Blocking glutamate mGlu₅ receptors with the negative allosteric modulator CTEP improves disease course in SOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract

Background and PurposeThe 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 SOD1 G93A mouse model of ALS and that knocking-down mGlu5 receptors in SOD1 G93A mice improved the disease scenario. Experimental ApproachWe treated SOD1 G93A mice with 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy) phenyl)-1Himidazol-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. Key ResultsCTEP, dose dependently ameliorated clinical features in SOD1 G93A 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.

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

“…Based on the above evidence, as the subsequent translational application of the data reported in this paper, our research groups are currently involved in carrying out studies aimed at testing the efficacy of MSC-derived EVs intranasally administered in SOD1 G93A ALS mice by performing a comprehensive panel of in vivo functional studies, as well as ex vivo histological and molecular analyses, as previously reported [ 89 , 90 , 91 , 92 ].…”

The Physio-Pathological Role of Group I Metabotropic Glutamate Receptors Expressed by Microglia in Health and Disease with a Focus on Amyotrophic Lateral Sclerosis

“…Unfortunately, the total genetic ablation of mGluR1 receptor in the SOD1 G93A mouse model produced a very serious ataxic and detrimental phenotype (unpublished results), thus excluding possible therapeutic approaches using mGluR1 pharmacological antagonists. Then, we tested the effect of the chronic oral administration of the mGluR5 NAM CTEP [ 311 ]. Differing from the mGluR5 genetic ablation, the pharmacological treatment was started after symptom onset and maintained until the late symptomatic stage of the disease [ 311 ].…”

Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

“…Perhaps confusingly, the same group treated SOD1 G93A mice with the mGlu 5 NAM CTEP and found that low doses improved motor skills and prolonged survival in female mice only. With an increased CTEP dose, improvements were seen in both sexes, but with improvements in the female mice being more pronounced ( Milanese et al, 2021 ). Why genetic blockade of mGlu 5 and blockade with a NAM showed differences in sex-specific responses requires further thought.…”

“…As with astrogliosis, the genetic or pharmacological blockade of mGlu 5 in AD and ALS rodent models led to a reduction in microgliosis ( Bonifacino et al, 2017 ; Abd-Elrahman K. S. et al, 2020 ; Milanese et al, 2021 ). As reactive microglia have a neurotoxic effect mediated by the secretion of proinflammatory cytokines and chemokines and the release of excitotoxic levels of glutamate ( Barger and Basile, 2001 ; Hemonnot et al, 2019 ), it could be assumed that reducing their levels would be neuroprotective.…”