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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. 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.Experimental ApproachWe 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.Key ResultsCTEP 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.Conclusion and ImplicationsOur 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.
Highlights
Background and PurposeThe pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death
The development of effective therapies is urgently required, but it is hampered by the lack of the complete understanding of neuronal and non-neuronal mechanisms underlying the motor neuron (MN) damage and death (Verber et al, 2019)
At least 15 genes have been associated with fALS (Chiò et al, 2014), implying that multiple causes may contribute to the disease (Ferraiuolo et al, 2011; Le Gall et al, 2020)
Summary
Our results suggest that mGlu receptors are promising targets for the treatment of ALS and highlight mGlu receptor NAMs as effective pharmacological tools with translational potential. The genetic ablation of mGlu receptors produced delayed pathology onset and survival improvement, ameliorated motor skills, enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca2+ and normalized the excessive glutamate release in the spinal cord of SOD1G93A mice (Bonifacino et al, 2017; Bonifacino, Provenzano, et al, 2019). With this genetically based functional and biochemical background, we have here explored the effects of the pharmacological. No 26/2014, Annex IV, table 3), but always before the pathology-induced death: humane endpoint, according to the clinical score with complete paralysis of hindlimbs (see Table S1), plus righting reflex (Solomon et al, 2011)
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