Neuroprotective effects of violacein in a model of inherited amyotrophic lateral sclerosis

Silvia Olivera-Bravo,Sofía Cerri,Lucía Canclini,Eugenia Isasi,Diego Alem,Danilo Davyt,María Noel Cuitiño,Paola Rodríguez,Marta Marco,Matías Stancov,Gabriel Otero Damianovich,Carmen Bolatto,Pablo Díaz-Amarilla,Daniela Boragno,Karina Hernández Mir,Fernanda Larrambembere

doi:10.1038/s41598-022-06470-7

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive death of motor neurons and muscle atrophy, with defective neuron-glia interplay and emergence of aberrant glial phenotypes having a role in disease pathology. Here, we have studied if the pigment violacein with several reported protective/antiproliferative properties may control highly neurotoxic astrocytes (AbAs) obtained from spinal cord cultures of symptomatic hSOD1G93A rats, and if it could be neuroprotective in this ALS experimental model. At concentrations lower than those reported as protective, violacein selectively killed aberrant astrocytes. Treatment of hSOD1G93A rats with doses equivalent to the concentrations that killed AbAs caused a marginally significant delay in survival, partially preserved the body weight and soleus muscle mass and improved the integrity of the neuromuscular junction. Reduced motor neuron death and glial reactivity was also found and likely related to decreased inflammation and matrix metalloproteinase-2 and -9. Thus, in spite that new experimental designs aimed at extending the lifespan of hSOD1G93A rats are needed, improvements observed upon violacein treatment suggest a significant therapeutic potential that deserves further studies.

Highlights

Of undifferentiated astrocytes such as high levels of S100β and connexin 43, low expression of glial fibrillary acidic protein (GFAP)[11], absence of gliofilaments and abundance of m icrotubules[14]
We have proposed that violacein could selectively control the aberrant glial cells named as Aberrant astrocytes (AbAs) that emerged during disease progression[11,14] in the rat Amyotrophic lateral sclerosis (ALS) model hSOD1G93A5, and have tested if the treatment of these animals with violacein may result in protective effects
Natural products are attractive sources of therapeutic agents, with the majority of commercially available drugs derived from microorganisms, plants and animals because of their multiple beneficial a ctions[18–22,30]

Summary

Introduction

Of undifferentiated astrocytes such as high levels of S100β and connexin 43, low expression of glial fibrillary acidic protein (GFAP)[11], absence of gliofilaments and abundance of m icrotubules[14]. Violacein actions linked to inflammation include the maintaining of the balance between pro- and anti-inflammatory c ytokines[22] and the modulation of tumor necrosis factor alpha (TNF-α)[22,31] or interleukin (IL) 630 levels Some of these actions include the inhibition of the proteolytic activity of matrix metalloproteinase (MMP) -2 and downregulation of the interactions that control cell migration and invasion in breast cancer cell lines[31]. Chronic n euroinflammation[8,11,31–33] may promote the emergence of reactive neurotoxic glial phenotypes that release pro-inflammatory molecules amplifying and perpetuating CNS damaging cascades[11,34] Violacein could disrupt this deleterious feedback through different mechanisms and targets. The violacein protective actions could extend to the CNS To validate this hypothesis, we have proposed that violacein could selectively control the aberrant glial cells named as AbAs that emerged during disease progression[11,14] in the rat ALS model hSOD1G93A5, and have tested if the treatment of these animals with violacein may result in protective effects

Methods

Results

Conclusion