Table 1.
Different approaches of application of BDNF in the treatment of posterior eye segment degenerative diseases
| Author, year | Animal model | Method administered/timing | Effect | Dosing |
|---|---|---|---|---|
| Administration of purified protein | ||||
| Mey and Thanos,107 1993 | Rat: axotomy | Intravitreous/single | Transient survival of injured RGCs | BDNF 50 ng/100 g body weight |
| Mansour-Robaey et al,92 1994 | Rat: axotomy | Intravitreous/single vs multiple (on day 0, 3, 7, and 10) | Multiple injections caused better survival of RGCs in comparison to single injection | BDNF 5 μg |
| Unoki and La Vail,197 1994 | Rat: pressure-induced ischemia | Intravitreous/single vs multiple (2 days before ischemic insult and 4 or 5 days after) | Transient protection of the retina after single injection, but second injection of BDNF prolonged the protective effect | BDNF 1 μg |
| Weibel et al,96 1995 | Young rat: axotomy | Intravitreous/single vs multiple | Positive effect of BDNF on the survival of injured optic nerve axons in comparison to other neurotrophic factors | BDNF 0.1 μg |
| Sawai et al,198 1996 | Rat: axotomy | Intravitreous/single | Injection of BDNF or NT-4/5 improved axonal branch growth within the retina, but injection of NT-3 did not | BDNF 5 μg |
| Peinado-Ramon et al,199 1996 | Rat: axotomy | Intravitreous/single | Survival, and delaying the onset of RGCs death | BDNF 5 μg |
| Cellerino et al,106 1998 | Development of rat retina | Intravitreous/multiple | BDNF regulated the growth of the retinal dopaminergic neurons | BDNF 1 μg ×3 |
| LaVail et al,108 1998 | Rat/mouse: light damage | Intravitreous/single | Protection of the photoreceptors from degeneration | Rat BDNF: 1, 5, 10 μg; mouse BDNF: 0.5, 2.5, 5 μg |
| Ikeda et al,102 1999 | Rat: potassium cyanide (KCN)-induced retinal damage | Intravitreous/single | BDNF attenuated the inner nuclear layer cell death | 125I-BDNF 1 μg |
| Cellerino et al,200 1999 | Development of rat retina | Intravitreous/single | BDNF activated NADPH-diaphorase in dopaminergic neurons and displaced amacrine cells to the ganglion cell layer, but did not protect them | BDNF 1 μg |
| Kurokawa et al,201 1999 | Rat: axotomy | Intravitreous/single | Cell death in RGCs and the caspase-2-positive cells were lower | BDNF 5 μg |
| Klöcker et al,93 2000 | Rat: axotomy | Intravitreous/multiple 4, 7, and 10 days after axotomy | Inhibition of PI3K did not reduce the BDNF effects on RGCs survival | BDNF 0.5 μg ×3 |
| Kido et al,103 2000 | Rat: NMDA excitotoxicity | Intravitreous/single | BDNF of 1 and 10 μg has protective effects on retinal damage | BDNF 0.1, 1, or 10 μg |
| Chen and Weber,97 2001 | Cat: optic nerve trauma | Intravitreous/single; intravitreous/multiple | 30 μg showed highest RGCs survival, whereas high doses showed low survival and inflammation | BDNF 15, 30, 60, 90 μg 30×2, 60×2 μg |
| Chen and Weber,202 2002 | Rat: axotomy | Intravitreous/single | No significant effect on glial fibrillary acidic protein or glutamine synthetase expression | BDNF 5 μg |
| Ota et al,203 2002 | Rat: axotomy | Intravitreous/single | Smaller change in soma cell-size distribution | BDNF 5 μg |
| Nakazawa et al,94 2002 | Rat: axotomy | Intravitreous/single | Both MAPK and PI3K-Akt pathways involved in neuroprotective signaling | BDNF 1 μg |
| Krueger-Naug et al,204 2003 | Rat: axotomy | Intravitreous/single | The expression of heat shock protein 27 in RGCs was reduced | BDNF 5 g |
| Chen and Weber,109 2004 | Rat: nerve crush | Intravitreous/single | BDNF decreased in TrkB.FL (both mRNA and protein) | BDNF 5 μg |
| Lee et al,205 2005 | Rat: axotomy | Intravitreous/single | BDNF affected the expression of anti-tyrosine hydroxylase immunoreactivity | BDNF 5 μg |
| Chen et al,206 2012 | Mouse: light damage | Intravitreous/single | Dose and time-dependent c-Jun expression in the retina | BDNF 0.1 μg; 0.2 μg |
| Galindo-Romero et al,98 2013 | Mouse: axotomy | Intravitreous/single | Neuroprotective effect on the axotomized RGCs | BDNF 2.5 μg |
| Administration of purified protein in combinations | ||||
| Klöcker et al,116 1998 | Rat: axotomy | Intravitreous/single | Single BDNF treatment rescued 27% of the RGCs transiently. Combined treatment of BDNF with free radical scavenger N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN) improved survival up to 68%, and with NOS-inhibitor N-ω-nitro-L-argininemethylester (L-NAME) –up to 55% | BDNF 0.2, 0.5, 2 μg + L-NAME, S-PBN |
| Yan et al,207 1999 | Rat: axotomy | Intravitreous/multiple 1, 7 days | Combination GDNF and BDNF showed better protection than each factor individually | 0.5 μg GDNF +0.5 μg BDNF ×2; 1.0 μg GDNF +1.0 μg BDNF ×2 |
| Ko et al,101 2000 | Rat: high IOP | Intravitreous/multiple 5, 13, 21, and 29 days after IOP elevation | Combination of BDNF and S-PBN substantially improved survival of RGCs up to 90.1% | BDNF 0.5 μg ×4 BDNF 1.0 μg ×4 BDNF 0.5 μg + S-PBN ×4 BDNF 1.0 μg + S-PBN ×4 |
| Koeberle and Ball,113 2002 | Rat: axotomy | Intravitreous/single | Neurturin, GDNF, and BDNF had different cellular targets in the retina to enhance RGCs survival | BDNF 0.05, 0.25, 0.5, 1.0, 2.5 μg 1.0 μg neurturin +1.0 μg BDNF 1.0 μg GDNF +1.0 μg BDNF |
| Watanabe et al,114 2003 | Cat: axotomy | Intravitreous/single | Combined injection of BDNF, CNTF, and forskolin (raises intracellular concentration of cAMP) resulted in a 4.7-fold increase of surviving increase of β-cells of RGCs | BDNF 0.5, 1 μg BDNF 1 μg + CNTF 1 μg +0.1 mg forskolin |
| Tropea et al,115 2003 | Long–Evans rats: retina lesion | Intravitreous/single; osmotic minipump | BDNF in a combination with chondroitinase ABC (C-ABC), which promotes CNS regeneration via degradation of chondroitin sulfate proteoglycans side chains, results in reinnervation of the collicular scotoma by unlesioned RGCs axons | BDNF 10 μg + C-ABC |
| Zhang et al,99 2005 | Hamster: axotomy | Intravitreous/single | Protection RGCs and increasing NOS activity by BDNF | BDNF 1.25, 5 μg or BDNF + CNTF |
| Fu et al,112 2009 | Rat: high IOP | Intravitreous/single | Long-term protection for RGCs | BDNF 1 μg + LINGO-1-Fc |
| Weber et al,117 2010; Weber and Harman,208 2013 | Cat: optic nerve trauma | Intravitreous/single; osmotic minipump into brain vision cortex 14, 28 day | Treatment eye + cortex animals showed better RGCs survival | BDNF 90 μg; 12.6, 25.2 μg |
| Goldenberg-Cohen et al,133 2014 | Mouse: anterior ischemic optic neuropathy | Intravitreous/single | Enhancing of neuroglial differentiation of the RGCs | BDNF 5 μg × BMSCs |
| Viral mediated BDNF delivery systems | ||||
| Di Polo et al,121 1998 | Rat: axotomy | Intravitreous/single | Ad.BDNF increased survival of RGCs in 4–5 fold in comparison with pure BDNF | BDNF 5 μg Ad.BDNF |
| Mo et al,125 2002 | Rat: axotomy | Electroporation of BDNF gene to RGCs | Protection axotomized RGCs against apoptosis | BDNF gene |
| Martin et al,124 1996 | Rat: high IOP | Intravitreous/single | Protection of RGC | AAV-BDNF-WPRE |
| Schuettauf et al,123 2004 | Rat: NMDA excitotoxicity | Intravitreous/multiple | Retinal cell survival | AAV2 3 μL ×3 |
| Gauthier et al,122 2005 | Rat: light damage | Intravitreous/single | BDNF gene delivery enhanced the survival and structural integrity of damaged photoreceptors | BDNF 5 μg or 5 μL AAV |
| Wang et al,209 2009 | Rabbit: high IOP | Intravitreous/single | Protecting the retinal structure | 10 μL AAV |
| Wan,210 2010 | Rat: streptozotocin induced diabetes | Intravitreous/single | Increase in tyrosine hydroxylase and density of retinal dopaminergic amacrine cells | 5 μL AAV |
| Ren et al,127 2012 | Rat: high IOP | Intravitreous/single | Sustained rescue of RGCs and visual function | BDNF 0.5 μg + AAV-BDNF |
| Cell-based BDNF delivery systems | ||||
| Lawrence,105 2004 | Dystrophic Royal College of Surgeons rats (animal with genetically transmitted progressive retinal dystrophy) | Transplantation into the subretinal space | Preserving photoreceptors from the cell death | SCTM41-BDNF Schwann Cell Line; SCTM41-GDNF Schwann Cell Line |
| Abe et al,132 2008 | Rat: retinitis pigmentosa | Transplantation into the subretinal space/topical doxycycline | BDNF expression possible to be controlled by doxycycline (DOX) for photoreceptors’ protection | Retinal pigment epithelial cell line that can express BDNF by exposure to DOX (Tet-BDNF-RPE) |
| Zhou et al,130 2009 | Rat: normal | Intravitreous subretinal/single | BDNF can promote neural stem cells (NSCs) migration and differentiation into neural cells | 10 μL NSC-BDNF suspension (105 cells) |
| Zhang and Wang,128 2010 | Rat: retinitis pigmentosa | Intraocular transplantation/2 weeks | Inhibition of photoreceptor apoptosis and slowing down retinal damage | 5 μL BMSC-BDNF suspension (5×104 cells) |
| Park et al,129 2012 | Rat: axotomy | Subretinal or intravitreal/4 weeks | Increased BDNF mRNA and protein expressions | 20 μL rat bone marrow mesenchymal stem cells (rMSC)-BDNF (3×105 cells) |
Abbreviations: BDNF, brain-derived neurotrophic factor; RGCs, retinal ganglion cells; NT, neurotrophin; NMDA, N-methyl-D-aspartate; MAPK, mitogen-activated protein kinases; PI3K-Akt, phosphoinositide 3-kinase; GDNF, glial cell-derived neurotrophic factor; IOP, intraocular pressure; CNTF, ciliary neurotrophic factor; cAMP, cyclic adenosine monophosphate; C-ABC, chondroitinase ABC; CNS, central nervous system; NOS, nitric oxide synthase; LINGO-1, leucine rich repeat and immunoglobulin domain containing NogoR interacting protein 1; NogoR, neurite outgrowth inhibitory protein receptor; BMSC, bone marrow stem cell; AAV, adeno-associated virus; DOX, doxycycline; NSCs, neural stem cells; rMSC, rat bone marrow mesenchymal stem cells; WPRE, woodchuck hepatitis posttranscriptional regulatory element; Ad.BDNF, adenovirus vector containing BDNF.