Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized β ganglion cells in cat retina

Watanabe, Masami; Tokita, Yoshihito; Kato, Momoko; Fukuda, Yutaka

doi:10.1016/s0306-4522(02)00562-6

Cited by 81 publications

(55 citation statements)

References 39 publications

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“…Of interest, CNTF was exploited for both retina and inner ear, and it showed positive effect for immediate and delayed after-deafness treatment, 192 while for retina treatment, no additive effect was observed. 114 Another study had proposed the usage of LINGO-1 antagonist in combination with BDNF in rats with progressive neuropathy secondary to high intraocular pressure. LINGO-1 antagonist prevented the negative regulation of activity for TrkB receptors during interaction with BDNF and showed long-term protection for RGCs.…”

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confidence: 99%

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

Khalin¹,

Alyautdin²,

Kocherga³

et al. 2015

IJN

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Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

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confidence: 99%

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

Khalin¹,

Alyautdin²,

Kocherga³

et al. 2015

IJN

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confidence: 99%

“…[1][2][3][4][5][6][7] NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration. [1][2][3][4][5][6][7] Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts.…”

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confidence: 99%

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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“…Watanabe et al suggested that the increase of regenerating beta-RGCs was mainly due to the enhanced effect of neurotrophic factors on their survival, and possibly to a change of RGC properties by cAMP to facilitate their axonal regeneration. 29 Inhibition of CNS axon growth is mediated in part by calcium-dependent phosphorylation of axonal EGFR. A local administration of EGFR kinase inhibitors AG1478 and PD168393 to an ON lesion site can promote axonal regeneration of adult RGCs.…”

Section: Neurotrophic Factorsmentioning

confidence: 99%

“…64 In the PN-grafted ON stump, a combinational intravitreal injection of neurotrophins such as BDNF, CNTF, and forskolin may increase neuronal survival and axonal regeneration of RGCs, and the cAMP elevation by forskolin may contribute to the promotion of the RGC regenerative profile. 29 Some small molecules including mannose and glucose were proved to have the effect of promoting axonal regeneration of RGCs in a cAMP-dependent manner in the higher or lower vertebrates. 54 High level of cAMP abrogates the ability of CNS molecules to inhibit axonal elongation.…”

Section: Cyclic Ampmentioning

confidence: 99%

Restoration of optic neuropathy

You¹,

Wu²,

Kuang³

et al. 2017

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Optic neuropathy refers to disorders involving the optic nerve (ON). Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs), may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP) and calcium levels affect axon guidance and growth cone response to guidance molecules. Many genes, such as Bcl-2, PTEN, and mTOR, are crucial in cell proliferation, axon guidance, and growth during development, and play important roles in the regeneration and extension of RGC axons. With transgenic mice and related gene regulations, robust regeneration of RGC axons has been observed after ON injury in laboratories. Although various means of experimental treatments such as cell transplantation and gene therapy have achieved significant progress in neuronal survival, axonal regeneration, and restoration of the visual function after ON injury, many unresolved scientific problems still exist for their clinical applications. Therefore, we still need to overcome hurdles before developing effective therapy to treat optic neuropathy diseases in patients.

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Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized β ganglion cells in cat retina

Cited by 81 publications

References 39 publications

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Restoration of optic neuropathy

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