Blocking metabotrobic glutamate receptor 5 by the negative allosteric modulator CTEP improves disease course of ALS in SOD1G93A mice.

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The pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. One and 5 metabotropic Glu (mGlu1,5) receptors are over-expressed in ALS and regulate cellular disease processes. We reported that mGlu5 receptor expression and function are already altered at early symptomatic stages in the SOD1G93A mouse model of ALS and that knocking-down mGlu5 receptors in SOD1G93A mice improved the disease scenario.We treated SOD1G93A mice with 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy) phenyl)-1H-imidazol-4-yl)ethynyl)-pyridine (CTEP), an orally available mGlu5 receptor negative allosteric modulator (NAM), at the doses of 2 mg/kg/48h or 4 mg/kg/24h from day 90, an early symptomatic disease stage. Disease progression was studied by behavioural and histological approaches.CTEP, dose dependently ameliorated clinical features in SOD1G93A mice. The lower dosage increased survival and improved motor skills in female mice, with barely positive effects in male mice. The higher dosage significantly ameliorated disease symptoms and survival in both males and females, being females more responsive. CTEP also reduced motor neurons death, astrocyte and microglia activation and abnormal Glu release in the spinal cord but no differences were observed between male and female mice. No differences were also observed as to the drug access to the brain.Our previous and present results suggest that mGlu5 receptor represents a promising target for the treatment of ALS and highlight mGlu5 receptor NAMs as favourable pharmacological tools with possible translational perspectives.

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Authors: Marco Milanese, Tiziana Bonifacino, Carola Torazza, Francesca Provenzano, Mandeep Kumar, Silvia Ravera, Arianna Roberta Zerbo, Giulia Frumento, Matilde Balbi, T P Nhung Nguyen, Nadia Bertola, Sara Ferrando, Maurizio Viale, Aldo Profumo, Giambattista Bonanno