title: Reducing systemic hypermetabolism by inducing hypothyroidism does not prolong survival in the SOD1-G93A mouse.
abstract: ALS is commonly associated with a hypermetabolic state. In this study, we assess whether inhibition of this hypermetabolism via the induction of hypothyroidism can forestall disease onset and prolong life in the SOD1-G93A mouse. We treated a cohort of 16 SOD1-G93A mice with methimazole, a potent inhibitor of thyroid hormone synthesis and followed a second group of 23 untreated littermate control animals from approximately five weeks of age onward. Total thyroxine (T4) levels, weights, and rectal temperatures were obtained on a regular basis and animals were sacrificed when they were no longer able to feed themselves. Results revealed that T4 levels were effectively suppressed within two weeks of drug initiation. However, there was no significant difference between the two groups either in terms of clinical disease onset (120.1±9.3 days for treated animals and 116.7±6.3 days for untreated animals) or in terms of survival (131.4±11.7 days for treated animals and 134.0±10.0 days for untreated animals). A correlation analysis between mean T4 levels for each animal versus survival showed that, contrary to our hypothesis, higher T4 levels correlated with longer survival. In conclusion, these studies show that drug-induced hypothyroidism does not alter the disease course in the SOD1-G93A ALS mouse.
authors.affiliation: Department of Neurology and Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jill M
authors.initials: JM
authors.lastname: Paulson
authors.forename: Felix D
authors.initials: FD
authors.lastname: Ye
authors.forename: Minhee
authors.initials: M
authors.lastname: Sung
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.forename: Seward B
authors.initials: SB
authors.lastname: Rutkove
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D013956:Antithyroid Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D018572:Disease-Free Survival; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism*; D008660:Metabolism / Q000187:drug effects*; D008713:Methimazole / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics*; D013961:Thyroid Gland / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D013956:Antithyroid Agents; D008713:Methimazole; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase