Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity.
Destruction of spiral ganglion neurons (SGNs) induced by injury and toxins is one of the major causes for hearing loss. Here we report that neurotrophin-4/5 (NT-4/5), a member of the nerve growth factor family, promoted survival of postnatal rat SGNs up to threefold in dissociated cell cultures. The survival-promoting potency of NT-4/5 was equivalent to that of BDNF and stronger than that of NT-3. In contrast, NGF showed no detectable effects. Immunohistochemistry, with TrkB and TrkA antisera, revealed that these neurons produced TrkB protein, the functional receptor for NT-4/5 and BDNF, but not TrkA protein, the high-affinity receptor for NGF. The survival-promoting activity of NT-4/5 was completely inhibited by TrkB-IgG fusion protein. These results suggest that NT-4/5 is a specific survival factor for SGNs. In addition, NT-4/5 protected the SGNs from neurotoxic effects of the anti-cancer drug, cisplatin. Thus, NT-4/5 may have therapeutic value in preventing hearing impairment caused by damage to primary auditory afferent neurons.
Zheng
J L
JL
Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
Stewart
R R
RR
Gao
W Q
WQ
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D007074:Immunoglobulin G / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020933:Neurotrophin 3; D051381:Rats; D017208:Rats, Wistar; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013136:Spiral Ganglion / Q000166:cytology*
D019208:Brain-Derived Neurotrophic Factor; D007074:Immunoglobulin G; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; C071951:neurotrophin 5; C073922:neurotrophin 4; D002945:Cisplatin