research10 - REPORTS examined sensitivity to the...

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examined sensitivity to the acetylcholin- esterase inhibitor aldicarb. Aldicarb causes paralysis of body movement resulting from the accumulation of acetylcholine at the neuromuscular junction ( 18 ). Mutations that reduce synaptic transmission cause resistance to aldicarb ( 18 ). In contrast, mutations that stimulate synaptic transmission cause hyper- sensitivity to aldicarb-mediated paralysis ( 19 ). Trimethadione treatment of wild-type animals caused hypersensitivity to aldicarb-mediated paralysis (Fig. 3E). The control drug, succin- imide, did not cause hyperactive motility or aldicarb hypersensitivity ( 3 ). These results indicate the anticonvulsants stimulate synaptic transmission in the neuromuscular system that controls body movement. Ethosuximide and trimethadione effec- tively treat absence seizures in humans by regulating neural activity. A likely target of ethosuximide is T-type calcium channels, although it is possible that these compounds act on multiple targets ( 20–22 ). These anti- convulsants also affected neural activity in nematodes, and the anticonvulsant and the life-span extension effects of the compounds may act through similar mechanisms. The findings presented here are consistent with the model that the effect on neural activity causes the life-span extension, although they do not exclude the possibility that the drugs affect neural activity and aging by different mechanisms. Furthermore, the interactions with the insulin-signaling mutants suggest the intriguing possibility that neural activity regulates aging by both daf-16 –dependent and daf-16 –independent mechanisms. References and Notes 1. L. Guarente, C. Kenyon, Nature 408 , 255 (2000). 2. Materials and methods are available as supporting material on Science Online. 3. S. Hughes, K. Evason, data not shown. 4. B. G. Katzung, Ed., Basic and Clinical Pharmacology (Appleton and Lange, Upper Saddle River, NJ, ed. 7, 1998). 5. R. H. Levy, R. H. Mattson, B. S. Meldrum, E. Perucca, Eds., Antiepileptic drugs (Lippincott, Williams and Wilkins, Philadelphia, ed. 5, 2002). 6. P. A. Reddy et al. , J. Med. Chem. 39 , 1898 (1996). 7. C. Huang, C. Xiong, K. Kornfeld, Proc. Natl. Acad. Sci. U.S.A. 101 , 8084 (2004). 8. D. Gems, D. L. Riddle, Genetics 154 , 1597 (2000). 9. D. A. Garsin et al. , Science 300 , 1921 (2003). 10. J. P. McKay, D. M. Raizen, A. Gottschalk, W. R. Schafer, L. Avery, Genetics 166 , 161 (2004). 11. B. Lakowski, S. Hekimi, Proc. Natl. Acad. Sci. U.S.A. 95 , 13091 (1998). 12. C. Kenyon, J. Chang, E. Gensch, A. Rudner, R. Tabtiang, Nature 366 , 461 (1993). 13. D. Gems, S. Pletcher, L. Partridge, Aging Cell 1 ,1 (2002). 14. J. Apfeld, C. Kenyon, Nature 402 , 804 (1999). 15. M. Ailion, T. Inoue, C. I. Weaver, R. W. Holdcraft,
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This note was uploaded on 12/04/2011 for the course CHEM 590A taught by Professor Staff during the Summer '10 term at University of Illinois, Urbana Champaign.

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research10 - REPORTS examined sensitivity to the...

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