title: Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1.
abstract: BACKGROUND
  Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.
  
  
  RESULTS
  Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.
  
  
  CONCLUSIONS
  These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.
authors.affiliation: I,R,C,C,S, Neuromed, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.
authors.forename: Serena
authors.initials: S
authors.lastname: Notartomaso
authors.forename: Cristina
authors.initials: C
authors.lastname: Zappulla
authors.forename: Francesca
authors.initials: F
authors.lastname: Biagioni
authors.forename: Milena
authors.initials: M
authors.lastname: Cannella
authors.forename: Domenico
authors.initials: D
authors.lastname: Bucci
authors.forename: Giada
authors.initials: G
authors.lastname: Mascio
authors.forename: Pamela
authors.initials: P
authors.lastname: Scarselli
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazio
authors.forename: Filippo
authors.initials: F
authors.lastname: Weisz
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Michele
authors.initials: M
authors.lastname: Signore
authors.forename: Aldamaria
authors.initials: A
authors.lastname: Puliti
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000577:Amides; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D009536:Niacinamide