Oxidative stress has detrimental effects on cardiovascular and neurological function. In one project, we are investigating the role of lipid peroxidation products, formed during oxidative stress, in the development of tolerance to the vasodilator effects of the antianginal drug, nitroglycerin. Oxidative stress is considered to be a causative factor in age-related Alzheimer’s disease, and in another project, we have developed a mouse model of increased oxidative stress in which animals exhibit a number of pathological changes associated with Alzheimer’s disease, and also exhibit age-related cognitive impairment. We believe this model will provide greater insight into the pathogenesis/cellular mechanisms of Alzheimer’s disease, and will be useful in assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing disease progression.
- J.D. Artz, V. Toader, S.I. Zavorin, B.M. Bennett and G.R.J. Thatcher. In vitro activation of soluble guanylyl cyclase and nitric oxide release: A comparison of NO-donors and NO-mimetics. Biochemistry. 40: 9256-9264, 2001.
- G.M. Petari, D.H. Maurice, B.M. Bennett, and S.A. Waldman. Cyclic nucleotides and protein phosphorylation in vascular smooth muscle relaxation. In Heart Physiology and Pathophysiology, 4th Edition. Edited by N. Sperelakis, Academic Press, San Diego pp. 805-828, 2001.
- J.N. Reynolds, B.M. Bennett, R.J. Boegman, K. Jhamandas, J.D. Ratz, S.I. Zavorin, D. Scutaru, and G.R.J. Thatcher. Neuroprotection against ischemic brain injury conferred by a novel nitrate ester. Bioorg. Med. Chem. Lett. 12: 2863-2866, 2002.
- J.D. Ratz, M.A. Adams and B.M. Bennett. Effect of in vivo nitrate tolerance on the hypersensitivity to NO-donors after NO-synthase blockade. Can. J. Physiol. Pharmacol. 80: 1106-1118, 2002.
- Y. Ji and B.M. Bennett. Activation of microsomal glutathione S-transferase by peroxynitrite. Mol. Pharmacol. 63: 136-146, 2003.
- J. Difabio, Y. Ji, V. Vasiliou, G.R.J. Thatcher and B.M. Bennett. Role of mitochondrial aldehyde dehydrogenase in nitrate tolerance. Mol. Pharmacol. 64: 1109-1116, 2003.
- G.R.J. Thatcher, B.M. Bennett, H.C. Dringenberg, and J.N. Reynolds. Novel nitrates as NO mimetics directed at Alzheimer's Disease. J. Alzheimer's Dis. 6:S75-84, 2004.
- Y. Ji, I. Neverova, J.E. Van Eyk and B.M. Bennett. Nitration of tyrosine 92 mediates the activation of rat microsomal glutathione S-transferase by peroxynitrite. J. Biol. Chem. 281: 1986-1991, 2006.
- J.D. MacPherson, T.D. Gillespie, H.A. Dunkerley, D.H. Maurice and B.M. Bennett. Inhibition of phosphodiesterase type 5 selectively reverses nitrate tolerance in the venous circulation. J. Pharmacol. Expt. Ther. 317: 188-195, 2006.
- B.M. Bennett, J.N. Reynolds, G.T. Prusky, R.M. Douglas, R.J. Sutherland, and G.R.J. Thatcher. Cognitive deficits in rats after forebrain cholinergic depletion are reversed by a novel NO mimetic nitrate ester. Neuropsychopharmacol. 32: 505-513,2007.
- L.S. Wilson, H.S. Elbatarny, S.W. Crawley, B.M. Bennett and D.H. Maurice. Compartmentation and compartment-specific regulation of phosphodiesterase 5 by protein kinase G allows selective cyclic GMP mediated regulation of platelet functions. Proc. Natl. Acad Sci. USA. 105:13650-13655, 2008.
- Y. Ji, D.J. Anderson and B.M. Bennett. Role of microsomal glutathione transferase 1 in the mechanism-based biotransformation of glyceryl trinitrate in LLC-PK1 cells. Biochem. Pharmacol. 77: 1702-1708, 2009.
- Y. D’Souza, S. Dowlatshahi and B.M. Bennett. Changes in aldehyde dehydrogenase 2 expression in rat blood vessels during glyceryl trinitrate tolerance development and reversal. Br. J. Pharmacol. 164: 632-643, 2011.
- Y. D’Souza, Y. Ji and B.M. Bennett. Effect of overexpression of human aldehyde dehydrogenase 2 in LLC-PK1 cells on glyceryl trinitrate biotransformation and cGMP accumulation. Br. J. Pharmacol. 168: 978-987, 2013.
L. VandeVrede, R. Abdelhamid, Z. Qin, J. Choi, S. Piyankarage, J. Luo, J. Larson, B.M.Bennett, and G.R. J. Thatcher. An NO donor approach to neuroprotective and procognitive estrogen therapy overcomes loss of NO synthase function and potentially thrombotic risk. PLoS 1 Aug 16;8(8):e70740, 2013.
D’Souza Y, Kawamoto T, and Bennett BM. Role of the lipid peroxidation product, 4-hydroxynonenal, in the in the development of nitrate tolerance. Chem Res Toxicol. 27: 663-673, 2014.
D’Souza Y, Elharram A, Soon-Shiong R, Andrew RD and Bennett BM. Characterization of Aldh2-/- mice as an age-related model of cognitive impairment and Alzheimer’s Disease. Mol Brain, 8:27, 2015.
- Ben Aissa M, Lee SH, Bennett BM and Thatcher GRJ. Targeting NO/cGMP signaling in the CNS for neurodegeneration and Alzheimer’s Disease. Current Med Chem. 23:2770-2788, 2016.
Luo J, Lee SH, VandeVrede L, Qin Z, Ben Aissa M, Larson J, Teich AF, Arancio O, D'Souza Y, Elharram A, Koster K, Tai LM, LaDu MJ, Bennett BM, Thatcher GR. A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease. Mol Neurodegener. 11:35, 2016.
Berkowitz BA, Lenning J, Khetarpal N, Tran C, Wu JWm, Berri AM, Dernay K, Haacke EM, Shafie-Khorassani F, Podolsky RH, Gant JC, Maimaiti S, Thibaut O, Murphy GG, Bennett BM, Roberts R. In Vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer’s disease and Angelman Syndrome. FASEB J. 31:4179-4186, 2017
Elharram A, Czegledy NM, Golod M, Milne GL, Pollock E, Bennett BM, Shchepinov MS. Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer’s disease. FEBS J 284:4083-4095, 2017.