther. 1999 Feb;288(2):820-6
references: 9918594
references: Cell. 1995 Jun 2;81(5):811-23
references: 7774020
references: Br J Pharmacol. 2010 Jun;160(3):747-61
references: 20590577
references: Neuron. 2010 Jul 29;67(2):199-212
references: 20670829
references: Psychopharmacology (Berl). 1995 May;119(2):222-30
references: 7659770
references: Neuropharmacology. 1997 Apr-May;36(4-5):621-9
references: 9225287
references: Am J Med Genet A. 2003 Jun 15;119A(3):279-82
references: 12784292
references: Biol Pharm Bull. 2006 Aug;29(8):1645-50
references: 16880620
references: Cell Mol Life Sci. 2006 Nov;63(22):2642-60
references: 17041811
references: Hum Mol Genet. 2010 Apr 15;19(R1):R98-R102
references: 20421366
references: Growth Factors. 2006 Mar;24(1):21-44
references: 16393692
references: Bioessays. 2012 Feb;34(2):142-8
references: 22334892
references: Life Sci. 2000 Nov 24;68(1):29-39
references: 11132243
references: Med J Aust. 2007 Aug 6;187(3):142-6
references: 17680738
references: NeuroRx. 2005 Jul;2(3):447-64
references: 16389308
references: Psychopharmacology (Berl). 2002 Jul;162(2):168-77
references: 12110994
references: Hum Mol Genet. 2000 Nov 22;9(19):2799-809
references: 11092756
references: Naunyn Schmiedebergs Arch Pharmacol. 1997 Jun;355(6):682-8
references: 9205951
references: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14525-30
references: 17726098
references: PLoS Curr. 2010 Oct 28;2:RRN1193
references: 21037797
references: Neuropsychopharmacology. 2003 Mar;28(3):519-26
references: 12629531
references: Neuron. 2003 Jul 17;39(2):227-39
references: 12873381
references: J Pharmacol Exp Ther. 1997 Oct;283(1):216-25
references: 9336327
references: FASEB J. 2008 Apr;22(4):1083-93
references: 18029446
references: J Biol Chem. 2010 Jul 9;285(28):21537-48
references: 20442398
references: Am J Hum Genet. 2009 Mar;84(3):351-66
references: 19249009
references: Hum Mol Genet. 2011 Jan 15;20(2):261-70
references: 20952447
references: Hum Mol Genet. 2011 Jan 15;20(2):294-300
references: 20977989