ABSTRACT To define whether oxidative stress and aging induce abnormal dissociation of neurotransmitter-enclosing synaptic vesicles in rat brain nerve terminals, we assessed the activation of Ca+/calmodulin dependent protein kinase II (CAM kinase II) and changes in the levels of synapsin I, which is a synaptic vesicle-associated protein involved in the modulation of neurotransmitter release. Assessment of young rats subjected to hyperoxia-induced oxidative stress and normal aged rats revealed that synaptic CAM kinase II in the rat brain was markedly activated through oxidative stress and aging. In accordance with the activation of CAM kinase II, the levels of phosphorylated synapsin I increased significantly in nerve terminals. Furthermore, it was found that vitamin E prevents these oxidative stress-induced abnormal processes in rat nerve terminals. These results suggest that oxidative stress and aging facilitate the mobilization of neurotransmitter-enclosing synaptic vesicles from the reserve pool in the nerve terminal, thereby inducing abnormal accumulation of synaptic vesicles in the synapse, and that vitamin E inhibits this process in the brain through its antioxidative action.
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Kaneai, N. , Fukui, K. , Koike, T. and Urano, S. (2012) Changes in the levels of CAM kinase II and synapsin I caused by oxidative stress in the rat brain, and its prevention by vitamin E. Advances in Bioscience and Biotechnology, 3, 1199-1205. doi: 10.4236/abb.2012.38146.
 Halliwell, B. (1989) Oxidants and the cerebral nervous system: Some fundamental questions. Acta neurologica Scandinavica, 126, 23-33.
 Keller, J.N., Schmitt, F.A., Scheff, S.W., Ding, Q., Chen, Q., Butterfield, D.A. and Markesbery, W.R. (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology, 64, 1152-1156.
 Yao, Y., Zhukareva, V., Sung, S., Clark, C.M., Rokach, J., Lee, V.N., Trojanowski, J.Q. and Pratico, D. (2003) Enhanced brain levels of 8,12-iso-iPF2alpha-VI differentiate AD from frontotemporal dementia. Neurology, 26, 436-437.
 Urano, S., Asai, Y., Makabe, S., Matsu., M, Izumiyama, N., Ohtsubo, K. and Endo, T. (1997) Oxidative injury of synapse and alteration of antioxidative defense systems in rats, and its prevention by vitamin E. European Journal of Biochemistry, 245, 64-70.
 Urano, S., Sato, Y., Otonari, T., Makabe, S., Suzuki, S., Ogata, M. and Endo, T. (1998) Aging and oxidative stress in neurodegeneration. BioFactor, 7, 103-112.
 Fukui, K., Omoi, N., Hayasaka, T., Shinkai, T., Suzuki, S., Abe, K. and Urano, S. (2002) Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Annals of the New York Academy of Sciences, 959, 275-284.
 Kaneai, N., Arai, M., Takatsu, H., Fuki, K. and Urano, S. (2012) Vitamin E inhibits oxidative stress-induced denaturation of nerve terminal proteins involved in neurotransmission. Journal of Alzheimer’s Disease, 28, 183-189.
 Arai, M., Saitoh, M., Takaysu, H., Fukui, K. and Urano, S. (2011) Dysfunction of the fusion of pre-synaptic plasma membranes and synaptic vesicles caused by oxidative stress, and its prevention by vitamin E. Journal of Alzheimer’s Disease, 24, 759-766.
 Hilfiker, S., Pierobone, V.A., Czernik, A.J., Kao, H.-T., Augustine, G.J. and Greengard, P. (1999) Synapsins as regulators of neurotransmitter release. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 354, 269-279.
 Greengard, P., Valtorta, F., Czernik, A.J. and Benfenati, F. (1993) Synaptic vesicle phosphoproteins and regulation of synaptic function. Science, 259, 780-785.
 Fukui, K. and Urano, S. (2007) Neuronal damage, cognitive impairment and alpha-tocopherol. In: Preedy, V.R. and Watson, R.R., Eds., The Encyclopedia of Vitamin E, CAB International, Oxon, 454-460.
 Dodd, P.R., Hardy, J.R., Oakley, A.E., Edwardson, J.A., Perry, E.K. and Delaunoy, J.P. (1981) A rapid method for preparing synaptosomes: Comparison with alternative procedures. Brain Research, 226, 107-118.
 Harman, D. (1956) Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology, 11, 298-300. doi:10.1093/geronj/11.3.298
 Harman, D. (1984) Free radical theory of aging: The free radical diseases. Age, 7, 111-131.
 Onodera, K., Omoi, N., Fuki, K., Hayasaka, T., Shinkai, T., Suzuki, S., Abe, K. and Urano, S. (2003) Oxidative damage of rat cerebral cortex and hippocampus, and changes in antioxidative defense systems caused by hyperoxia. Free Radical Research, 37, 367-372.
 Nishio, T., Miyadera, R., Sakai, R., Abe, K., Kanazawa, H., Fukui, K. and Urano, S. (2006) Increased F2-isoprostane levels in the rat brain and plasma caused by oxidative stress and aging, and inhibitory effect of vitamin E. Journal Clinical Biochemistry and Nutrition, 38, 161-166. doi:10.3164/jcbn.38.161
 Fukui, K., Takatsu, H., Shinkai, T., Suzuki, S., Abe, K. and Urano, S. (2005) Appearance of amyloid-β-like substances and delayed-type apoptosis in rat hippocampus CA1 region through aging and oxidative stress. Journal of Alzheimer’s Disease, 8, 299-309.
 Zhu, X., Smith M.A., Honda, K., Aliev, G., Moreira, P.I., Nunomura, A., Casadesus, G., Harris, P.L., Siedlak, S.L. and Perry, G. (2007) Vascular oxidative stress in Alzheimer’s disease. Journal of the Neurological Sciences, 257, 240-246. doi:10.1016/j.jns.2007.01.039
 Tretter, L. and Adam-Vizi, V. (1996) Early events in free radical-mediated damage of isolated nerve terminals: Effect of peroxides on membrane potential and intracellular Na+ and Ca2+ concentrations. Journal of Neurochemistry, 66, 2057-2066.
 Azzi, A. and Stocker, A. (2000) Vitamin E: Non-antioxidant roles. Progress in Lipid Research, 39, 231-255.
 Qin, S., Hu, X.Y., Xu, H. and Zhou, J.N. (2004) Regional alteration of synapsin I in the hippocampal formation of Alzheimer’s disease patients. Acta Neuropathologica, 107, 209-215. doi:10.1007/s00401-003-0800-4
 Sano, M., Ernest, C., Thomas, R.G., Klauber, M.R., Schafer, K., Grundman, M., Woodbury, P., Cotman, C.W., Pfeiffe, R.E., Schneide, R.L.S. and Thal, L.J. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s disease cooperative study. The New England Journal of Medicine, 336, 1216-1222.