Erythropoietin for Neurologic Protection and Diabetic Neuropathy
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《新英格兰医药杂志》
The majority of drugs developed for neurologic indications fail because they are not clinically tolerated. A sensible strategy, therefore, is to explore the efficacy of drugs in the nervous system that have already been approved for other indications. When I was in medical school, erythropoietin was known to be a cytokine produced in the kidney and was thought to be important only for the development of red cells, which bear receptors for erythropoietin. But recent results have shown that nerve cells also have erythropoietin receptors and that this cytokine is made in the nervous system and can function as a neuroprotective agent. It ameliorates damage from a variety of insults, both in vitro and in animal models, including oxidative and nitrosative stress, cerebral ischemia (stroke), spinal cord and peripheral-nerve trauma, experimental autoimmune encephalomyelitis (a model of multiple sclerosis), neuronal injury related to infection with human immunodeficiency virus, and retinal damage.1,2,3 Moreover, a recent phase 1–2 clinical trial suggests that erythropoietin can ameliorate neural damage in patients who have had a stroke.4 Against this background, Bianchi et al.5 have now shown that erythropoietin can prevent and even reverse diabetic neuropathy in rats.
Painful neuropathy, manifested not only by pain but also by paresthesias and neuropathic injury, is a major source of disability worldwide and the most common complication of diabetes mellitus. So far, no single therapy has been completely effective, although decreasing the severity of hyperglycemia can relieve the symptoms to some extent, and several agents have been shown to have some effect in animal models and early clinical studies; among them are antioxidants (N-acetylcysteine and lipoic acid), neurotrophic peptides (nerve growth factor and prosaposin), and agents that affect the actions of neurotransmitters and ion channels (memantine and gabapentin). To this list, we now add erythropoietin. Bianchi et al.5 show that intraperitoneal erythropoietin for up to 10 weeks prevents and even reverses (to some extent) abnormalities in nerve conduction velocity, Na+,K+-ATPase activity (a biochemical abnormality associated with diabetic neuropathy), compound-muscle action potentials, nociception (pain thresholds), and loss of cutaneous nerve fibers in rats with streptozocin-induced diabetes.
At first glance, these results suggest that a clinical trial of erythropoietin might be warranted in patients with diabetic neuropathy. A potential drawback of erythropoietin therapy, however, is an unwanted increase in red-cell mass. In the diabetic rats, the hematocrit increased as much as 45 percent with long-term treatment. Unfortunately, such increases in the hematocrit would predispose patients to stroke. However, the ongoing development of erythropoietin derivatives, asialo forms, and alternative methods of administration that deliver the drug directly to nerve cells may soon overcome this potentially dose-limiting side effect. And it bodes well that short-term administration of erythropoietin as a neuroprotectant in clinical trials of stroke has not resulted in elevated hematocrits.4
In animals with diabetes, apoptosis leads to the loss of dorsal-root ganglion neurons and Schwann cells, which produce the myelin sheath covering the nerve axons. In addition, biochemical changes, oxidative stress, microvascular alterations, and inflammation may all play a role not only in the death of nerve cells but also in neuronal dysfunction. Erythropoietin may protect neurons against these processes through a variety of actions. Evidence is mounting in both the peripheral and central nervous systems that activation of erythropoietin receptors can trigger neuroprotective pathways, including the phosphoinositide 3 kinase–Akt (protein kinase B) cascade and the transcription factor nuclear factor-B pathway, to activate antiapoptotic peptides such as Bcl-xL and antioxidant enzymes such as superoxide dismutase (Figure 1).3 In addition, there is some evidence that erythropoietin may increase the proliferation of neural progenitor cells, which leads to the generation of neurons, even in the adult nervous system.
Figure 1. The Effect of Erythropoietin on Neurons.
Binding of erythropoietin to its receptor can trigger the activation — through enzymatic phosphorylation (P) — of both the phosphoinositide 3 kinase (PI3K)–Akt pathway and the nuclear factor-B (NF-B) transcription-factor pathway. This, in turn, results in the activation of several proteins (such as inhibitors of apoptosis [XIAP]) that inactivate caspase enzymes, which would otherwise trigger neuronal apoptosis. Other activated enzymes (such as superoxide dismutase [SOD]) metabolize free radicals and mediate survival pathways (such as that involving extracellular signal-regulated kinase [ERK]). In addition, activated Akt blocks several pathways associated with cell death, including those involving glycogen synthase kinase 3 (GSK3), caspase-9, Bcl-2–associated death-promoting protein (BAD), Jun N-terminal kinase (JNK), and forkhead transcription factor. JAK 2 denotes Janus kinase 2, IKK inhibitor of B kinase, p85 the regulatory subunit of PI3K, NO nitric oxide, and O2– superoxide anion.
Clinical trials of erythropoietin or its derivatives in patients with diabetic neuropathy and neurodegenerative disorders seem to be a good idea. Recent data from my laboratory suggest that when given in combination with other growth factors, such as insulin-like growth factor I, erythropoietin may act synergistically to activate neuroprotective pathways — an approach that should allow the use of lower and consequently even better-tolerated doses of both factors.6 The discovery that previously approved, clinically tolerated drugs such as erythropoietin can protect neurons and ameliorate neuropathic pain should expedite neurologic clinical trials.
Dr. Lipton reports having received an honorarium from Johnson & Johnson.
Source Information
From the Burnham Institute, the Salk Institute for Biological Studies, the Scripps Research Institute, and the University of California at San Diego — all in La Jolla.
References
Digicaylioglu M, Bichet S, Marti HH, et al. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A 1995;92:3717-3720.
Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000;97:10526-10531.
Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-B signalling cascades. Nature 2001;412:641-647.
Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002;8:495-505.
Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A 2004;101:823-828.
Digicaylioglu M, Garden GA, Timberblake S, Fletcher L, Lipton SA. Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I. Proc Natl Acad Sci U S A (in press).
Related Letters:
Erythropoietin, Glutamate, and Neuroprotection
Roesler R., Quevedo J., Schroder N., Lipton S. A.(Stuart A. Lipton, M.D., P)
Painful neuropathy, manifested not only by pain but also by paresthesias and neuropathic injury, is a major source of disability worldwide and the most common complication of diabetes mellitus. So far, no single therapy has been completely effective, although decreasing the severity of hyperglycemia can relieve the symptoms to some extent, and several agents have been shown to have some effect in animal models and early clinical studies; among them are antioxidants (N-acetylcysteine and lipoic acid), neurotrophic peptides (nerve growth factor and prosaposin), and agents that affect the actions of neurotransmitters and ion channels (memantine and gabapentin). To this list, we now add erythropoietin. Bianchi et al.5 show that intraperitoneal erythropoietin for up to 10 weeks prevents and even reverses (to some extent) abnormalities in nerve conduction velocity, Na+,K+-ATPase activity (a biochemical abnormality associated with diabetic neuropathy), compound-muscle action potentials, nociception (pain thresholds), and loss of cutaneous nerve fibers in rats with streptozocin-induced diabetes.
At first glance, these results suggest that a clinical trial of erythropoietin might be warranted in patients with diabetic neuropathy. A potential drawback of erythropoietin therapy, however, is an unwanted increase in red-cell mass. In the diabetic rats, the hematocrit increased as much as 45 percent with long-term treatment. Unfortunately, such increases in the hematocrit would predispose patients to stroke. However, the ongoing development of erythropoietin derivatives, asialo forms, and alternative methods of administration that deliver the drug directly to nerve cells may soon overcome this potentially dose-limiting side effect. And it bodes well that short-term administration of erythropoietin as a neuroprotectant in clinical trials of stroke has not resulted in elevated hematocrits.4
In animals with diabetes, apoptosis leads to the loss of dorsal-root ganglion neurons and Schwann cells, which produce the myelin sheath covering the nerve axons. In addition, biochemical changes, oxidative stress, microvascular alterations, and inflammation may all play a role not only in the death of nerve cells but also in neuronal dysfunction. Erythropoietin may protect neurons against these processes through a variety of actions. Evidence is mounting in both the peripheral and central nervous systems that activation of erythropoietin receptors can trigger neuroprotective pathways, including the phosphoinositide 3 kinase–Akt (protein kinase B) cascade and the transcription factor nuclear factor-B pathway, to activate antiapoptotic peptides such as Bcl-xL and antioxidant enzymes such as superoxide dismutase (Figure 1).3 In addition, there is some evidence that erythropoietin may increase the proliferation of neural progenitor cells, which leads to the generation of neurons, even in the adult nervous system.
Figure 1. The Effect of Erythropoietin on Neurons.
Binding of erythropoietin to its receptor can trigger the activation — through enzymatic phosphorylation (P) — of both the phosphoinositide 3 kinase (PI3K)–Akt pathway and the nuclear factor-B (NF-B) transcription-factor pathway. This, in turn, results in the activation of several proteins (such as inhibitors of apoptosis [XIAP]) that inactivate caspase enzymes, which would otherwise trigger neuronal apoptosis. Other activated enzymes (such as superoxide dismutase [SOD]) metabolize free radicals and mediate survival pathways (such as that involving extracellular signal-regulated kinase [ERK]). In addition, activated Akt blocks several pathways associated with cell death, including those involving glycogen synthase kinase 3 (GSK3), caspase-9, Bcl-2–associated death-promoting protein (BAD), Jun N-terminal kinase (JNK), and forkhead transcription factor. JAK 2 denotes Janus kinase 2, IKK inhibitor of B kinase, p85 the regulatory subunit of PI3K, NO nitric oxide, and O2– superoxide anion.
Clinical trials of erythropoietin or its derivatives in patients with diabetic neuropathy and neurodegenerative disorders seem to be a good idea. Recent data from my laboratory suggest that when given in combination with other growth factors, such as insulin-like growth factor I, erythropoietin may act synergistically to activate neuroprotective pathways — an approach that should allow the use of lower and consequently even better-tolerated doses of both factors.6 The discovery that previously approved, clinically tolerated drugs such as erythropoietin can protect neurons and ameliorate neuropathic pain should expedite neurologic clinical trials.
Dr. Lipton reports having received an honorarium from Johnson & Johnson.
Source Information
From the Burnham Institute, the Salk Institute for Biological Studies, the Scripps Research Institute, and the University of California at San Diego — all in La Jolla.
References
Digicaylioglu M, Bichet S, Marti HH, et al. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A 1995;92:3717-3720.
Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000;97:10526-10531.
Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-B signalling cascades. Nature 2001;412:641-647.
Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002;8:495-505.
Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A 2004;101:823-828.
Digicaylioglu M, Garden GA, Timberblake S, Fletcher L, Lipton SA. Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I. Proc Natl Acad Sci U S A (in press).
Related Letters:
Erythropoietin, Glutamate, and Neuroprotection
Roesler R., Quevedo J., Schroder N., Lipton S. A.(Stuart A. Lipton, M.D., P)