The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington's disease.
Chronic glutamate mediated excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Both, inhibition of glutamate release through stimulation of presynaptic metabotropic glutamate receptor (mGluR) 2 and blockade of postsynaptic mGluR5 have been demonstrated to be neuroprotective against excitotoxicity. R6/2 HD transgenic mice which express an expanded CAG triplet repeat serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with either the mGluR2 agonist LY379268 (1.2 mg/kg) or with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (100 mg/kg) orally from a presymptomatic stage until death to investigate their potential disease modifying effects. We found that survival time in both the MPEP treated mice and the LY379268 treated mice was significantly increased in comparison to placebo treated transgenic controls (14.87+/-0.14 and 14.22+/-0.11 weeks versus 12.87+/-0.11 weeks, respectively). Additionally, the progressive decline in motor coordination of HD transgenic mice as tested with the rotarod test was significantly attenuated in MPEP- but not in LY379268-treated mice. Early pathological hyperactivity, which can be found in placebo treated HD transgenic mice, was significantly attenuated by both MPEP and LY379268 treatment. Immunohistologial examination of HD characteristic neuronal intranuclear inclusion (NII), however, demonstrated no effect on NII formation by either of the treatments applied. These data suggest that inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment in HD.
Department of Neurology, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Johannes
J
Schiefer
Arne
A
Sprünken
Christiane
C
Puls
Hans-Gerd
HG
Lüesse
Anna
A
Milkereit
Eva
E
Milkereit
Verena
V
Johann
Christoph M
CM
Kosinski
D000596:Amino Acids / Q000627:therapeutic use*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011725:Pyridines / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C578936:Grm5 protein, mouse; C118218:LY 379268; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C121465:6-methyl-2-(phenylethynyl)pyridine