TY - JOUR
T1 - Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model
AU - Kreple, Collin J.
AU - Searles Nielsen, Susan
AU - Schoch, Kathleen M.
AU - Shen, Tao
AU - Shabsovich, Mark
AU - Song, Yizhe
AU - Racette, Brad A.
AU - Miller, Timothy M.
N1 - Funding Information:
Funding provided by Richard Olney Clinician Scientist Development Award in ALS, funded by the ALS Association, and the American Brain Foundation (C.J.K.); Washington University in St. Louis – Hope Center for Neurological Disorders (B.A.R., T.M.M., and S.S.N.); The Michael J. Fox Foundation for Parkinson's Research (B.A.R. and S.S.N.); Tambourine/Northeast ALS Consortium (B.A.R.); NIH/NIEHS K01ES028295 (S.S.N.), and K24ES017765 (B.A.R.); NIH/NINDS R01NS078398 (T.M.M.); Lyle Rakers Foundation (T.M.M.); and a gift from Rodger and Paula Riney. Histological experiments were performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI‐CORE‐2015‐505 and CDI‐CORE‐2019‐813) and the Foundation for Barnes‐Jewish Hospital (3770 and 4642).
Publisher Copyright:
© 2023 American Neurological Association.
PY - 2023/5
Y1 - 2023/5
N2 - Objective: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. Methods: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. Results: We observed previously established medical associations for MND and an inverse dose–response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. Interpretation: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881–892.
AB - Objective: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. Methods: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. Results: We observed previously established medical associations for MND and an inverse dose–response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. Interpretation: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881–892.
UR - http://www.scopus.com/inward/record.url?scp=85147349466&partnerID=8YFLogxK
U2 - 10.1002/ana.26600
DO - 10.1002/ana.26600
M3 - Article
C2 - 36627836
AN - SCOPUS:85147349466
SN - 0364-5134
VL - 93
SP - 881
EP - 892
JO - Annals of Neurology
JF - Annals of Neurology
IS - 5
ER -