Table 2.
Different approaches of application of BDNF in the treatment of inner ear degenerative diseases
| Author, year | Animal model | Method of administration/timing/dosing | Effect | Total dose |
|---|---|---|---|---|
| Administration of purified protein | ||||
| Implanted osmotic minipump (single) | ||||
| Miller et al,153 1997 | Guinea pigs: kanamycin (400 mg/kg) and ethacrynic acid (40 mg/kg) | 14 days/BDNF (50 ng/mL) | Statistically significant enhanced SGCs survival | BDNF 8.4 ng |
| Ruan et al,152 1999 | Guinea pigs: kanamycin (400 mg/kg) | 15, 30, 60 days/BDNF (100 μg/mL) | Protective effect on HCs was observed at 30 days, but not at 15 and 60 days | BDNF 9 μg BDNF 18 μg BDNF 36 μg |
| Shoji et al,149 2000 | Guinea pigs: 5-hour noise exposure (4 kHz octave band noise, 115 dB sound pressure level) | 12 days/BDNF (1 μg/mL; 10 μg/mL) | BDNF did protect the sensory epithelium | BDNF 0.144 μg; 1.44 μg |
| Gillespie et al,155 2003 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (62.5 μg/mL) | SGCs survival is increased; decrease in SGCs survival after cessation of treatment | BDNF 10 μg |
| McGuinness and Shepherd,211 2005 | Rats: gentamicin, 350 mg/kg + furosemide, 175 mg/kg | 28 days/BDNF (5.4 μg/mL) | Significant rescue of SGCs | BDNF 1.35 μg |
| Radeloff and Smolders,151 2006 | Adult pigeons (Columba livia): collagen sponges loaded with 0.5 mg gentamicin placed in front of the round window membrane | 56 days/BDNF (625 ng/mL) | BDNF did not enhance the time course or the extent of functional recovery and did not decrease the evoked ABR threshold | BDNF 0.42 μg |
| Agterberg et al,212 2008 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (100 μg/mL) | Increased SGCs shape and survival rate and density; no change in ABR | BDNF 16.8 μg |
| Song et al,213 2008 | Rats: gentamicin, 250 mg/kg + furosemide 85 mg/kg | Delayed intervention (30 days after deafening)/28 days/BDNF (5.4 μg/mL) | BDNF enhances SGCs bodies and peripheral processes survival | BDNF 1.35 μg |
| Agterberg et al,214 2009 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (100 μg/mL) | Increased SGCs survival rate; preserved SGCs shape, response comparable | BDNF 16.8 μg |
| Sly et al,215 2012 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (62.5 μg/mL) | Improved survival of SGCs, but not an increase in SGCs somal area; decreased tone and click eABR thresholds | BDNF 10.5 μg |
| Leake et al,216 2011 | Young cats: neomycin sulfate, 60 mg/kg | 70 days/BDNF (94 μg/mL) | Improved survival of the cochlear SGC neurons; reduction in thresholds for electrical ABR | BDNF 37.5 μg |
| Waaijer et al,217 2013 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (94 μg/mL) | Quantitative and qualitative improvement of peripheral processes | BDNF 16.8 μg |
| van Loon et al,218 2013 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (100 μg/mL) | SGCs significantly bigger in comparison with normal throughout the cochlea | BDNF 16.8 μg |
| Implanted osmotic minipump (combinations) | ||||
| Shinohara et al,192 2002 | Intracochlear infusion of 24 μL of 10% neomycin | 26 days/BDNF (100 μg/mL) + CNTF (100 ng/mL) | SGCs survival rate is increased; ABR threshold is decreased | BDNF 31.2 μg + CNTFAX1 31.2 μg |
| Yamagata et al,219 2004 | Guinea pigs: intracochlear infusion of 10% neomycin sulfate for 2 days | 14 days/BDNF (100 μg/mL) + CNTFAX1 (100 ng/mL). Delay 2 or 6 weeks | Density of SGCs is increased; ABR threshold is decreased; 6-week delay increases in ABR threshold in comparison with 2-week delay | BDNF 8.4 μg + CNTFAX1 8.4 μg |
| Wise et al,220 2005 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | Delay treatment 5 or 33 days/28 days/BDNF (50 μg/mL) + NTF (50 μg/mL) | Increased SGCs survival rate | BDNF 8.4 μg + NTF |
| Shepherd et al,193 2005 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (62.5 μg/mL) | Increased SGCs survival rate; ES did not provide trophic support of SGCs | BDNF 10 μg + ES |
| Miller et al,221 2007 | Guinea pigs: kanamycin (420 mg/kg) and ethacrynic acid (60 mg/kg) | Delay treatment: 4 days, 3 weeks or 6 weeks/26 days/BDNF (100 μg/mL) | Increased SGCs survival rate at different treatment delays, but longer delay led to decreased overall SGCs density | BDNF 31.2 μg + FGF 1 |
| Shepherd et al,163 2008 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | 28 days/BDNF (62.5 μg/mL) +14 or 28 days of ES | Chronic ES averted the rapid loss of SGCs that occurred after the withdrawal of exogenous BDNF | BDNF 10 μg + ES |
| Glueckert et al,165 2008 | Guinea pigs: kanamycin (450 mg/kg) followed (2 hours later) with ethacrynic acid (60 mg/kg) | Immediate and delay (21 days) treatment/26 days/BDNF (100 μg/mL) + aFGF (50 ng/mL) | SGCs survival is enhanced, number of afferent peripheral processes is increased | BDNF 15.6 μg + aFGF |
| Song et al,161 2009 | Rats: gentamicin, 250 mg/kg + furosemide 85 mg/kg | Delayed intervention (30 days after deafening)/28 days BDNF (5.4 μg/mL) | Combination of ES and BDNF had a synergistic effect: SGCs soma and peripheral process survival was increased | BDNF 1.35 μg + ES |
| Landry et al,162 2011 | Guinea pigs: kanamycin sulfate, 420 mg/kg + furosemide 130 mg/kg | 28 days/BDNF (30 μg/mL) | Greater SGCs survival and lower response thresholds for eABR. ES in combination with BDNF did not enhance SGCs | BDNF 5 μg + ES |
| Leake et al,160 2013 | Young cats: neomycin sulfate, 60 mg/kg | 70 days/BDNF (100 μg/mL) | SGCs numerical density had been increased | BDNF 37.5 μg + ES |
| Viral mediated BDNF delivery systems | ||||
| Staecker et al,170 1998 | CBA/6J mice: 10 μL of neomycin 10−1 mol/L solution | Intracochlear injection through RWM into scala tympani of 10 μL HSV containing BDNF cDNA for transfection of the SGCs | Up to 95% of the original population of SGCs survived at 28 days | HSV.BDNF |
| Lalwani et al,222 2002 | Guinea pigs: kanamycin (400 mg/kg) and ethacrynic acid (40 mg/kg) | Implanted osmotic minipump/8.3 days/AAV-BDNF/GFP (3×106 viral particles/mL) | SGCs survival was increased in basal turn | AAV-BDNF/GFP |
| Nakaizumi et al,172 2004 | Guinea pigs: kanamycin (400 mg/kg) and ethacrynic acid (50 mg/kg) | 5 μL of an adenoviral suspension injected into the scala tympani through the RWM/28 days | SGCs survival was increased; no protective action of CNTF was observed | Ad.BDNF; Ad.BDNF + Ad.CNTF |
| Rejali et al,171 2007 | Guinea pigs: with kanamycin (420 mg/kg) and ethacrynic acid (52.5 mg/kg) | CI electrode coated by fibroblast cells transduced by a viral vector with a BDNF gene insert/48 days | Spiral ganglion survival was enhanced in basal turn. Cells infected by Ad.BDNF placed on the CI in an agarose matrix could survive for weeks | Ad.BDNF, fibroblast cells |
| Chikar et al,173 2008 | Guinea pigs: direct infusion of 60 μL of 10% neomycin into the perilymph | Single injection + intracochlear implant/80 days expression | Increased SGC survival rate; decrease in eABR threshold | 5 μL Ad.BDNF (20×109 adenoviral particles) |
| Wise et al,169 2010 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | Single injection of viral vectors into the scala media | Detection of localized gene expression; protection SGCs from degeneration | BDNF Ad vectors |
| Shibata et al,177 2010 | Guinea pigs: 10 μL of 10% neomycin sulfate solution into the scala tympani perilymph | Inoculation with viral vectors into the scala media (adenoviral or adeno-associate viral particle)/14 or 30 days | Increase in the density of SGCs and inducing of nerve fibers growth | 5 μL of Ad.BDNF, 20×109 Ad particles; 5 μL of AAV2.GFP-BDNF, 8.4×109 AAV2 particles |
| Fukui et al1432012 | Deaf Pou4f3 mutant mice | Adenoviral vector with a mouse BDNF gene insert, driven by the cytomegalovirus promoter | Increased number of nerve fibers in the auditory epithelium and survival rate of the auditory neurons in Rosenthal’s canal | 1 mL of Ad.BDNF (4×109 adenoviral particles) |
| Other delivery systems | ||||
| Li et al2232005 | Rats: the induction of bacterial meningitis by Streptococcus pneumoniae | Intracerebroventricular administration 6 μg BDNF once a day, 7 days + antibiotic therapy | Decrease in the eABR threshold | BDNF 42 μg |
| Ito et al1782005 | Guinea pigs: kanamycin (420 mg/kg) and ethacrynic acid (25 mg/kg) | Biodegradable hydrogel immersed in 84 μg BDNF was placed on the RWM | Successful development of a novel strategy for drug application to the inner ear; number of surviving SGCs was increased; significant reduce in the eABR threshold was detected | BDNF 84 μg |
| Meen et al1482009 | Guinea pigs: 15 mg/kg intraperitoneal cisplatin | Cochleostomy, single placement of pure BDNF into the cochlea | Prevention of hearing loss | BDNF 0.05 μg |
| Meen et al1542010 | Guinea pigs: 15 mg/kg intraperitoneal cisplatin | Cochleostomy, single placement of pure BDNF into the cochlea | No changes in eABR click thresholds | BDNF 0.05 μg |
| Havenith et al1792011 | Guinea pigs: kanamycin sulfate, 400 mg/kg + furosemide 100 mg/kg | Gelfoam® (Pharmacia and Upjohn) containing BDNF, placed on the round window membrane/28 days | Increased SGC survival rate in basal turn, but no effect on SGC shape and size; no effect on eABR thresholds | BDNF 6 μg |
| Pettingill et al1822011 | Guinea pigs: kanamycin sulfate, 520 mg/kg + furosemide 130 mg/kg | Shwann cell-based gene transfer combined with alginate encapsulation technology/28 days | Greater auditory SGCs survival | BDNF-Schwann cells encapsulated in a biocompatible matrix |
Abbreviations: BDNF, brain-derived neurotrophic factor; SGCs, spiral ganglion cells; HCs, hair cells; ABRs, auditory brainstem responses; CNTF, ciliary neurotrophic factor; NTF, neurotrophic factor; ES, electrical stimulation; FGF1, fibroblast growth factor 1; aFGF, acidic fibroblast growth factor; eABR, electronic ABR; HSV, herpes simplex virus; RWM, round window membrane; AAV, adeno-associated virus; GFP, green fluorescent protein; CI, cochlear implant; Ad.BDNF, adenovirus vector containing BDNF.