A Neurotrophic Rationale for the Therapy of Neurodegenerative Disorders

Saragovi, H. Uri; Hamel, Edith; Polo, Adriana Di

doi:10.2174/156720509789207912

Cited by 44 publications

(39 citation statements)

References 42 publications

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“…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.…”

Section: In Normal Adult Retinas Ngf Receptor Trka Is Expressed In Rmentioning

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

100

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: In Normal Adult Retinas Ngf Receptor Trka Is Expressed In Rmentioning

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

100

123

View full text Add to dashboard Cite

show abstract

“…Neurotrophic factors (NTFs) are secreted peptides essential for the phenotypic development and maintenance of specific neuronal populations in developing and adult vertebrate nervous system [7][8][9][10][11][12][13][14]. These diffusible proteins act via retrograde signaling from targetneurons and by paracrine and autocrine mechanisms, and regulate many aspects of neuronal and glial structure and function.…”

Section: Introductionmentioning

confidence: 99%

“…For example, ICV injection of nerve growth factor (NGF) has shown to improve the learning and memory ability, and the survival of basal forebrain cholinergic neurons in aged or fimbria-fornix lesioned animals. Furthermore, NTFs have been used for the experimental therapies in Parkinson's, Alzheimer's and Huntington's diseases and spinal cord injury [4][5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Controlled Release Strategy Based on Biodegradable Microspheres for Neurodegenerative Disease Therapy

Gu¹,

Yue²

2012

Basic Principles of Peripheral Nerve Disorders

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“…Several reviews have recently appeared about small-molecule disruptors of protein-protein associations; such compounds could prove beneficial for the treatment of AD and other related neurodegenerative diseases. [44][45][46][47][48][49][50][51] Two of the reviewed topics may be of particular interest to medicinal chemists, as one focuses on small molecules that can enhance autophagy of mutated toxic protein aggregates, typical of late-onset AD, [52,34] and the other is focused on the role of Ca 2 + in the formation of these aggregates. [54,55] There is also growing evidence that neurodegenerative diseases such as AD and PD may involve prion-like mechanisms.…”

mentioning

confidence: 99%