Details

Autor(en) / Beteiligte

• das Neves Duarte, João Miguel

Titel

Beneficial Effects of Caffeine Consumption on Diabetes-Induced Alterations in the Hippocampus

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2009

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The decline in memory and cognitive function is a normal consequence of aging and is accentuated by neurodegenerative pathologies, such as Alzheimer's disease, which cause progressive deterioration of learning and memory, attention and concentration, use of language, and other mental functions. Also peripheral glucose regulation decreases with age, leading to diabetes mellitus that contributes to the incidence of cognitive dysfunction. In fact, diabetes and insulin resistance are associated with modifications of morphology and plasticity in the hippocampus, a brain structure involved in learning and memory processing. Namely, there is a modification of neurotransmitter synthesis and release, long-term potentiation (which is an electrophysiological paradigm for memory formation and storage), synaptic connectivity and neuronal viability. The affection of the brain by diabetes has been called diabetic encephalopathy. The experimental work leading to the present doctoral thesis aimed at understanding which molecular and metabolic modifications occur in the hippocampus that may contribute to the dementia observed in diabetic patients. Different animal models of diabetes mellitus were studied: a model of type 1 diabetes that consisted on the treatment of rats with streptozotocin (STZ), a drug that destroys pancreatic β-cells, ceasing insulin production; Goto-Kakizaki (GK) rats that are spontaneously insulin resistant; and NONcNZO10/LtJ mice fed on 11% fat diet that constitute a model for type 2 diabetes associated with obesity, displaying a phenotype very similar to the human type 2 diabetes. As occurs with human diabetic patients, these animal models of diabetes display hippocampal-dependent memory impairment, suggested by reduced spontaneous alternation in a Y-maze. Learning and memory processes involve synaptic events and, accordingly, the different diabetic animal models displayed synaptic alterations in the hippocampus, namely synaptic degeneration characterized by a reduction of the density of proteins involved in neurotransmission such as syntaxin, synaptophysin or SNAP25. Along with synaptic degeneration, diabetes induced the occurrence of astrogliosis in the hippocampus, evaluated by both immunohistochemistry and Western blot analysis of glial fibrillary acidic protein (GFAP) and vimentin. The study of the kinetics of glucose transport in the hippocampus revealed that the transport of glucose across the blood-brain-barrier (BBB) is not altered in STZ-induced and GK diabetic rats. However, diabetes was found to alter the metabolism of [1-13C]glucose in the hippocampus, in particular suggesting that pathways of intermediary metabolism are rearranged in the diabetic hippocampus to deal with high glucose concentration (found in the hippocampus of these animals). Furthermore, in vivo 1H nuclear magnetic resonance (NMR) spectroscopy showed that, in comparison to controls, diabetic rats have alterations of the neurochemical profile of the hippocampus, which are related to osmolarity regulation rather than energy metabolism. Thus, uncontrolled diabetes characterised by chronic hyperglycaemia triggers mechanisms of osmotic compensation and induce an adaptation of intermediary metabolic pathways, possibly in the astrocytic compartment, in order to counteract the high glucose concentration and to maintain proper energetic balance for cellular homeostasis and neurotransmission. Since the mechanism of glucose transport across the BBB is not altered upon diabetes, chronic hyperglycaemia causes a permanent increase of glucose concentration in the hippocampus, leading to neurotoxicity and degeneration, which was observed to begin at the level of the synapse. Neuromodulation systems that are able to control both synaptic transmission and intermediary metabolism, namely those operated by adenosine, ATP and endocannabinoids, were found to be affected by diabetes, in particular in the hippocampus. Thus, chronic hyperglycaemia was observed to alter these three modulation systems in membranes from the synapse, where such systems modulate neurotransmission, and principally in membranes from the whole hippocampus that include membrane from neuronal cell bodies and glial cells, where they can be involved in the control of metabolism, cellular homeostasis, glial proliferation and neuroinflammation. In the particular case of the adenosinergic system, diabetes caused both down-regulation of inhibitory A1 receptors and up-regulation of facilitatory A2A receptors in the hippocampus. The antagonism of adenosine A2A receptors has been referred as having neuroprotective properties in the central nervous system subjected to chronic insults such as neurodegenerative pathologies. Thus it was tested the ability of caffeine (1 g/L in the drinking water), the most widely consumed psycho-active drug that acts as a non-selective antagonist of adenosine receptors, to counteract the hippocampal modifications found in the animal models of diabetes. The results obtained showed that caffeine may have beneficial effects on the management of diabetic encephalopathy. Thus, chronic caffeine consumption was able to prevent or attenuate most of the diabetes-induced molecular and metabolic alterations in the hippocampus, as well as the impairment of hippocampal-dependent spatial memory. In conclusion, the present work found several alterations induced by diabetic conditions to the hippocampus. Such alterations, in particular the synaptic degeneration, can contribute to the impairment of hippocampal-dependent learning and memory. Habitual caffeine intake was found to prevent or ameliorate these hippocampal alterations, as well as the memory deficits.