Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1G⁹³A ALS mice: overlapping effects or limited therapeutic opportunity?

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2-5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1G93A ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4',5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1G93A mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1G93A ALS mice. METHODS: We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests. RESULTS: RSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1G93A animals. CONCLUSIONS: Although combined PRE and RSV treatment significantly ameliorated SOD1G93A mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups.