Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease

Br J Pharmacol. 2012 Aug;166(8):2317-30. doi: 10.1111/j.1476-5381.2012.01943.x.


Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Anilides / therapeutic use*
  • Animals
  • Biomarkers
  • Cyclohexanecarboxylic Acids / therapeutic use*
  • Dopamine / metabolism
  • Inflammation / metabolism
  • Male
  • Neuroprotective Agents / therapeutic use*
  • Oxidopamine / toxicity*
  • Parkinsonian Disorders / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Substantia Nigra / drug effects


  • Anilides
  • Biomarkers
  • Cyclohexanecarboxylic Acids
  • Neuroprotective Agents
  • Receptors, Metabotropic Glutamate
  • VU 0155041
  • Oxidopamine
  • Dopamine
  • metabotropic glutamate receptor 4