Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3

Abstract

Degeneration of auditory neurons occurs after deafening and is associated with damage to the organ of Corti. The administration of neurotrophins can protect auditory neurons against degeneration if given shortly after deafening. However, it is not known whether the delayed administration of neurotrophins, when significant degeneration has already occurred, will provide similar protection. Furthermore, little is known about the effects of neurotrophins on the peripheral processes of the auditory neurons or whether these neurons can resprout. This study examined the morphological effects on auditory neurons following deafening and the administration of brain-derived neurotrophic factor and neurotrophin-3. Results showed that neurotrophins were effective in preventing death of auditory neurons if administered 5 days after deafening and were also effective in preventing the continued loss of neurons if the administration was delayed by 33 days. The peripheral processes of auditory neurons in cochleae that received neurotrophins were in greater number and had larger diameters compared with the untreated cochleae. Localized regions of resprouting peripheral processes were observed in deafened cochleae and were enhanced in response to neurotrophin treatment, occurring across wider regions of the cochlea. These findings have significant implications for an improvement in the performance of the cochlear implant and for future therapies to restore hearing to the deaf.

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

“…The finding of an increase in the number of surviving radial nerve fibers after BDNF treatment is consistent with the results of Wise et al (2005) who reported increased fiber survival after infusion of BDNF and NT-3 in adult guinea pigs and also the findings reported by Glueckert et al (2008) after combined BDNF and aFGF infusion. Importantly, the latter study also used immunohistochemical techniques to demonstrate that both the fibers in the osseous spiral lamina and ectopic sprouting fibers were afferent peripheral processes of SG neurons.…”

“…Profound deafness has been reported to result in reduction in the size of SG neuron perikarya in many previous studies and in various deaf animal models (Agterberg et al 2008(Agterberg et al , 2009Araki et al 1998;Elverland and Mair 1980;Glueckert et al 2008;Leake et al 1999Leake et al , 2007Leake et al , 2011; Leake and Hradek 1988;McGuinness and Shepherd 2005;Shepherd et al 2005;Wise et al 2005). Presumably, reduction in somatic size reflects reduced metabolic requirements of these neurons due to reduced spike activity after deafness (Hartmann et al 1984;Liberman and Kiang 1978;Shepherd and Javel 1997).…”

“…Recent studies have shown highly significant effects of BDNF in promoting SG survival (Agterberg et al 2008;Glueckert et al 2008;Miller et al 2007;Shepherd et al 2008;Wise et al 2005), and trophic effects also have been reported with other neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) (Kanzaki et al 2002;Maruyama et al 2008;Yagi et al 2000;Ylikoski et al 1998) and fibroblast growth factor (FGF) (Glueckert et al 2008). Other studies have reported that the survival-promoting effects of NTs are enhanced by concomitant electrical stimulation and that these effects can be maintained by stimulation after cessation of NT infusion (Kanzaki et al 2002;.…”

Transplantation of Mouse Embryonic Stem Cells into the Cochlea of an Auditory-Neuropathy Animal Model: Effects of Timing after Injury

“…CD45R (RA3-6B2) is a rat monoclonal IgG2a antibody raised against an extracelluar domain of the transmembrane glycoprotein CD45 and is expressed broadly among hematopoietic cells including macrophages and microglia (Bhave et al 1998). Monoclonal anti-neurofilament 200 reacts with a single 200-kDa band in both alkaline phosphatase dephosphorylated and untreated preparations of rat spinal cord (manufacturer's technical information from Sigma) and specifically stains nerve fibers in the inner ear (Lang et al 2006;Wise et al 2005). The GFAP monoclonal antibody recognizes a 50-kDa band by immunoblotting (manufacturer's technical information from Chemicon) and has been used extensively to label astrocytes and neoplastic cells of glial lineage in the central nervous system (McLendon and Bigner 1994;Kasischke et al 2006;Ward et al 2004).…”

“…It is well known that angiogenesis is associated with neurogenesis in the subventricular zone and subgranular zone of the adult mammalian brain (Leventhal et al 1999;Alvarez-Buylla and Lim 2004;Wurmser et al 2004), but a direct link between the survival and differentiation of transplanted stem cells with the remodeling of blood vessels in the host microenvironment of injured tissues has not been reported. The vascular remodeling combined with formation of transplanted ESC masses within RC and the perilymphatic space was seen in several EPI ears, but not in LPI and normal ears (Table 1, Figs.…”