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Enhanced survival of spiral ganglion cells after cessation of treatment with brain-derived neurotrophic factor in deafened guinea pigs.

Agterberg MJ, Versnel H, van Dijk LM, de Groot JC, Klis SF - J. Assoc. Res. Otolaryngol. (2009)

Bottom Line: The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals.The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment.The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, GA, Utrecht, The Netherlands.

ABSTRACT
Exogenous delivery of neurotrophic factors into the cochlea of deafened animals rescues spiral ganglion cells (SGCs) from degeneration. To be clinically relevant for human cochlear implant candidates, the protective effect of neurotrophins should persist after cessation of treatment and the treated SGCs should remain functional. In this study, the survival and functionality of SGCs were investigated after temporary treatment with brain-derived neurotrophic factor (BDNF). Guinea pigs in the experimental group were deafened, and 2 weeks later, the right cochleae were implanted with an electrode array and drug delivery cannula. BDNF was administered to the implanted cochleae during a 4-week period via a mini-osmotic pump. After completion of the treatment, the osmotic pumps were removed. Two weeks later, the animals were killed and the survival of SGCs was analyzed. To monitor the functionality of the auditory nerve, electrically evoked auditory brainstem responses (eABRs) were recorded in awake animals throughout the experiment. BDNF treatment resulted in enhanced survival of SGCs 2 weeks after cessation of the treatment and prevented the decreases in size and circularity that are seen in the untreated contralateral cochleae. The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals. The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment. The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals. These morphological and functional findings demonstrate that neurotrophic intervention had a lasting effect, which is promising for future clinical application of neurotrophic factors in implanted human cochleae.

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Treatment schedule of four different animal cohorts (A‚ÄďD). A Deafened and 2¬†weeks later implanted and treated with BDNF; B deafened and 2¬†weeks later implanted; C first implanted and 4¬†weeks later deafened; D only implanted. Deafening was performed systemically affecting both ears. Cochlear implantation (A‚ÄďD) and BDNF treatment (A) was applied to the right ear. After implantation, eABRs were regularly recorded in each group (by electrically stimulating the implanted right ear). For electrophysiological analysis, eABRs of the BDNF-treated animals (A) were compared to eABRs of normal-hearing animals (Cbefore deafening, D) and to eABRs of deafened animals (B, Cafter deafening). Note that data in normal-hearing and deafened conditions were obtained in the same animals (C). For histological analysis, the main comparison was made within the animals treated with BDNF (A): BNDF-treated right ears were compared to untreated left ears.
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Fig1: Treatment schedule of four different animal cohorts (A‚ÄďD). A Deafened and 2¬†weeks later implanted and treated with BDNF; B deafened and 2¬†weeks later implanted; C first implanted and 4¬†weeks later deafened; D only implanted. Deafening was performed systemically affecting both ears. Cochlear implantation (A‚ÄďD) and BDNF treatment (A) was applied to the right ear. After implantation, eABRs were regularly recorded in each group (by electrically stimulating the implanted right ear). For electrophysiological analysis, eABRs of the BDNF-treated animals (A) were compared to eABRs of normal-hearing animals (Cbefore deafening, D) and to eABRs of deafened animals (B, Cafter deafening). Note that data in normal-hearing and deafened conditions were obtained in the same animals (C). For histological analysis, the main comparison was made within the animals treated with BDNF (A): BNDF-treated right ears were compared to untreated left ears.

Mentions: After implantation, eABRs in BDNF-treated animals were recorded weekly to assess auditory function in relation to electrical stimulation of the treated cochleae. This paradigm is schematically explained in Figure¬†1 A. The eABR data of the treated animals were compared to eABRs in both normal-hearing and deafened untreated animals. For this, we used three groups of control animals (Fig.¬†1 B‚ÄďD). A group of two animals were deafened and implanted in the right cochlea with a regular electrode array (without drug delivery cannula) 2¬†weeks thereafter, and eABRs were recorded up to more than 8¬†weeks after deafening (Fig.¬†1 B). A second group of eight normal-hearing control animals were implanted in the right cochlea with a regular electrode array and eABRs were recorded weekly (Fig.¬†1 C). In order to examine the effect of deafening on the eABRs in the same animals, these animals were deafened after 4¬†weeks and killed another 6¬†weeks later (in one of these animals, eABRs could not be recorded anymore in later sessions due to electrode failure). A third group of four animals were implanted as the second group but killed after 4¬†weeks while in normal-hearing condition (Fig.¬†1 D). All surgical and experimental procedures were approved by the Animal Care and Use Committee of Utrecht University (DEC-UMC # 03.04.036).FIG.¬†1


Enhanced survival of spiral ganglion cells after cessation of treatment with brain-derived neurotrophic factor in deafened guinea pigs.

Agterberg MJ, Versnel H, van Dijk LM, de Groot JC, Klis SF - J. Assoc. Res. Otolaryngol. (2009)

Treatment schedule of four different animal cohorts (A‚ÄďD). A Deafened and 2¬†weeks later implanted and treated with BDNF; B deafened and 2¬†weeks later implanted; C first implanted and 4¬†weeks later deafened; D only implanted. Deafening was performed systemically affecting both ears. Cochlear implantation (A‚ÄďD) and BDNF treatment (A) was applied to the right ear. After implantation, eABRs were regularly recorded in each group (by electrically stimulating the implanted right ear). For electrophysiological analysis, eABRs of the BDNF-treated animals (A) were compared to eABRs of normal-hearing animals (Cbefore deafening, D) and to eABRs of deafened animals (B, Cafter deafening). Note that data in normal-hearing and deafened conditions were obtained in the same animals (C). For histological analysis, the main comparison was made within the animals treated with BDNF (A): BNDF-treated right ears were compared to untreated left ears.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2717388&req=5

Fig1: Treatment schedule of four different animal cohorts (A‚ÄďD). A Deafened and 2¬†weeks later implanted and treated with BDNF; B deafened and 2¬†weeks later implanted; C first implanted and 4¬†weeks later deafened; D only implanted. Deafening was performed systemically affecting both ears. Cochlear implantation (A‚ÄďD) and BDNF treatment (A) was applied to the right ear. After implantation, eABRs were regularly recorded in each group (by electrically stimulating the implanted right ear). For electrophysiological analysis, eABRs of the BDNF-treated animals (A) were compared to eABRs of normal-hearing animals (Cbefore deafening, D) and to eABRs of deafened animals (B, Cafter deafening). Note that data in normal-hearing and deafened conditions were obtained in the same animals (C). For histological analysis, the main comparison was made within the animals treated with BDNF (A): BNDF-treated right ears were compared to untreated left ears.
Mentions: After implantation, eABRs in BDNF-treated animals were recorded weekly to assess auditory function in relation to electrical stimulation of the treated cochleae. This paradigm is schematically explained in Figure¬†1 A. The eABR data of the treated animals were compared to eABRs in both normal-hearing and deafened untreated animals. For this, we used three groups of control animals (Fig.¬†1 B‚ÄďD). A group of two animals were deafened and implanted in the right cochlea with a regular electrode array (without drug delivery cannula) 2¬†weeks thereafter, and eABRs were recorded up to more than 8¬†weeks after deafening (Fig.¬†1 B). A second group of eight normal-hearing control animals were implanted in the right cochlea with a regular electrode array and eABRs were recorded weekly (Fig.¬†1 C). In order to examine the effect of deafening on the eABRs in the same animals, these animals were deafened after 4¬†weeks and killed another 6¬†weeks later (in one of these animals, eABRs could not be recorded anymore in later sessions due to electrode failure). A third group of four animals were implanted as the second group but killed after 4¬†weeks while in normal-hearing condition (Fig.¬†1 D). All surgical and experimental procedures were approved by the Animal Care and Use Committee of Utrecht University (DEC-UMC # 03.04.036).FIG.¬†1

Bottom Line: The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals.The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment.The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, GA, Utrecht, The Netherlands.

ABSTRACT
Exogenous delivery of neurotrophic factors into the cochlea of deafened animals rescues spiral ganglion cells (SGCs) from degeneration. To be clinically relevant for human cochlear implant candidates, the protective effect of neurotrophins should persist after cessation of treatment and the treated SGCs should remain functional. In this study, the survival and functionality of SGCs were investigated after temporary treatment with brain-derived neurotrophic factor (BDNF). Guinea pigs in the experimental group were deafened, and 2 weeks later, the right cochleae were implanted with an electrode array and drug delivery cannula. BDNF was administered to the implanted cochleae during a 4-week period via a mini-osmotic pump. After completion of the treatment, the osmotic pumps were removed. Two weeks later, the animals were killed and the survival of SGCs was analyzed. To monitor the functionality of the auditory nerve, electrically evoked auditory brainstem responses (eABRs) were recorded in awake animals throughout the experiment. BDNF treatment resulted in enhanced survival of SGCs 2 weeks after cessation of the treatment and prevented the decreases in size and circularity that are seen in the untreated contralateral cochleae. The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals. The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment. The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals. These morphological and functional findings demonstrate that neurotrophic intervention had a lasting effect, which is promising for future clinical application of neurotrophic factors in implanted human cochleae.

Show MeSH
Related in: MedlinePlus