Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice
| Autor: | Oluwamolakun Bankole, Ilaria Scambi, Edoardo Parrella, Matilde Muccilli, Roberta Bonafede, Ermanna Turano, Marina Pizzi, Raffaella Mariotti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
QH301-705.5 Mice Transgenic AMP-Activated Protein Kinases Catalysis Histones Inorganic Chemistry Mice Sirtuin 1 Animals Biology (General) Physical and Theoretical Chemistry motor neuron QD1-999 Molecular Biology Spectroscopy epigenetics Superoxide Dismutase Valproic Acid Amyotrophic Lateral Sclerosis Organic Chemistry NF-kappa B General Medicine Computer Science Applications Histone Deacetylase Inhibitors Chemistry Disease Models Animal Resveratrol valproate Female amyotrophic lateral sclerosis resveratrol |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 3; Pages: 1047 International journal of molecular sciences International Journal of Molecular Sciences, Vol 23, Iss 1047, p 1047 (2022) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23031047 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice. |
| Databáze: | OpenAIRE |
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