Simvastatin treatment induces morphology alterations and apoptosis in murine cochlear neuronal cells.
CONCLUSIONS
Simvastatin presented neurodegenerative morphological changes and cell death via its specific inhibition of mevalonate pathway induced apoptosis in cultured cochlear neuronal cells. These findings might contribute to understanding the auditory neurobiological effects of HMG-CoA reductase inhibitors.


OBJECTIVE
The statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that are widely used as anti-hypercholesterol drugs because of their beneficial cardiovascular effects. However, the effects of statins in neuronal cells are controversial, and no studies have examined the effect of statins in cochlear neuronal cells. The objective of this study was to evaluate the direct effect of simvastatin on cochlear neuronal cells and examine the mechanisms underlying these effects.


METHODS
Cultured mouse cochlear neuroblasts (VOT-33) and primary rat cochlear explants containing spiral ganglion neurons were treated with simvastatin in the absence or presence of mevalonate.


RESULTS
Simvastatin caused a loss of the cytoplasmic projections in VOT-33. In primary rat cochlear nerve cells, simvastatin decreased staining for NF200, a neuro-cytoskeletal protein. We also found that simvastatin-induced VOT-33 apoptosis, as indicated by accumulation of the sub G0/G1 fraction, DNA-ladder formation, and caspase-3 activation. The above-mentioned effects were abolished by mevalonate treatment.
Park
Do-Sim
DS
Department of Laboratory Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan, Korea.
So
Hong-Seob
HS
Lee
Jeong-Han
JH
Park
Hyun-Young
HY
Lee
Young-Jin
YJ
Cho
Ji-Hyun
JH
Yoon
Kui-Hyun
KH
Park
Channy
C
Yun
Kijung
K
Park
Raekil
R
D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003056:Cochlear Nerve / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000633:toxicity*; D013136:Spiral Ganglion / Q000187:drug effects* / Q000473:pathology
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D053148:Caspase 3; D008798:Mevalonic Acid