Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“…Resveratrol treatment has also been shown to be beneficial in a model of Alzheimer's disease (SAMP8 mice) (Porquet et al 2013). In vivo treatment with Resveratrol (160 mg/kg) from a pre-symptomatic timepoint (8 weeks old) significantly improved upper and lower motor neuron survival and increased life span in SOD1 G93A mice (Mancuso et al 2014). However, Resveratrol has a very limited safety profile available and has not been used in many clinical trials to date (Patel et al 2011, Smoliga et al 2011.…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…Studies using resveratrol, a polyphenolic compound that activates SIRT1 and other targets, have shown mixed effects in the SOD1 G93A mouse model of ALS, with some dosing regimens showing protection and others indicating no effect on disease progression (Han, Choi, Soon Shin, & Kang, 2012; Kim et al, 2007; Mancuso et al, 2014; Markert, Kim, Gifondorwa, Childers, & Milligan, 2010; Song, Chen, & Zhang, 2014). Overexpressing PGC1α slows ALS‐related pathologies in SOD1 G93A mice (Zhao et al, 2011), and more directly, elevating SIRT1 expression using the prion promoter has shown lifespan extension in the SOD1 G93A low copy transgenic mouse line (Watanabe et al, 2014).…”

Diffusion Efficiency and Bioavailability of Resveratrol Administered to Rat Brain by Different Routes: Therapeutic Implications

“…Resveratrol (trans-3,5,4′-trihydroxystilbene, C 14 H 12 O 3 , MW 228.2), a polyphenolic compound, possesses multifaceted pharmacological activities [1][2][3] and, importantly, resveratrol is not harmful to normal cells/tissues of the central nervous system [4,5]. Because of the lipophilic nature of resveratrol, it is able to penetrate the cell membrane via simple diffusion.…”