title: Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease.
abstract: OBJECTIVE
  We recently reported that broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the substantia nigra pars compacta using L-2-amino-4-phosphonobutyrate provided functional neuroprotection in the 6-hydroxydopamine lesion rat model of Parkinson's disease. The aim of this study was to establish whether selective activation of the mGlu(4) receptor alone could afford similar functional neuroprotection.
  
  
  METHODS
  The neuroprotective effects of 8 days of supranigral treatment with a positive allosteric modulator of mGlu(4) receptors, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), were investigated in rats with unilateral 6-hydroxydopamine lesions. The effects of VU0155041 treatment on motor function were assessed using both habitual (cylinder test) and forced (adjusted stepping, amphetamine-induced rotations) behavioural tests. Nigrostriatal tract integrity was examined by analysis of tyrosine hydroxylase, dopa decarboxylase or dopamine levels in the striatum and tyrosine hydroxylase-positive cell counts in the substantia nigra pars compacta.
  
  
  RESULTS
  VU0155041 provided around 40% histological protection against a unilateral 6-hydroxydopamine lesion as well as significant preservation of motor function. These effects were inhibited by pre-treatment with (RS)-α-cyclopropyl-4-phosphonophenylglycine, confirming a receptor-mediated response. Reduced levels of inflammatory markers were also evident in the brains of VU0155041-treated animals.
  
  
  CONCLUSIONS
  Allosteric potentiation of mGlu(4) receptors in the substantia nigra pars compacta provided neuroprotective effects in the 6-hydroxydopamine rat model A reduced inflammatory response may contribute, in part, to this action. In addition to the reported symptomatic effects, activation of mGlu(4) receptors may also offer a novel approach for slowing the progressive degeneration observed in Parkinson's disease.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betts
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: Susan
authors.initials: S
authors.lastname: Duty
mesh_terms: D000494:Allosteric Regulation; D000813:Anilides / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects
chemical_list: D000813:Anilides; D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C544970:VU 0155041; D016627:Oxidopamine; D004298:Dopamine; C108823:metabotropic glutamate receptor 4