Abstract
Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A1 and A2A receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7–11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A2A receptors and down-regulated A1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes.
Highlights
Reduced peripheral glucose regulation and diabetic conditions affect the central nervous system, contributing to diabetic encephalopathy [1]
This diabetes-induced memory impairment was prevented by caffeine consumption (P,0.05 between diabetes and diabetes+caffeine; Fig. 1), which was devoid of effects in control nondiabetic mice (P.0.05 between control and control+caffeine; Fig. 1)
Albeit the use of a single behavioural 1 day paradigm only allows a rough estimate of short term memory performance and do not allow determining if memory impairment results from deficits of memory formation and/or consolidation, the data obtained fulfils the targeted goal of supporting that a type 2 diabetic-like condition is associated with memory impairment, as occurs in humans [2,3,4]; these data suggest that longterm caffeine consumption might prevent diabetes-induced memory impairment
Summary
Reduced peripheral glucose regulation and diabetic conditions affect the central nervous system, contributing to diabetic encephalopathy [1]. The mechanisms underlying the development of diabetic encephalopathy and associated cognitive impairments remain unknown. Caffeine consumption alleviates cognitive impairment in both humans and animals [6,7], namely in Alzheimer’s disease [8,9,10], and affords protection upon CNS injury [11,12]. We found that streptozotocin-induced diabetes modifies the expression and density of adenosine receptors in the hippocampus [14], as occurs in most noxious brain conditions [11] and caffeine prevents streptozotocin-induced neurotoxicity [15,16]. We hypothesize that chronic caffeine treatment could prevent the alterations of neuropathology and function associated with the hippocampus known to occur in type 2 diabetes
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