Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity

Abstract

We are grateful to Dr. Franz Hefti for his inspiration and val uabl e suggestions and Dr. Arnon Rosenthal for helpful discussions. We also thank Davi d Shelton for providing TrkB-IgC and T&C-IgG fusion proteins,

Trophic Support of Cultured Spiral Ganglion Neurons by Depolarization Exceeds and Is Additive with that by Neurotrophins or cAMP and Requires Elevation of [Ca2+]iwithin a Set Range

“…After 48 hr in culture in N2 medium with no additional trophic agents (control medium), fewer than 10 neurons remained alive in each well. As shown in Figure 1 A, the neurotrophins NT-3 and BDNF promoted survival in a dose-dependent manner, with the effect saturating at 100 ng /ml, as has been shown previously (Lefebvre et al, 1994;Pirvola et al, 1994;Zheng et al, 1995). The permeant cAMP analog chlorphenylthio-cAMP (cpt-cAMP) promoted survival, with a maximal effect (at 1 mM), quantitatively comparable with the effect of the neurotrophins.…”

“…Mice homozygous for NT-3 knockout are born lacking Ͼ85% of the SGNs (Fariñas et al, 1994;Ernfors et al, 1995), whereas mice homozygous for BDNF knockout show only a small loss of SGNs at birth (Conover et al, 1995;Ernfors et al, 1995). Nonetheless, BDNF, like NT-3, supports survival of cultured embryonic and postnatal SGNs (Avila et al, 1993;Lefebvre et al, 1994;Pirvola et al, 1994;Vazquez et al, 1994;Zheng et al, 1995). It is not clear why only NT-3, and not BDNF, is necessary for prenatal trophic support of SGNs; possibly, SGNs lack access to sufficient BDNF at this time.…”

“…SGNs express TrkB and TrkC (Ylikoski et al, 1993;Schecterson and Bothwell, 1994) and are supported by BDNF, NT-4, and NT-3 in vitro (Avila et al, 1993;Vazquez et al, 1994;Zheng et al, 1995). SGNs can receive target-derived neurotrophic support by either BDNF or NT-3 in vivo, because both are expressed in the cochlear nucleus (Lefebvre et al, 1994).…”

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

“…Within the developing cochlea, neurotrophins are differentially distributed, with NT-3 expressed predominantly in the supporting cells of the organ of Corti, and BDNF expressed only in hair cells (Farinas, et al, 2001). Further, many in vivo studies have reported that exogenous administration of neurotrophins (Ernfors et al, 1996;Kanzake et al, 2002;McGuinnes and Shepherd, 2005;Miller et al, 1997;Schindler et al 1995;Shepherd et al, 2005;Staecker et al, 1996Staecker et al, , 1998Zheng et al, 1995;Zheng and Gao, 1996) and other neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) (Ylikoski et al, 1998;Yagi et al, 2000) can protect SG neurons in adult animals from injury and promote improved survival after various insults, including ototoxic drugs.…”

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

“…Neurotrophic factors are known to enhance neuronal survival. Several studies report neurotrophin protection of spiral ganglion neurons in the primary auditory pathway from the neurotoxic effects of the anti-cancer drug, cisplatin (Bowers et al, 2002;Zheng et al, 1995). Nerve growth factor (NGF) is effective against the toxic sympathetic nerve injury induced by cisplatin, taxol, and vincristine (Fischer et al, 2001;Hayakawa et al, 1998;Hayakawa et al, 1999;Peterson and Crain, 1982) Antineoplastic agents attack cancer cells via different mechanisms; therefore, the actions of neuroprotectants would conceivably differ as well.…”