An Agonistic TrkB mAb Causes Sustained TrkB Activation, Delays RGC Death, and Protects the Retinal Structure in Optic Nerve Axotomy and in Glaucoma

Bai, Yujing; Xu, Jing; Brahimi, Fouad; Zhuo, Yehong; Sarunic, Marinko V.; Saragovi, H. Uri

doi:10.1167/iovs.09-5032

Cited by 83 publications

(80 citation statements)

References 47 publications

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“…Fluorogold Retrograde Labeling-RGCs were retrogradely labeled with a 4% Fluorogold solution (Fluorochrome, Englewood, CO) applied bilaterally to the superior culliculous (4,11), with minor modifications as described (5). In ON, axotomy retrograde labeling was performed 7 days before surgical transection.…”

Section: Methodsmentioning

confidence: 99%

“…OCT is a non-invasive method that allows time kinetic studies in the same animal, acquisition of retinal images with axial tissue resolution nominally better than 4 m, and repeatability of the measurements from B-scans better than 1 m. Details of the method have been published (5). During retinal scanning, 3 volumes were acquired in different sectors of the retina containing the ON head and retinal blood vessels as landmarks.…”

Section: Quantification Of Retinal Structures Using Fourier Domain Opmentioning

confidence: 99%

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Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

Bai

Dergham

Nedev

et al. 2010

Journal of Biological Chemistry

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123

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In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75NTR . During retinal injury, endogenous NGF, TrkA, and p75 NTR are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75 NTR affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75 NTR agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75 NTR action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-␣ and ␣ 2 -macroglobulin. Antagonists of p75 NTR inhibit TNF-␣ and ␣ 2 -macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.Neuropathic diseases of the retina that involve the death of retinal ganglion cells (RGCs) 4 are irreversible. This is because RGCs are neurons whose fibers and axons make up the optic nerve (ON) and relay visual input from the retina to the cerebral cortex.Commonly used animal models of neuropathy that cause RGC death include ON axotomy and glaucoma. ON axotomy is an acute model of trauma where the optic nerve is completely severed, causing rapid death of the RGCs (ϳ90% within 2 weeks). Glaucoma is a chronic and progressive optic nerve neuropathy often concomitant with elevated intraocular pressure (IOP) (1). The etiology of RGC death in glaucoma remains unknown.One mechanism is the deprivation of survival signals that neurotrophins provide by acting through the TrkA and TrkB receptors expressed in RGCs (2, 3). Indeed, activation of TrkA (4) or TrkB (5) directly activate pro-survival signals during glaucoma and rescues RGCs from death during ON axotomy or glaucoma. However, it seems paradoxical that whereas TrkA activity is protective, neither endogenous nerve growth factor (NGF) (up-regulated in glaucoma (6)) nor exogenous NGF applied as a drug afford effective RGC neuroprotection during ON axotomy or glaucoma (4, 7).A second mechanism of RGC death in glaucoma is the increased production of tumor necrosis factor-␣ (TNF-␣) (8-10) and ␣ 2 -macroglobulin (␣ 2 M) (11). These neurotoxic factors are produced by activated microglia (12), which express the neurotrophin receptor p75 NTR (7). Indeed, the p75 NTR receptor has been implicated in the acute release of TNF-␣ during acute toxicity leading to RGC death within a few hours after intravitreal injection of glutamate (13) or after activatio...

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Section: Methodsmentioning

confidence: 99%

Section: Quantification Of Retinal Structures Using Fourier Domain Opmentioning

confidence: 99%

Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

Bai

Dergham

Nedev

et al. 2010

Journal of Biological Chemistry

Self Cite

123

View full text Add to dashboard Cite

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“…Another approach consists on the selective stimulation of trophic factor receptors using specific agonists. Thus, it has been shown that a selective agonist of TrkB (BDNF receptor) causes a long term TrKB activation and significantly delays RGC degeneration after IOP increase and after optic nerve transection (Bai et al, 2010). Brimonidine, an α-2 adrenergic agonist, has been shown to neuroprotect RGCs after retinal ischemia (Lafuente et al, 2001Lafuente Lopez-Herrera et al, 2002;Vidal-Sanz et al, 2001a,b, 2007Aviles-Trigueros et al, 2003;Mayor-Torroglosa et al, 2005;Lonngren et al, 2006), after optic nerve crush (Wheeler et al, 1999) and after laser-induced ocular hypertension Lambert et al, 2011).…”

Section: Therapies To Increase the Resistance Of The Injured Neuronsmentioning

confidence: 99%

Anatomical and Molecular Responses Triggered in the Retina by Axonal Injury

Agudo‐Barriuso¹,

Nadal-Nicolás²,

Parrilla–Reverter³

et al. 2011

The Mystery of Glaucoma

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“…This ob ser va tion was reproduced by other groups [42,55,56], but results also trig gered scepticism regarding the magnitude and duration of exogenously ad ministered BDNF [57][58][59]; these latter workers also attempted co-ad mi ni stration with radical scavengers, gene therapy and more long-lasting synthetic TrkB agonists, and despite positive data in these animal models, no clinical studies with topical instillation of BDNF have been carried out. Domenici et al [60] investigated the utility of exogenous BDNF in the DBA/2J mouse, which develops chronic IOP elevation and subsequent loss of vision.…”

Section: Bdnf and Poagmentioning

confidence: 76%

Role of Brain-Derived Neurotrophic Factor for the Treatment of Glaucoma and Retinitis Pigmentosa

Spaccapelo¹

2016

MOJT

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Primary open-angle glaucoma (POAG) is the most common form of glau¬co¬ma, representing up to 90% of cases. POAG is described as a multifactorial optic neuropathy that is chronic and progressive with a characteristic acquired loss of optic nerve fibres. The cause for the elevated is generally IOP accepted to be decreased facility of aqueous outflow through the trabecular meshwork. Retinitis pigmentosa (RP) is a group of relatively rare, inherited disorders characterized by progressive peripheral vision loss and night vision difficulties (nyctalopia) that can lead to central vision loss due to the degeneration of the rod photoreceptor cells in the retina. RP manifests initial symptoms in-dependent of age; thus, RP diagnosis occurs anywhere from early infancy to late adulthood. Brain-derived neurotrophic factor (BDNF) is a 14 kDa protein belonging to the neurotrophin family of growth factors. BDNF has trophic functions in the hippocampus, cortex, and basal forebrain as well as the retina, motor neurons, the kidneys, saliva, and the prostate. The notion that BDNF may have a role in treating the neurodegenerative aspects of POAG is underpinned by convincing preclinical evidence in animal models of glaucoma that BDNF administered intravitreously can, at least in part, rescue retinal ganglion cells (RGCs) under conditions such as those induced by increased intraocular pressure(IOP). Overall, and despite a mechanistically sound rationale, the pharmacokinetic challenges indicate that instilled BDNF topical administration is associated with higher than normal risks, likely explaining the emphasis on alternative approaches (such as synthetic small molecule BDNF analogues or gene therapy approaches) in the last decade. Moreover, the high BDNF doses required to drive efficacy (and low target tissue penetration) also raise concerns over promotion of tumour growth resulting from BDNF taken up from non-retinal tissues. In conclusion, even if preliminary evidences are available, further studies are necessary in order to clarify the role of BDNF for the treatment of glaucoma and retinitis pigmentosa. Keywords:

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An Agonistic TrkB mAb Causes Sustained TrkB Activation, Delays RGC Death, and Protects the Retinal Structure in Optic Nerve Axotomy and in Glaucoma

Cited by 83 publications

References 47 publications

Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

Anatomical and Molecular Responses Triggered in the Retina by Axonal Injury

Role of Brain-Derived Neurotrophic Factor for the Treatment of Glaucoma and Retinitis Pigmentosa

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