TY  - JOUR
AU  - Milanese, Marco
AU  - Bonifacino, Tiziana
AU  - Torazza, Carola
AU  - Provenzano, Francesca
AU  - Kumar, Mandeep
AU  - Ravera, Silvia
AU  - Zerbo, Arianna Roberta
AU  - Frumento, Giulia
AU  - Balbi, Matilde
AU  - Nguyen, Quynh Tram Julia
AU  - Bertola, Nadia
AU  - Ferrando, Sara
AU  - Viale, Maurizio
AU  - Profumo, Aldo
AU  - Bonanno, Giambattista
TI  - Blocking glutamate mGlu5 receptors with the negative allosteric modulator CTEP improves disease course in SOD1G93A mouse model of amyotrophic lateral sclerosis.
JO  - British journal of pharmacology
VL  - 178
IS  - 18
SN  - 1476-5381
CY  - Malden, MA
PB  - Wiley
M1  - DZNE-2021-00664
SP  - 3747-3764
PY  - 2021
AB  - 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. Two metabotropic glutamate receptors (mGlu1 and mGlu5 ) are overexpressed in ALS and regulate cellular disease processes. Expression and function of mGlu5 receptors are altered at early symptomatic stages in the SOD1G93A mouse model of ALS and knockdown of mGlu5 receptors in SOD1G93A mice improved disease progression.We treated male and female 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), using doses of 2 mg·kg-1 per 48 h or 4 mg·kg-1 per 24 h 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 dose increased survival and improved motor skills in female mice, with barely positive effects in male mice. Higher doses significantly ameliorated disease symptoms and survival in both males and females, females being more responsive. CTEP also reduced motor neuron death, astrocyte and microglia activation, and abnormal glutamate release in the spinal cord, with equal effects in male and female mice. No differences were also observed in CTEP access to the brain.Our results suggest that mGlu5 receptors are promising targets for the treatment of ALS and highlight mGlu5 receptor NAMs as effective pharmacological tools with translational potential.
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Animals
KW  - Disease Models, Animal
KW  - Disease Progression
KW  - Female
KW  - Glutamic Acid
KW  - Male
KW  - Mice
KW  - Mice, Transgenic
KW  - Receptor, Metabotropic Glutamate 5
KW  - Spinal Cord
KW  - Superoxide Dismutase
KW  - Superoxide Dismutase-1: genetics
KW  - 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) (Other)
KW  - SOD1G93A mice (Other)
KW  - amyotrophic lateral sclerosis (ALS) (Other)
KW  - in vivo pharmacological treatment (Other)
KW  - metabotropic glutamate receptor 5 (mGlu5 receptor) (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8457068
C6  - pmid:33931856
DO  - DOI:10.1111/bph.15515
UR  - https://pub.dzne.de/record/155465
ER  -