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Neuroprotective synergy of erythropoietin and insulin-like growth factors

a technology of erythropoietin and growth factor, which is applied in the field of neuroprotective synergy of erythropoietin and insulinlike growth factor and analogs, can solve the problems of speech impairment and coordination loss, no effective treatment or cure, and reduced the effect of l-dopa treatment typically occurring, so as to prevent or reduce the severity of cerebral neurologic conditions, prevent or reduce the effect of neurologic conditions

Inactive Publication Date: 2005-09-08
BURNHAM INST FOR MEDICAL RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method of providing acute neuroprotection by inducing the erythropoietin (EPO) pathway in neuronal cells close to or subsequent to the time of excitatory insult. This is achieved by contacting the neuronal cells with EPO or an active fragment thereof close to or subsequent to the time of excitatory insult. The invention also provides a method of preventing or reducing the severity of an acute neurological condition in a subject by administering EPO or an active fragment thereof close to or subsequent to the time of acute injury, and an insulin-like growth factor (IGF) or an active fragment thereof close to or subsequent to the time of acute injury. The two methods can be performed simultaneously or in any order. The invention can provide a synergistic effect and prevent or reduce the severity of the acute neurological condition.

Problems solved by technology

For a variety of serious neurodegenerative diseases, there exist no effective therapies or cures.
However, reduced efficacy of L-DOPA treatment typically occurs over time.
In Alzheimer's disease, the most common neurodegenerative disease and most frequent cause of dementia, progressive failure of memory and degeneration of temporal and parietal association cortex result in speech impairment and loss of coordination, and, in some cases, emotional disturbance.
Present therapies are relatively ineffective or are accompanied by unwanted side effects.
In particular, erythropoietin (EPO) can be neuroprotective when administered in high doses; however, such doses also promote the formation of new red blood cells, consequently causing side effects such as “sludging” of the blood and leading to increased risk of stroke.

Method used

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  • Neuroprotective synergy of erythropoietin and insulin-like growth factors
  • Neuroprotective synergy of erythropoietin and insulin-like growth factors
  • Neuroprotective synergy of erythropoietin and insulin-like growth factors

Examples

Experimental program
Comparison scheme
Effect test

example i

Amelioration Of NMDA-Induced Neurotoxicity by EPO in Combination with IGF-I does not Require Preincubation Before Neurotoxic Insult

[0160] This example demonstrates that simultaneous application of EPO and IGF-I at the time of neurotoxic insult effectively reduces apoptosis of mature neurons in rat primary cerebrocortical cultures exposed to NMDA.

[0161] The neuroprotective effects of concurrent EPO and IGF-I administration were compared to individual treatment with EPO or IGF-I in rat primary cerebrocortical cultures. Incubation of the cultures with 200 μM NMDA for 20 minutes induced death only in neurons in the mixed neuronal / glial cultures as reported previously (Bonfoco et al., supra, 1995).

[0162] Neuronal apoptosis was quantified by double labeling for TUNEL reactivity, which in conjunction with condensed morphology is indicative of apoptosis, and the neuron-specific protein microtubule associated protein-2 (MAP2) 16 hours after NMDA insult. As shown in FIG. 3, a brief 20 minu...

example ii

PI3-Kinase is Required for Neuroprotection by EPO And IGF-I

[0169] This example demonstrates that the PI3 kinase can play a role in mediating the neuroprotective effects of EPO and IGF-I.

[0170] PI3-kinase is involved in IGF-I and EPO signaling (Mayeux et al., supra, 1993; Kermer et al., supra, 2000; and Damen et al., J. Biol. Chem. 270:23402-23408 (1995)). In order to elucidate the role of PI3-kinase in the neuroprotective effects of EPO and IGF-I, rat cerebrocortical neurons were preincubated for three hours with EPO, IGF-I, or EPO in combination with IGF-I (EPO / IGF-I) in the presence or absence of 10 μM LY294002, a specific PI3-kinase inhibitor. As shown in FIG. 4, neuronal apoptosis resulting from NMDA exposure (200 μM NMDA and 5 μM glycine for 20 minutes) decreased in cells preincubated with EPO, IGF-I or EPO / IGF-I. As further shown in FIG. 4, LY294002 abolished the neuroprotective effect of EPO and IGF-I either alone or in combination (p<0.05) but did not itself cause neuronal...

example iii

EPO And IGF-I Cooperate in Activating Akt

[0177] This example demonstrates that the Akt kinase can be cooperatively activated by EPO and IGF-I in neuronal cells.

[0178] Akt-kinase is activated downstream of PI3-kinase-mediated production of 3′ phospholipids. In response to production of phosphotidylinositol-3,4,5-trisphosphate, Akt is phosphorylated at two critical sites: serine-473 and threonine-308 (Russell et al., Nuerobiol. 36:455-467 (1998); Scheid and Woodgett, supra, 2001).

[0179] To assess possible activation of the Akt kinase, cerebrocortical-cultures were exposed to EPO or IGF-I for three hours and immunoblotted as described above using anti-phospho Akt (anti-pAkt) and anti-Akt antibodies from Cell Signaling Technologies at 1:2000 dilution. A three hour incubation with EPO or IGF-I resulted in moderate Akt activation, as evidenced by increased phospho-serine-473 Akt detected by western blotting (FIG. 6A). Co-incubation with EPO and IGF-I resulted in a much larger increase ...

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Abstract

The present invention provides a method of providing acute neuroprotection by inducing the erythropoietin (EPO) signaling pathway in neuronal cells close to or subsequent to the time of excitatory insult; and inducing an insulin-like growth factor (IGF) signaling pathway in the neuronal cells close to or subsequent to the time of excitatory insult, thereby producing a synergistic acute neuroprotective effect in the neuronal cells. The invention also provides a method of preventing or reducing the severity of a neurologic condition in a subject by administering to the subject EPO or an active fragment or analog thereof at a dose of at most 2000 U / kg; and administering to the subject an IGF or an active fragment or analog thereof, thereby providing neuroprotection and preventing or reducing the severity of the neurologic condition. Such a method can be used to prevent or reduce the severity of, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, a movement disorder, HIV-associated dementia, HIV-associated neuropathy, neuropathic pain, migraine, glaucoma, drug addiction, drug withdrawal, drug dependency, depression or anxiety.

Description

[0001] This application claims benefit of the filing date of U.S. Provisional Application No. 60 / 388,058, filed Jun. 11, 2002, and of U.S. Provisional Application No. 60 / 458,145, filed Mar. 26, 2003, which are incorporated herein by reference.[0002] This application was made with government support under P01 HD29587, R01 NS43242 and NS43242 awarded by the National Institute of Health. The government has certain rights in the invention.FIELD OF THE INVENTION [0003] The invention relates to the prevention and treatment of acute and chronic neurodegenerative conditions, and to erythropoietin and insulin-like growth factors and analogs of these factors. BACKGROUND INFORMATION [0004] For a variety of serious neurodegenerative diseases, there exist no effective therapies or cures. For example, Parkinson's disease is a progressive and ultimately fatal neurodegenerative disorder characterized by loss of the pigmented dopaminergic neurons of the substantia nigra. The symptoms of Parkinson's ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/22A61K38/27C12N15/09A61K38/30A61P9/10A61P21/02A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/22A61P25/24A61P25/28A61P25/30A61P25/36A61P27/06A61P31/18A61P43/00C07K7/08C07K14/505C07K14/65
CPCA61K38/30A61K2300/00A61P21/02A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/22A61P25/24A61P25/28A61P25/30A61P25/36A61P27/06A61P31/18A61P43/00A61P9/10
Inventor DIGICAYLIOGLU, MURATLIPTON, STUART
Owner BURNHAM INST FOR MEDICAL RES
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