The mGlu5 receptor negative allosteric modulator CTEP as a pharmacological tool to dampen ALS disease progression: in-vivo preclinical studies and clinical perspectives

Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease due to a progressive degeneration of motor neurons (MNs). The aetiology is still largely obscure, and several mechanisms have been proposed, including glutamate (Glu)-mediated excitotoxicity. In this context, group I metabotropic Glu receptors (mGluR1/5) play an active role, since their expression and functions are altered, especially in glial cells. Moreover, we previously showed that group I mGluRs sustains the excessive Glu release in the spinal cord of the SOD1G93A mouse model of ALS, and that this alteration is already present at the onset of the pathology. We also demonstrated that the constitutive in-vivo genetic ablation of mGluR5 in the SOD1G93A mouse model of ALS delayed the disease onset and prolonged survival probability. These effects were paralleled by decreased astrocyte and microglia activation, normalization of the excessive Glu release, and significant MNs preservation, compared to age matched SOD1G93A mice. Based on our results, we investigated the effect of a pharmacological treatment with the orally available and selective mGluR5 negative allosteric modulator CTEP, in ALS mice. We treated SOD1G93A mice with two doses of CTEP (2 mg/kg/48h or 4 mg/kg/24h), starting at 90 days of life, as early symptomatic stage. Disease progression was monitored by in-vivo functional studies and ex-vivo histological analyses, in both male and female animals. The pharmacological modulation of mGluR5 by CTEP demonstrated beneficial effects both in behavioural and histological analyses. Concerning the in-vivo studies, CTEP treatment dose dependently slowdown the progression of the pathology, ameliorated functional outcomes and increased the survival probability, in SOD1G93A mice. Interestingly, the lower dosage increased survival and improved motor skills in female mice, while it barely produced beneficial effects in male mice. The higher dose of CTEP further ameliorated disease symptoms and survival in both male and female SOD1G93A mice compared to controls. CTEP treatment also decreased astrocyte and microglia activation, reduced the excessive Glu release, and preserved MN death in the spinal cord of treated mice. We couldn’t observe sex difference in the ex-vivo histological studies as well as we did not detect significant differences in CTEP concentration measured in blood, liver, and CNS tissues, comparing male and female mice. Our results demonstrate that the pharmacological blockade of the mGlu5 receptor, produces beneficial effects in the SOD1G93A mouse model of ALS. The in-vivo effects can be ascribed to a reduced reactive gliosis that in turn contributes to preserve MN. Our pre-clinical evidence suggests mGluR5 as a promising target and highlights the potential application of mGluR5 modulators as favorable pharmacological tools that can be tested in clinical trials for ALS treatment.