NDLI: Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

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Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

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NeuroRX : Volume 9, Issue 3, July 2012

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Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Content Provider	Springer Nature Link
Author	Mancuso, Renzo Oliván, Sara Rando, Amaya Casas, Caty Osta, Rosario Navarro, Xavier
Copyright Year	2012
Abstract	Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1$^{G93A}$ mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1$^{G93A}$ animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca$^{2+}$ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.
Starting Page	814
Ending Page	826
Page Count	13
File Format	PDF
ISSN	19337213
Journal	NeuroRX
Volume Number	9
Issue Number	4
e-ISSN	18787479
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-08-31
Publisher Institution	American Society for Experimental NeuroTherapeutics
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Motoneuron disease Amyotrophic lateral sclerosis Sigma-1 receptor PRE-084 SOD1$^{G93A}$ mice Neurosciences Neurology Neurobiology Neurosurgery
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Pharmacology Pharmacology (medical)

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