Modulation of excitable tissue function by peripherally administered erythropoietin

Abstract

Methods and compositions are provided for protecting or enhancing excitable tissue function in mammals by systemic administration of an erythropoietin receptor activity modulator, such as erythropoietin, which signals via an EPO-activated receptor to modulate the function of excitable tissue. Excitable tissues include central neuronal tissues, such as the brain, peripheral neuronal tissues, retina, and heart tissue. Protection of excitable tissues provides treatment of hypoxia, seizure disorders, neurodegenerative diseases, hypoglycemia, and neurotoxin poisoning. Enhancement of function is useful in learning and memory. The invention is also directed to compositions and methods for facilitating the transport of molecules across endothelial cell tight junction barriers, such as the blood-brain barrier, by association of molecules with an erythropoietin receptor activity modulator, such as an erythropoietin.

Description

[0001] This application is a continuation application under 35 U.S.C. § 120 of U.S. application Ser. No. 09 / 717,057, filed Nov. 21, 2000, which is a divisional of U.S. application Ser. No. 09 / 547,220, filed Apr. 11, 2000, now abandoned, which claims benefit under 35 U.S.C. § 119(e) of U.S. provisional patent application No. 60 / 129,131, filed Apr. 13, 1999, the entire contents of each of which is incorporated herein by reference in its entirety.1. FIELD OF THE INVENTION [0002] The present invention is directed to the use of peripherally administered erythropoietin and other erythropoietin receptor activity modulators or EPO-activated receptor modulators to positively affect excitable tissue function. This includes the protection of excitable tissue, such as neuronal and cardiac tissue, from neurotoxins, hypoxia, and other adverse stimuli, and the enhancement of excitable tissue function, such as for facilitating learning and memory. The present invention is further drawn to methods f...

AI Technical Summary

Benefits of technology

[0012] The present invention is directed to compositions and methods for modulating excitable tissue function in mammals, as well as methods and compositions for drug delivery to excitable tissues. The invention is based, in part, on the Applicants' discovery that erythropoietin (EPO), administered systemically and at a high dosage, is specifically taken up by the brain. In particular, the Applicants have found that EPO, delivered in high doses, can cross the blood-brain barrier, where it can enhance cognitive function, and protect neural tissue from damage resulting from stressful conditions, such as hypoxia Erythropoietin and EPO, used interchangeably herein, and EPO receptor activity modulators, and EPO-activated receptor modulators refer to compounds, which, when administered systemically (outside the blood-brain barrier), are capable of activating EPO-activated receptors of electrically excitable tissues to enhance and / or protect from injury and death. Thus, EPO can refer to any form of erythropoietin that can modulate excitable tissue, as well as EPO analogs, fragments and mimetics thereof. In a preferred embodiment, for use in the methods of the present invention, the erythropoietin displays increased specificity for the brain EPO receptor. In another embodiment, the erythropoietin is nonerythropoietic. In yet another embodiment, the erythropoietin is administered at a dose greater than the dose necessary to maximally stimulate erythropoiesis.

[0016] In another embodiment, the modulation of excitable tissue provides protection from pathology resulting from injury to excitable tissue, for example, to neurons of the central nervous system, peripheral nervous system, or heart tissue. Such pathology may result from injuries including, but not limited to hypoxia, seizure disorders, neurodegenerative diseases, neurotoxin poisoning, multiple sclerosis, hypotension, cardiac arrest, radiation, or hypoglycemia. In one embodiment, the pathology is a result of hypoxia, and may be prenatal or postnatal oxygen deprivation, suffocation, choking, near drowning, post-surgical cognitive dysfunction, carbon monoxide poisoning, smoke inhalation, chronic obstructive pulmonary disease, emphysema, adult respiratory distress syndrome, hypotensive shock, septic shock, insulin shock, anaphylactic shock, sickle cell crisis, cardiac arrest, dysrhythmia or nitrogen narcosis. In the instance wherein the pathology is a seizure disorder, it may be, by way of non-limiting example, epilepsy, convulsions or chronic seizure disorder. In the instance wherein the pathology is a neurodegenerative disease, it may be, for example, stroke, Alzheimer's disease, Parkinson's disease, cerebral palsy, brain or spinal cord trauma, AIDS dementia, age-related loss of cognitive function, memory loss, amyotrophic lateral sclerosis, seizure disorders, alcoholism, retinal ischemia, aging, glaucoma or neuronal loss. In another embodiment, administration of EPO may be used to prevent injury or tissue damage during surgical procedures, such as, for example, tumor resection or aneurysm repair.

Problems solved by technology

It is widely understood that decreases in energy supply available to the brain, such as glucose or oxygen, results in a profound impairment of brain function, including cognition.

Many (but not all) neurons in the central nervous system are easily damaged while working under metabolically-limited conditions, e.g., hypoxia, hypoglycemia, stress, and / or prolonged, strong excitation.

Under these circumstances, the electrochemical gradients of these cells often collapse, resulting in irreversible neuronal injury and cell death.

Although the consequences of limited energy substrate on brain function are well known, the effects of improving energy delivery in an otherwise normal brain has been less extensively explored.

To date, however, this possibility has not been evaluated for EPO by any direct study.

Although studies have established that EPO injected intracranially protects neurons against hypoxic neuronal injury, intracranial administration is an impractical and unacceptable route of administration for therapeutic use, particularly for normal individuals.

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