Amyotrophic Lateral Sclerosis — A New Role for Old Drugs
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《新英格兰医药杂志》
Over the past decade, there have been extraordinary advances in understanding the molecular physiology of the brain and its disorders. Unfortunately, few if any of these insights have been translated into meaningful therapies. This failure undoubtedly reflects the general complexity of the central nervous system and the "orphan" status of many of the disorders, including most of the neurodegenerative diseases. Because the potential market value of drugs for these orphan diseases is small, they are usually viewed as inappropriate targets for drug development by pharmaceutical companies.
In this context, a recent study by Rothstein and colleagues1 is notable. This team has long-standing expertise in the pathological effects of the excitatory neurotransmitter glutamate. They and others have demonstrated that excessive levels of synaptic glutamate are neurotoxic in diseases as diverse as epilepsy, stroke, and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). They therefore devised a screening assay to identify drugs that reduce synaptic levels of glutamate by accelerating its uptake into astroglial cells in slice cultures of spinal cord. Using this screening assay, Rothstein and colleagues found that -lactam antibiotics enhance astroglial transport of glutamate in vitro and that these agents do so at levels that are routinely achieved during the treatment of central nervous system infections. They determined that the effect was mediated by enhancing surface expression — both in vitro and in vivo — of the glutamate transporter GLT1. They went on to show that one -lactam agent, ceftriaxone, could prevent neuronal death in two neuronal-culture models of glutamate excitotoxicity (Figure 1). Perhaps most striking was their finding that long-term ceftriaxone therapy slowed the course of disease in a mouse model of ALS caused by transgenic expression of mutant superoxide dismutase. If administered at high doses at the onset of the disease, ceftriaxone preserved grip strength, slowed weight loss, and increased the overall duration of survival from 122 to 132 days. The slowing of motor-neuron death was accompanied by a marked increase in the expression of GLT1 protein in the mice.
Figure 1. Potential Role of a Glutamate Transporter in the Treatment of ALS.
Expression of the glutamate transporter GLT1 is muted in the astroglia of patients with ALS. An excess of glutamate at the synaptic cleft is thought to trigger excitotoxicity and thus neuronal death (Panel A). Using a method to screen FDA-approved drugs for those that up-regulate GLT1, Rothstein and colleagues1 recently identified the -lactam antibiotics — ceftriaxone in particular — as potential treatments for ALS. They showed that exposure to ceftriaxone increased transcription of the GLT1 gene in fetal astrocytes (Panel B) and that the levels and activity of GLT1 protein increased in the spinal cord of mice treated with ceftriaxone. When tested in a mouse model of ALS, ceftriaxone delayed the onset of symptoms (loss of muscle strength and weight loss), the loss of motor neurons at the lumbar spine, and death, most likely because of the enhanced clearance of glutamate resulting from the increased levels of GLT1 on astrocytes.
The study was carried out by a consortium — funded by the National Institutes of Health, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the ALS Association — whose mission was to devise petri-dish drug-screening assays for neurodegenerative disorders. It is one of the first collaborative studies to develop rapid-throughput drug assays for any brain disease, and its success is a tribute to the efficacy of an investigative partnership between the federal government and academia. It also represents the first use of a screening assay on all drugs that have been approved by the Food and Drug Administration (FDA) and tests the hypothesis that compounds approved for safe use in one setting may have desirable effects in others. In effect, the identification of ceftriaxone as a potential therapy for ALS represents a cost-saving end run around the protracted process of drug discovery.
Finally, this study illustrates the power of contemporary molecular genetics to delineate a route to drug discovery. The finding that a mutant gene causes a disease in humans (in this case, ALS) permits the creation of a corresponding transgenic mouse model. Detailed studies of the mouse provide insight into key pathophysiological events (in this case, the toxic effects of glutamate). These insights, in turn, drive the development of high-throughput in vitro assays that lead to the identification of drug candidates whose usefulness can then be validated in the mouse model and, ultimately, in humans. The remaining link in the ceftriaxone-discovery cycle is a clinical trial. The National Institutes of Health has approved funding for a multicenter trial of ceftriaxone in patients with ALS; pending final assessment of safety issues, the study will begin in mid-2005.
A cautionary point illustrated by this report is that the beneficial effects of a given drug cannot always be attributed to a single mechanism. For example, there are anecdotal claims that chronic fatigue syndromes respond to ceftriaxone (or other antibiotics) because the underlying problem is chronic Lyme disease. However, the study by Rothstein and colleagues1 indicates that ceftriaxone may exert important effects on the central nervous system that are independent of its role as an antibiotic.
The pace of therapeutic discovery in areas of medicine such as inherited degenerative brain disorders has been frustratingly slow, especially when contrasted with the wealth of new insights that have been made with respect to the primary defects. The study by Rothstein et al.1 highlights a novel approach to an accelerated process of drug discovery that is a tribute to a government–academic collaboration and an excellent model for future programs of rational drug discovery.(Robert H. Brown, Jr., D.P)
In this context, a recent study by Rothstein and colleagues1 is notable. This team has long-standing expertise in the pathological effects of the excitatory neurotransmitter glutamate. They and others have demonstrated that excessive levels of synaptic glutamate are neurotoxic in diseases as diverse as epilepsy, stroke, and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). They therefore devised a screening assay to identify drugs that reduce synaptic levels of glutamate by accelerating its uptake into astroglial cells in slice cultures of spinal cord. Using this screening assay, Rothstein and colleagues found that -lactam antibiotics enhance astroglial transport of glutamate in vitro and that these agents do so at levels that are routinely achieved during the treatment of central nervous system infections. They determined that the effect was mediated by enhancing surface expression — both in vitro and in vivo — of the glutamate transporter GLT1. They went on to show that one -lactam agent, ceftriaxone, could prevent neuronal death in two neuronal-culture models of glutamate excitotoxicity (Figure 1). Perhaps most striking was their finding that long-term ceftriaxone therapy slowed the course of disease in a mouse model of ALS caused by transgenic expression of mutant superoxide dismutase. If administered at high doses at the onset of the disease, ceftriaxone preserved grip strength, slowed weight loss, and increased the overall duration of survival from 122 to 132 days. The slowing of motor-neuron death was accompanied by a marked increase in the expression of GLT1 protein in the mice.
Figure 1. Potential Role of a Glutamate Transporter in the Treatment of ALS.
Expression of the glutamate transporter GLT1 is muted in the astroglia of patients with ALS. An excess of glutamate at the synaptic cleft is thought to trigger excitotoxicity and thus neuronal death (Panel A). Using a method to screen FDA-approved drugs for those that up-regulate GLT1, Rothstein and colleagues1 recently identified the -lactam antibiotics — ceftriaxone in particular — as potential treatments for ALS. They showed that exposure to ceftriaxone increased transcription of the GLT1 gene in fetal astrocytes (Panel B) and that the levels and activity of GLT1 protein increased in the spinal cord of mice treated with ceftriaxone. When tested in a mouse model of ALS, ceftriaxone delayed the onset of symptoms (loss of muscle strength and weight loss), the loss of motor neurons at the lumbar spine, and death, most likely because of the enhanced clearance of glutamate resulting from the increased levels of GLT1 on astrocytes.
The study was carried out by a consortium — funded by the National Institutes of Health, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the ALS Association — whose mission was to devise petri-dish drug-screening assays for neurodegenerative disorders. It is one of the first collaborative studies to develop rapid-throughput drug assays for any brain disease, and its success is a tribute to the efficacy of an investigative partnership between the federal government and academia. It also represents the first use of a screening assay on all drugs that have been approved by the Food and Drug Administration (FDA) and tests the hypothesis that compounds approved for safe use in one setting may have desirable effects in others. In effect, the identification of ceftriaxone as a potential therapy for ALS represents a cost-saving end run around the protracted process of drug discovery.
Finally, this study illustrates the power of contemporary molecular genetics to delineate a route to drug discovery. The finding that a mutant gene causes a disease in humans (in this case, ALS) permits the creation of a corresponding transgenic mouse model. Detailed studies of the mouse provide insight into key pathophysiological events (in this case, the toxic effects of glutamate). These insights, in turn, drive the development of high-throughput in vitro assays that lead to the identification of drug candidates whose usefulness can then be validated in the mouse model and, ultimately, in humans. The remaining link in the ceftriaxone-discovery cycle is a clinical trial. The National Institutes of Health has approved funding for a multicenter trial of ceftriaxone in patients with ALS; pending final assessment of safety issues, the study will begin in mid-2005.
A cautionary point illustrated by this report is that the beneficial effects of a given drug cannot always be attributed to a single mechanism. For example, there are anecdotal claims that chronic fatigue syndromes respond to ceftriaxone (or other antibiotics) because the underlying problem is chronic Lyme disease. However, the study by Rothstein and colleagues1 indicates that ceftriaxone may exert important effects on the central nervous system that are independent of its role as an antibiotic.
The pace of therapeutic discovery in areas of medicine such as inherited degenerative brain disorders has been frustratingly slow, especially when contrasted with the wealth of new insights that have been made with respect to the primary defects. The study by Rothstein et al.1 highlights a novel approach to an accelerated process of drug discovery that is a tribute to a government–academic collaboration and an excellent model for future programs of rational drug discovery.(Robert H. Brown, Jr., D.P)