Despite recent advances in our understanding of dementia of Alzheimer type (DAT) its etiology is still unknown. It is not known if the cholinergic deficit, detected in most DAT patients, is the primary pathological process or a consequence of other processes. There is considerable evidence indicating involvement of neurotransmitters other than acetylcholine in DAT. We have found a strong evidence for involvement of the dopaminergic and serotoninergic systems and would like to continue this investigation. This work will include application of a new approach to electrochemical detection of substances in cerebrospinal fluid (CSF). This detection involves use of multiple coulometric electrodes which are set at different voltages. We have a preliminary evidence indicating that liquid chromatography using amperometric detection leads to erroneously high estimates of CSF concentrations of DOPAC, HVA, MHPG, 5-HT and 5-HIAA. This error is due to presence of co-eluting interfering compounds which are indistinguishable by the amperometric method but can be differentiated from the authentic monoamine metabolites by the use of coulometric gates and multiple sensors. In addition to the coulometric method is more sensitive than the amperometric one and allows detection of norepinephrine, epinephrine and dopamine in CSF. Investigation with a 6-sensor system coulometric system also indicated presence of 5-HTP and 5-HT in a form which had already undergone oxidation of the 5-hydroxy group, presumably to the quinone. The partially oxidized 5-HT (5-HT-e) in DAT CSF is not metabolized by monomine oxidase. This could explain the aberrant relationship of 5-HT and 5-HIAA levels in rostral fraction of DAT CSF found by us previously. It is possible that 5-HT-e- participates in pathogenesis of DAT, since the neurotoxic effect of 6-hydroxy-dopamine is mediated by formation of a quinone intermediate. In this project we will investigate monoamines and their metabolites, as well as the abnormal form of 5-HT and other interfering substances, using an advanced version of the multidetector coulometric system. We plan to investigate these compounds and compare them in CSF from controls and DAT patients. The presence of a specific change of monoamine concentration or a specific interfering compound would provide not only a diagnostic procedure for DAT but it would give us also a clue for the pathogenesis of DAT. The possible role of 5-HT-e- in DAT will be tested by measuring 5-HT-e- in DAT brains and by investigation of 5-HT-e-neurotoxicity.
| Chen, J C; Fine, R E; Squicciarini, J et al. (1996) Neurotoxicity of free-radical-mediated serotonin neurotoxin in cultured embryonic chick brain neurons. Eur J Pharmacol 303:109-14 |
| Chen, J C; Schnepper, P W; To, A et al. (1992) Neurochemical changes in the rat brain after intraventricular administration of tryptamine-4,5-dione. Neuropharmacology 31:215-9 |
| Crino, P B; Vogt, B A; Volicer, L et al. (1990) Cellular localization of serotonin 1A, 1B and uptake sites in cingulate cortex of the rat. J Pharmacol Exp Ther 252:651-6 |
| Chen, J C; Crino, P B; Schnepper, P W et al. (1989) Increased serotonin efflux by a partially oxidized serotonin: tryptamine-4,5-dione. J Pharmacol Exp Ther 250:141-8 |
| Crino, P B; Ullman, M D; Vogt, B A et al. (1989) Brain gangliosides in dementia of the Alzheimer type. Arch Neurol 46:398-401 |
| Volicer, L; Chen, J C; Crino, P B et al. (1989) Neurotoxic properties of a serotonin oxidation product: possible role in Alzheimer's disease. Prog Clin Biol Res 317:453-65 |
