Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension

Lambìase, Alessandro; Centofanti, Marco; Micera, Alessandra; Manni, Gianluca; Mattei, E.; Gregorio, Alessandra De; Feo, Giuseppe De; Bucci, Massimo G.; Aloe, Luigi

doi:10.1007/bf02332863

Cited by 61 publications

(48 citation statements)

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“…Inhibition consists of reduced maturation of NGF from proNGF, as well as a reduced ability of NGF to activate TrkA. RGC death ensues because NGF/TrkA function is required for function and maintenance of these neurons (41,42). Disease states replicate the conditions of this experiment because ␣ 2 M is endogenously upregulated in vivo and causes RGC death (23).…”

Section: Resultsmentioning

confidence: 91%

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Barcelona

Saragovi

2015

Molecular and Cellular Biology

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Nerve growth factor (NGF) is generated from a precursor, proNGF, that is proteolytically processed. NGF preferentially binds a trophic tyrosine kinase receptor, TrkA, while proNGF binds a neurotrophin receptor (NTR), p75NTR , that can have neurotoxic activity. Previously, we along with others showed that the soluble protein ␣ 2 -macroglobulin (␣ 2 M) is neurotoxic. Toxicity is due in part to ␣ 2 M binding to NGF and inhibiting trophic activity, presumably by preventing NGF binding to TrkA. However, the mechanisms remained unclear. Here, we show ex vivo and in vivo three mechanisms for ␣ 2 M neurotoxicity. First, unexpectedly the ␣ 2 M-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, ␣ 2 M makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, ␣ 2 M-proNGF complexes bind p75 NTR and are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-␣) production. Hence, ␣ 2 M regulates proNGF/p75 NTR positively and mature NGF/TrkA negatively, causing neuronal death ex vivo. These three mechanisms are operative in vivo, and ␣ 2 M causes neurodegeneration in a p75 NTR -and proNGF-dependent manner. ␣ 2 M could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.S oluble hormones and growth factors (GF) are first produced as precursors that are processed by proteolytic cleavage to mature forms (1). Precursors and mature growth factors often mediate distinct signals. One example is the family of growth factors called neurotrophins that includes nerve growth factor (NGF). A precursor proNGF binds with high affinity to a neurotrophin receptor (NTR), p75 NTR (2, 3), an interaction generally considered to be neurotoxic. proNGF induces tumor necrosis factor alpha (TNF-␣) production by p75 NTR -expressing activated glia (4-6) and directly causes death in p75 NTR -expressing neurons (7-9). proNGF is proteolytically cleaved to produce mature NGF (2). Mature NGF binds with high affinity to a receptor tyrosine kinase called TrkA, an interaction that is neuroprotective. Mature NGF also binds to p75 NTR , and TrkA and p75 NTR crossregulate ligand affinity and signal transduction positively or negatively (10-12).The balance of neurotrophic versus neurotoxic signals depends on many factors, including receptor density and stoichiometry, the cell type and environment, and the proteolytic processing that influences the ratio of proNGF to mature NGF ligands. Thus, we hypothesized that additional mechanisms might exist to tightly regulate these heterogeneous and sometimes opposing signals.Proteins called growth factor binding proteins (BPs) regulate the proteolytic processing, half-life or stability, extracellular matrix interactions, and receptor binding specificity of growth factors. For example, insulin-like growth factors (IGFs) are bound by several IGF BPs, each regulating a distinct feature of IGF functions (13). A protein present in se...

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Section: Resultsmentioning

confidence: 91%

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Barcelona

Saragovi

2015

Molecular and Cellular Biology

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“…Furthermore, intravitreal NGF delivery to the retina and optic nerve is crucial to the survival of RGCs and NGF is known to be responsible for functional recovery of the retina following ocular ischemia and hypertension in animal models (13)(14)(15). Lastly, an ophthalmic solution of NGF administered topically to the ocular surface has been shown to reach the retina and optic nerve where it is biologically active (17).…”

Section: Discussionmentioning

confidence: 99%

“…Intracerebral administration of NGF has been shown to be beneficial in Parkinson's and Alzheimer's patients (10)(11)(12), and intraocular administration of NGF in animal models has been shown to inhibit RGC degeneration after mechanical, ischemic or hypertensive injury (13)(14)(15). NGF applied topically to the eye has also been shown to restore sensory nerve function to the ocular surface of patients with neurotrophic keratitis (16).…”

mentioning

confidence: 99%

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

Lambìase¹,

Aloe

Centofanti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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208

162

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Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 g/mL) were tested on 24 rats, and the higher dose was found to be more effective. NGF ͉ optic nerve ͉ retina

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“…Also, pharmacological induction of retinal NGF synthesis may be useful. Indeed, partial neuroprotection has been demonstrated by vitreal injection of NGF (Mey and Thanos, 1993;Peinado-Ramon et al, 1996), and conversely when an anti-NGF antibody is injected intraocularly it increases high IOP-induced RGC loss (Lambiase et al, 1997). These observations suggest a protective role for the NGF ⅐ TrkA axis.…”

Section: Possible Therapeutic Rationalementioning

confidence: 92%

“…This may be detrimental to the neighboring RGCs, which are already depleted of trophic support because of poor retrograde transport of growth factors. Second, Müller cells may be activated by high IOP stress and other factors, including vitreal neurotrophins (Lambiase et al, 1997) via their functional p75 receptors Wexler et al, 1998;Harada et al, 2000). Because truncated TrkC can regulate p75 function (Hapner et al, 1998), it is possible that Müller cell up-regulation of truncated TrkC may be biologically relevant.…”

Section: Early Eventsmentioning

confidence: 98%

Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension

2004

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Open angle glaucoma is defined as a progressive and time-dependent death of retinal ganglion cells concomitant with high intraocular pressure, leading to loss of visual field. Because neurotrophins are a family of growth factors that support neuronal survival, we hypothesized that quantitative and qualitative changes in neurotrophins or their receptors may take place early in ocular hypertension, preceding extensive cell death and clinical features of glaucoma. We present molecular, biochemical, and phenotypic evidence that significant neurotrophic changes occur in retina, which correlate temporally with retinal ganglion cell death. After 7 days of ocular hypertension there is a transient up-regulation of retinal NGF, while its receptor TrkA is up-regulated in a sustained fashion in retinal neurons. After 28 days of ocular hypertension there is sustained up-regulation of retinal BDNF, but its receptor TrkB remains unchanged. Throughout, NT-3 levels remain unchanged but there is an early and sustained increase of its receptor TrkC in Müller cells but not in retinal ganglion cells. These newly synthesized glial TrkC receptors are truncated, kinase-dead isoforms. Expression of retinal p75 also increases late at day 28. Asymmetric up-regulation of neurotrophins and neurotrophin receptors may preclude efficient neurotrophic rescue of RGCs from apoptosis. A possible rationale for therapeutic intervention with Trk receptor agonists and p75 receptor antagonists is proposed.

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Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension

Abstract: These findings demonstrate a protective effect of NGF on RGC damaged by ocular hypertension and prompt further investigations to evaluate a possible therapeutic use of NGF to retard RGC death in humans.

Cited by 61 publications

References 30 publications

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension

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Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension

Abstract: These findings demonstrate a protective effect of NGF on RGC damaged by ocular hypertension and prompt further investigations to evaluate a possible therapeutic use of NGF to retard RGC death in humans.

Cited by 61 publications

References 30 publications

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension

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Resources

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A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α₂-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo