ACTH (Acthar Gel) Reduces Toxic SOD1 Protein Linked to Amyotrophic Lateral Sclerosis in Transgenic Mice: A Novel Observation

Hasan Arrat, Thomas J Lukas, Teepu Siddique, Hasan Arrat, Thomas J Lukas, Teepu Siddique

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology and pathology that makes the development of new therapies difficult. ACTH has neurotrophic and myotrophic effects, but has not been tested in an ALS mouse model. The G93A-SOD1 mouse model of ALS was used to test the ability of this drug to delay ALS-like symptoms. We showed that within a specific dose range, ACTH significantly postponed the disease onset and paralysis in the mouse model. To our surprise and of greater significance is that ACTH significantly reduced the levels of soluble SOD1 in the spinal cord and CNS tissues of G93A-SOD1 treated mice as well as cultured fibroblasts.

Conflict of interest statement

Competing Interests: The authors have the following interests. Questcor Pharmaceuticals provided funds to support this project and was the sole source of Acthar gel to be used only in our animal experiments. Questcor is the owner of the drug and has retained rights for its distribution. Questcor is conducting clinical trials for ALS and other diseases. There are no restrictions on data generated during the course of the study. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Therapeutic effects of ACTH on…
Fig 1. Therapeutic effects of ACTH on ALS-like symptoms in G93A-SOD1 mice.
Proportion of onset (A), paralysis (B), and survival (C). Kaplan Meier was used to plot the survival curves.
Fig 2. ACTH has variable dose-dependent effects…
Fig 2. ACTH has variable dose-dependent effects on changes in the weight of G93A-SOD1 transgenic mice.
Panel A shows the fractional weight change of males, while l B shows the change in female mice over the time course of treatment. Error bars are the standard deviation for each point. Bars are not visible when they are smaller than the size of the symbol.
Fig 3. Effect of ACTH on SOD1…
Fig 3. Effect of ACTH on SOD1 protein expression in different parts of the central nervous system.
SOD1 was measured in the corresponding tissue lysates by ELISA and then normalized to GAPDH activity. Ctl: the nontreated animals, SC, spinal cord, CB: cerebellum, BS: brain stem, CX: cortex. n = 6 for the non-treated mice, n = 4 for treated animals. Mice treated with ACTH showed decreased expression of SOD1 protein in spinal cord and selected brain tissues.
Fig 4. Effects of ACTH on SOD1…
Fig 4. Effects of ACTH on SOD1 expression in G93A-SOD1 mouse fibroblasts.
Cells were treated at the indicated concentrations of ACTH (1–39) peptide for 48 hr. Error bars indicate the standard error of the mean (n = 3, * p

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