engleski

The survey on brain monoamine alterations in diabetes mellitus and its possible causes

Diabetes mellitus is accompanied by numerous structural, biochemical and behavioral alterations of the central nervous system. In agreement with the frequent co-existence of diabetes and some mental, neurological and neuroendocrinological disorders whose etiopathogenesis is related to brain monoamine dysfunction, the most prominent neurochemical alterations in diabetes mellitus have been observed in brain monoaminergic transmission. Here we summarize the results of our neurochemical research on this topic. The experiments have been performed on rats with alloxan- and streptozotocin-induced diabetes and techniques used were spectrofluorimetry, HPLC with electrochemical detection, radioactive ligand binding methods and in situ hybridization. A part of research has been done on postmortal brain tissue of diabetic humans. We found a gradual, progressive increase in the level of brain dopamine (DA), noradrenaline (NA) and serotonin (5-HT) and a gradual decrease in the level of their respective metabolites and the turnover rate of these monoamines with the course of experimental diabetes. Alterations were seen only in particular brain regions and pronounced in striatum and hypothalamus (especially in human post mortal brain tissue). Regionally altered density, but unchanged affinity of dopaminergic D1 receptors have been found in experimental diabetes. Imbalance in monoamine synaptic transmission has been further documented in diabetic animals by a finding of altered expression of the membrane DA-, NA- and 5-HT-transporter mRNAs, which was regionally and monoamine specific. Our data on regional specificity of monoamine changes in the context of literature data on lack of concomitant regional specificity of blood brain barrier permeability for monoamine precursors in diabetes argued against the classical hypothesis that monoamine changes are due to reduced brain uptake of monoamine precursor amino acids. In order to investigate the possible cause of brain monoamine alterations in diabetes, we introduced a new experimental model, rats treated intracerebroventricularly (icv) with low, nondiabetogenic doses of alloxan and streptozotocin, drugs known to be selectively toxic to insulin-producing cells. Alterations of brain DA, NA and 5-HT (and its metabolite) content, turnover rate, receptor density and membrane transporter mRNA expression in brain of alloxan- and streptozotocin-icv treated animals were similar to those found in brain of alloxan- and streptozotocin-diabetic ones. However, in betacytotoxic-icv treated (nondiabetic) animals changes seemed to be reversible. Bearing in mind that insulin receptors and insulin, with its neuromodulatory role and monoamine interactions, have been found in brain, similarity of the brain monoamine changes produced by the two betacytotoxic drugs albeit via different mechanism of betacytotoxicity, suggests that monoamine changes may be related to these drugs-induced damage of the potentially insulin releasing/producing cells in brain. Supported by the Ministry of Science of Republic of Croatia and by a Wellcome Trust Travelling Research Fellowship awarded to M. Šalković-Petrišić.

diabetes mellitus; monoamines; brain

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