University of Genoa, Genoa, Italy
Posters & Accepted Abstracts: J Neurol Neurosci
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) death, whose aetiologyis not clear, although glutamate (Glu)-mediated excitotoxicity represents one major factor. Group I metabotropic glutamate receptors (mGluR1 and mGluR5) may be implicated in ALS, since they are largely over-expressed during disease progression and involved in altered cellular processes. In this scenario, we recently demonstrated that mGluR1 and mGluR5 at Glu synapses produces abnormal Glu release and that knockingdown mGluR1 in SOD1G93A mice significantly prolongs survival and ameliorates disease progression.
Aim. To study the function of mGluR5 in ALS, we investigated the effects of the genetic down-regulation of mGluR5in SOD1G93A mice (SOD1G93AmGluR5+/-) or its ablation (SOD1G93AmGluR5-/-) and the pharmacological treatment of SOD1G93A mice with the mGluR5 NAM, CTEP.
Results. SOD1G93AmGluR5+/- mice showed delayed disease onset and prolonged survival probability, accompanied by spinal MN preservation, decreased astrocyte and microglia activation and normalization of the excessive cytosolic [Ca2+] I and Glu release. Unexpectedly, motor skills were improved in male SOD1G93AmGluR5+/- mice only. SOD1G93AmGluR5-/- presented a more evident amelioration of all disease features, including motor skills, both in males and females. Furthermore, we treated 90 days-old SOD1G93A mice with CTEP (2mg/kg/48hs;4mg/kg/24hs) until death. The lower dose CTEP-treated-SOD1G93A mice showed a significant prolonged survival probability only in female mice, paralleled by improved clinical parameters. The higher dose CTEP produced a marked clinical amelioration, both in female and male SOD1G93A mice.
Conclusion. These results support the hypothesis that mGluR5 represents a useful target to counteract ALS.