Kern R C, Conley D B, Haines G K, Robinson A M
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.
Laryngoscope. 2004 Dec;114(12):2200-4. doi: 10.1097/01.mlg.0000149458.21501.6f.
OBJECTIVES/HYPOTHESIS: 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.
Histological analysis of animal olfactory tissue.
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.
Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals.
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.
目的/假设：自20世纪70年代初以来，嗅觉丧失的治疗方法变化甚微，尽管在嗅觉分子生物学的理解方面取得了巨大进展。作者实验室最近的研究表明，临床嗅觉功能障碍的最常见原因，包括鼻窦炎，似乎与嗅觉感觉神经元凋亡死亡增加有关。尽管嗅觉上皮具有再生能力，但这似乎导致功能成熟的嗅觉感觉神经元数量下降。本研究评估了抗生素米诺环素抑制嗅觉感觉神经元凋亡的能力。已知这种药物除了具有抗感染特性外，还能抑制凋亡。嗅觉感觉神经元凋亡是由手术去传入神经（“嗅球切除术”）触发的，这是标准的实验模型。早期研究表明，嗅球切除术和鼻窦炎在嗅觉感觉神经元中引发类似的蛋白水解酶级联反应。
对动物嗅觉组织进行组织学分析。
对小鼠进行单侧嗅球切除术，以诱导凋亡性嗅觉感觉神经元死亡，术前12小时及术后每12小时腹腔注射45mg/kg米诺环素直至死亡，或不注射。在嗅球切除术后2天和4天处死小鼠，通过免疫组织化学分析评估caspase-3的激活情况和嗅觉感觉神经元的存活情况。
与未治疗的动物相比，米诺环素在术后2天导致细胞死亡部分受到抑制。
面对强大的促凋亡刺激，米诺环素可抑制嗅觉感觉神经元死亡。这种药物耐受性良好，目前正在进行人体试验，用于治疗与凋亡相关的多种神经系统疾病。目前的结果表明，米诺环素在外周嗅觉丧失的治疗中可能也有效。
