Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss.
Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss.
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DOI：
10.1021/acs.bioconjchem.8b00022
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发表时间：
2018-04-18
影响因子：
4.7
通讯作者：
McKenna CE
中科院分区：
文献类型：
--
作者：
Kempfle JS;Nguyen K;Hamadani C;Koen N;Edge AS;Kashemirov BA;Jung DH;McKenna CE
Hearing loss affects more than two-thirds of the elderly population, and more than 17% of all adults in the U.S. Sensorineural hearing loss related to noise exposure or aging is associated with loss of inner ear sensory hair cells (HCs), cochlear spiral ganglion neurons (SGNs), and ribbon synapses between HCs and SGNs, stimulating intense interest in therapies to regenerate synaptic function. 7,8-Dihydroxyfla-vone (DHF) is a selective and potent agonist of tropomyosin receptor kinase B (TrkB) and protects the neuron from apoptosis. Despite evidence that TrkB agonists can promote survival of SGNs, local delivery of drugs such as DHF to the inner ear remains a challenge. We previously demonstrated in an animal model that a fluorescently labeled bisphosphonate, 6- FAM-Zol, administered to the round window membrane penetrated the membrane and diffused throughout the cochlea. Given their affinity for bone mineral, including cochlear bone, bisphosphonates offer an intriguing modality for targeted delivery of neurotrophic agents to the SGNs to promote survival, neurite outgrowth, and, potentially, regeneration of synapses between HCs and SGNs. The design and synthesis of a bisphosphonate conjugate of DHF (Ris-DHF) is presented, with a preliminary evaluation of its neurotrophic activity. Ris-DHF increases neurite outgrowth in vitro, maintains this ability after binding to hydroxyapatite, and regenerates synapses in kainic acid-damaged cochlear organ of Corti explants dissected in vitro with attached SGNs. The results suggest that bisphosphonate—TrkB agonist conjugates have promise as a novel approach to targeted delivery of drugs to treat sensorineural hearing loss.
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影响因子：
6.2
作者：
Roelofs, Anke J.;Stewart, Charlotte A.;Coxon, Fraser P.
通讯作者：
Coxon, Fraser P.
影响因子：
3
作者：
Bharadwaj HM;Verhulst S;Shaheen L;Liberman MC;Shinn-Cunningham BG
通讯作者：
Shinn-Cunningham BG
影响因子：
5.3
作者：
Kujawa, SG;Liberman, MC
通讯作者：
Liberman, MC
DOI：
10.1523/jneurosci.2845-09.2009
发表时间：
2009-11-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kujawa SG;Liberman MC
通讯作者：
Liberman MC
影响因子：
64.5
作者：
KLEIN, R;NANDURI, V;BARBACID, M
通讯作者：
BARBACID, M