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Science,
Vol 308, Issue 5723, 778-781, 6 May 2005 Long ignored, the nervous system's glial cells may turn out to be key players in disease and prime targets for therapy. When Linda Watkins gave an invited lecture a few years ago, she ruffled the feathers of at least one senior researcher in the audience. Drawing on her studies at the University of Colorado, Boulder, Watkins had argued that nervous system cells called glia contribute to the chronic pain resulting from nerve injury. This was at odds with the predominant thinking in the field, which held that such pain was purely a matter of miscommunication between neurons. The disapproving researcher, "a big-name person in the pain field whom I respect," Watkins says, wasn't ready to accept that glia were involved. "[He] stood up after my talk and announced in front of the whole audience that he was greatly bothered by my being so glia-centric," she recalls. These days such grumblings are becoming more rare. Recent research has shifted the once-heretical view that glia are key players in neuropathic pain into the mainstream. Indeed, on 2 April, the American Pain Society honored Watkins for her contributions to understanding the mechanisms of pain. Other researchers who have recently demonstrated new roles for glia say their work has also begun to garner more attention from colleagues who used to view the cells as mere support staff for the all-important neurons. The emerging realization of the importance of glia has given new life to an idea that has long lurked at the margins of neuroscience: that glia may have key roles in central nervous system disorders from neuropathic pain and epilepsy to neurodegenerative diseases such as Alzheimer's--and may even contribute to schizophrenia, depression, and other psychiatric disorders. There are also hints that glia may be promising therapeutic targets--a possibility that researchers have scarcely begun to explore. "We have been very neuron-chauvinistic," concedes Christopher Power, a neurovirologist at the University of Calgary in Canada. "But it's clear [now] that you cannot ignore the roles of glia as important effectors of health and disease." ................... Falling apart One of the first clues that glia may be involved in neurodegenerative disorders came from studies on a form of dementia that afflicts 10% to 20% of those infected with HIV. The virus's target of choice in the brain is microglia; it infects neurons very rarely, if at all. How infected microglia conspire to kill off neurons and cause dementia is not known. One possibility is that inflammatory cytokines and other compounds released by microglia injure neurons directly; another is that the microglia activate astrocytes, which abandon their glutamate-recycling duties, allowing the neurotransmitter to build up and kill neurons by overexciting them. Both mechanisms may also be at work in a wide range of neurodegenerative disorders, says Robert Nagele, who studies Alzheimer's disease at the University of Medicine and Dentistry of New Jersey in Stratford. For example, activated microglia invade the amyloid plaques in the brain that are the hallmark of Alzheimer's disease. Activated astrocytes also form a halo around the plaques. Many researchers agree that the inflammatory glial response contributes to the damage seen in Alzheimer's brains, says Nagele, but exactly how is a matter of debate. "There's a long list of [brain] diseases that are now appreciated to have an inflammatory component," says Gary Landreth, an Alzheimer's disease researcher at Case Western Reserve University in Cleveland, Ohio. Although many anti-inflammatory drugs are being tested for Alzheimer's disease and other neurodegenerative disorders, the results have been mixed. These drugs probably reduce neurodegeneration in part by inhibiting the inflammatory response of glia, Landreth says, but they act throughout the body. A drug that targeted glia specifically might be very valuable, he says, if it dampened inflammation in the brain without weakening the immune system--but so far, no such compounds have been developed. Tackling glutamate excitotoxicity has also been tricky. The drug memantine, which is intended to protect neurons from this threat and was approved in the United States in 2003 for Alzheimer's disease, modestly slows cognitive decline in patients but doesn't seem to thwart the brain's eventual neurodegeneration. Although memantine blocks a type of glutamate receptor on neurons, a paper published in January in Nature suggests another way to prevent excitotoxicity: boosting the activity of the glutamate transporter on astrocytes, the molecular pump responsible for clearing glutamate from the synapse. Jeffrey Rothstein of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues screened more than 1000 FDA-approved drugs and discovered that a class of widely used antibiotics, the so-called -lactam antibiotics, which includes penicillin and its derivatives, spurs astrocytes' production of glutamate transporters and increases the glial cells' uptake of glutamate. In a mouse model of the fatal neurodegenerative disease amyotrophic lateral sclerosis, one of these antibiotics delayed neuron loss and prolonged survival. On 22 February, the European Commission approved a drug that appears to work primarily on glia for Parkinson's disease, another neurodegenerative disorder. The drug rasagiline is already on the market for Parkinson's disease in Israel and is under consideration by FDA for use in the United States. The drug inhibits the monoamine oxidase B enzyme, which is found predominantly in microglia and astrocytes, says its inventor Moussa Youdim, a pharmacologist at Technion-Israel Institute of Technology in Haifa. Rasagiline was thought to work largely by preventing the enzyme from breaking down the neurotransmitter dopamine, which is deficient in Parkinson's patients. But the drug also appears to have glia-based neuroprotective effects, Youdim says. His team reported in February in the journal Mechanisms of Ageing and Development that the drug and related compounds sop up iron, preventing the metal from building up inside glia and undergoing chemical reactions that create dangerous free radical compounds that can seep out and wreak havoc on neurons. Researchers suspect that this process plays a role in other neurodegenerative disorders, and Youdim and colleagues are now testing rasagiline--as well as related compounds they've created recently that are even more effective at binding iron--in animal models of Alzheimer's and Huntington's disease. Volume 308, Number 5723, Issue of 6 May 2005, pp. 778-781. Find article online: |
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