Treatment of olfactory dysfunction, II: studies with minocycline.
OBJECTIVE
The treatment of anosmia has changed minimally since the early 1970s, despite dramatic advances in the understanding of the molecular biology of olfaction. Recent studies from the authors' laboratory have suggested that most common causes of clinical olfactory dysfunction, including rhinosinusitis, appear to be associated with increased apoptotic death of olfactory sensory neurons. This appears to result in a decline in the number of functioning mature olfactory sensory neurons, despite the capacity of the olfactory epithelium for regeneration. The current study evaluated the ability of the antibiotic minocycline to inhibit olfactory sensory neuron apoptosis. This drug is known to inhibit apoptosis separate from its anti-infective properties. Olfactory sensory neuron apoptosis was triggered by surgical deafferentation ("bulbectomy"), the standard experimental model. Earlier studies have indicated that bulbectomy and sinusitis invoke similar proteolytic enzyme cascades in olfactory sensory neurons.


METHODS
Histological analysis of animal olfactory tissue.


METHODS
Mice underwent unilateral olfactory bulbectomy to induce apoptotic olfactory sensory neuron death, with and without 45 mg/kg intraperitoneal minocycline given 12 hours before surgery and every 12 hours until death. Mice were killed at 2 and 4 days after bulbectomy and assessed for activation of capsase-3 and olfactory sensory neuron survival by immunohistochemical analysis.


RESULTS
Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals.


CONCLUSIONS
Minocycline inhibits olfactory sensory neuron death in the face of a potent pro-apoptotic stimulus. This drug is well tolerated and is currently undergoing human trials for the management of a variety of neurological disorders associated with apoptosis. The current results suggest that minocycline may be efficacious in the management of peripheral olfactory loss as well.
Kern
R C
RC
Department of Otolaryngology-Head and Neck Surgery, Northwestern University School of Medicine, 675 North St. Clair, Suite 15-200, Chicago, IL 60611, U.S.A. r-kern@northwestern.edu
Conley
D B
DB
Haines
G K
GK
Robinson
A M
AM
D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D000857:Olfaction Disorders / Q000188:drug therapy* / Q000473:pathology; D009830:Olfactory Bulb / Q000601:surgery; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology*; D018034:Olfactory Receptor Neurons / Q000187:drug effects*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity
D008911:Minocycline