Mice help sort out benzodiazepine side-effects

Mice help sort out benzodiazepine side-effects xperiments done in mice are throwing more light onto how benzodiazepines exert their numerous effects and may make it possible to design better drugs for the future. Mammalian brain cells have five different subtypes for the neurotransmitter ␥-aminobutyric acid receptor (GABAA). All five subtypes —␣1 to ␣5—respond to the benzodiazepine drugs currently in clinical use but they mediate different brain functions. Thus, benzodiazepine drugs have numerous side-effects including sedation, muscle relaxation, motor impairment, memory loss, and excessive sensitivity to alcohol. In a new study, the effects of diazepam on wild-type mice was compared with its effects on mice in which a point mutation in the ␣1-type GABA receptor had greatly reduced diazepam binding in mouse brain tissue. In the mutant mice, diazepam did not cause sedation and memory impairment was much less

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than in wild-type mice. The drug was slightly less effective as an anticonvulsant in the mutant mice, but its muscle relaxant and anxiolytic effects were unaffected (Nature 1999; 401: 796–800). Our study could point the way to the design of benzodiazepine drugs that would target specific GABAA subtypes and so produce selected neuronal responses, for example, anxiolytics without sedation, says principal author Hanns Möhler (University of Zürich, Switzerland). Such drugs would be less likely to produce tolerance, and thus dependence, in patients, he says. But, he adds, they will only be found by screening thousands of candidate compounds for activity on the mice receptors. The scientists are now generating mutant mice to investigate the role of other GABAA subtypes. Peter Mitchell

Particulate pollution puzzles pondered anew impaired lung function when exposed ow atmospheric particulates of to increased road traffic near their less than 10␮m diameter (PM10) home, she said. —mainly produced by the burning of At the International Symposium on fossil fuels, in particular diesel—cause Particle Toxicity (Maastricht, Netherrespiratory symptoms in children and lands; Oct 13–15) G cardiovascular disease Oberdörster (University in adults was addressed of Rochester, MN, at two recent meetings. USA), reported how in But as the co-chair of rats, inhalation of ultrathe second meeting, fine carbon particles (a K Donaldson (Napier surrogate for diesel University, Edinburgh, exhaust pollution) did UK) noted, “we still do not cause airway not know why some inflammation, but that particles are especially there was a synergistic toxic and what makes increase in lung inflamsome people especially mation when ozone vulnerable to their exposure preceded pareffects”. ticle exposure. At the European Pumping out the pollution The puzzling associaRespiratory Society tion between cardiovascular mortality meeting (Madrid, Spain; Oct 9–13), in adults and particulate pollution E Strauch (University Children’s was also discussed in Maastricht. J Hospital, Freiburg, Germany) Godleski (Harvard School of Public reported a weak inverse correlation Heath, Boston, MA USA) gave data between PM10 exposure and lung from work in dogs which suggested function in 1101 healthy school chilthat particulates stimulate sympadren in rural Baden-Württemberg— thetic and parasympathetic nervous ozone was a confounding factor. system effects on cardiac electrical O van Ehrenstein (University activity. Godleski said that direct toxiChildren’s Hospital, Munich, city of pollutants on the heart may Germany) reported on genetic susalso be important since inhaled particeptibility to particulate pollution in cles can be seen in cardiac myocytes. 1256 healthy school children. Those with the ␣1-antitrypsin alleles PiS or PiZ are at increased risk of developing Jonathan Grigg

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THE LANCET • Vol 354 • October 23, 1999

Thymic transplants help in DiGeorge syndrome

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hymic transplantation in infants with complete DiGeorge syndrome can restore normal immune function, report Louise Markert (Duke University Medical Center, Durham, NC, USA) and colleagues. “This study is important”, says Markert, “because it shows that thymus transplantation could save the lives of babies with complete DiGeorge syndrome and that immature bone-marrow stem cells can find a thymus transplant located in the thigh muscle and develop there into T cells”. In DiGeorge syndrome, a rare congenital disorder, the thymus fails to develop, resulting in T-cell deficiency. To test whether transplanted thymus tissue could correct this deficiency, Markert and co-workers implanted thymus tissue taken from infants who were having corrective heart surgery into the thighs of five infants (aged 1–4 months) with DiGeorge syndrome. T-cell proliferative responses to mitogens developed in four patients. Two of the patients survived with restoration of their immune system; three died from causes not related to transplantation (N Engl J Med 1999; 341: 1180–89). These findings not only provide an important contribution for patients with DiGeorge Syndrome, says Rosa Ten (Mayo Clinic, Rochester, MN, USA), but also “open a new area to develop novel therapeutic strategies for the treatment of patients with other primary or acquired immune disorders”. In an editorial, Irving Weissman (Stanford University School of Medicine, CA, USA) notes: “It is a medical and scientific triumph . . . [and] tells us that immune reconstruction is possible and that thymus transplants can be key elements in that reconstruction.” These results, he adds, “also force us to reconsider the common but erroneous notion that we neither have nor need a thymus beyond puberty”. Markert now plans to try thymic transplantation in patients with cancer whose T cells have been damaged by chemotherapy. She also has a grant to study thymic transplantation in HIV-seropositive individuals who have been treated with the latest antiviral therapies but still lack mature T cells. Khabir Ahmad

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