Valproic acid promotes neural regeneration of olfactory epithelium in adult mice after methimazole-induced damage.
BACKGROUND
Recent experiments have revealed that valproic acid (VPA), a histone deacetylase inhibitor, has neuroregenerative effects in rodent models of spinal cord and optic nerve injury. VPA has a potential to provide a new therapeutic strategy for sensorineural olfactory dysfunction. To elucidate the effects of VPA on regeneration of olfactory sensory neurons, we examined the in vivo effects of oral VPA administration on recovery from methimazole-induced degeneration of olfactory neuroepithelium in mice.


METHODS
Male ICR mice (10 weeks old) were intraperitoneally injected with methimazole (75 mg/kg), an olfactory toxic reagent, to induce degenerative changes in the olfactory neuroepithelium. The effects of daily VPA administration on recovery from methimazole-induced changes were examined histologically.


RESULTS
Oral VPA administration dose dependently enhanced increases in epithelial thickness and number of olfactory marker protein (OMP) positive cells in the olfactory epithelium during recovery from methimazole-induced degeneration. VPA also enhanced early increases in the number of Ki-67(+) and growth-associated protein-43(+) cells during the regeneration of olfactory neuroepithelium.


CONCLUSIONS
VPA administration promotes regeneration of olfactory sensory neurons in damaged neuroepithelium by stimulating the proliferation and differentiation of olfactory precursor cells. VPA has been used for several decades to safely treat neurological disorders. VPA may provide a new therapeutic strategy for the treatment of olfactory dysfunction caused by degeneration of the olfactory neuroepithelium.
Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Takao
T
Ogawa
Kumiko
K
Takezawa
Shino
S
Shimizu
Takeshi
T
Shimizu
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008713:Methimazole / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D009416:Nerve Regeneration; D000857:Olfaction Disorders / Q000139:chemically induced / Q000628:therapy*; D051842:Olfactory Marker Protein / Q000235:genetics / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects
D000927:Anticonvulsants; D019922:GAP-43 Protein; D019394:Ki-67 Antigen; D051842:Olfactory Marker Protein; D008713:Methimazole; D014635:Valproic Acid; D051548:Histone Acetyltransferases