Selected statins produce rapid spinal motor neuron loss in vitro.
BACKGROUND
Hmg-CoA reductase inhibitors (statins) are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited.


METHODS
We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers.


RESULTS
7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of < 2 μM. Profound neurite loss was observed after 4 days exposure in culture. Other statins were found to produce toxic effects at much higher concentrations. In contrast, no such toxicity was observed for cultured Schwann cells or cortical neurons.


CONCLUSIONS
It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA. bmurins1@jhmi.edu
Beth B
BB
Murinson
Norman J
NJ
Haughey
Nicholas J
NJ
Maragakis
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007150:Immunohistochemistry; D007211:Indoles / Q000633:toxicity; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D017035:Pravastatin / Q000633:toxicity; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000633:toxicity; D013127:Spinal Nerves / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques
D015415:Biomarkers; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D019821:Simvastatin; D017035:Pravastatin