Treatment with Autophagy Inducer Trehalose Alleviates Memory and Behavioral Impairments and Neuroinflammatory Brain Processes in db/db Mice

Abstract

Autophagy attenuation has been found in neurodegenerative diseases, aging, diabetes mellitus, and atherosclerosis. In experimental models of neurodegenerative diseases, the correction of autophagy in the brain reverses neuronal and behavioral deficits and hence seems to be a promising therapy for neuropathologies. Our aim was to study the effect of an autophagy inducer, trehalose, on brain autophagy and behavior in a genetic model of diabetes with signs of neuronal damage (db/db mice). A 2% trehalose solution was administered as drinking water during 24 days of the experiment. Expressions of markers of autophagy (LC3-II), neuroinflammation (IBA1), redox state (NOS), and neuronal density (NeuN) in the brain were assessed by immunohistochemical analysis. For behavioral phenotyping, the open field, elevated plus-maze, tail suspension, pre-pulse inhibition, and passive avoidance tests were used. Trehalose caused a slight reduction in increased blood glucose concentration, considerable autophagy activation, and a decrease in the neuroinflammatory response in the brain along with improvements of exploration, locomotor activity, anxiety, depressive-like behavior, and fear learning and memory in db/db mice. Trehalose exerted some beneficial peripheral and systemic effects and partially reversed behavioral alterations in db/db mice. Thus, trehalose as an inducer of mTOR-independent autophagy is effective at alleviating neuronal and behavioral disturbances accompanying experimental diabetes.

Trehalose Activates Hepatic and Myocardial Autophagy and Has Anti-Inflammatory Effects in db/db Diabetic Mice

“…Liver weight was greater both in untreated ( p < 0.001) and trehalose-treated db/db mice ( p < 0.01) vs. respective controls ( Figure 3 B). The consumption of trehalose with drinking water decreased the body weight of db/db mice compared to untreated db/db mice, which is in agreement with our previous results [ 10 ]. Spleen weight was ~2-fold greater in untreated db/db mice than in untreated C57BL/6 mice ( p < 0.001, Figure 4 ).…”

“…This beneficial effect of trehalose treatment was successfully demonstrated in our study in liver morphological analyses and in a liver functional test: the ALT activity assay [ 10 ]. A similar effect was documented when exogenous trehalose administration inhibited atherosclerosis development and attenuated hepatic steatosis in apoE −/− mice [ 72 ].…”

“…The aim of this study was to evaluate the effect of autophagy inducer trehalose on liver and heart autophagy in db/db mice and to investigate inflammation dysregulation and the suitability of chitinases’ expression levels as diabetes markers. Earlier, we showed a positive effect of trehalose as an autophagy inducer in brain structures (hypothalamus and amygdala) with a significant improvement of performance in behavioral tests [ 10 ]. Nonetheless, it still was not clear what the effects of trehalose are in organs such as the liver and heart.…”

“…Some compounds (β-glucans) have been proven to reduce risk factors of cardiovascular events, thereby improving the treatment of diabetes and of its complications [ 65 ]. Recently, trehalose, a known inducer of autophagy [ 10 , 66 , 67 ], was suggested as a possible therapeutic agent for the control of neurodegeneration and for the regulation of blood glucose levels. Trehalose treatment has significantly attenuated pathological changes in the hypothalamus (by inducing autophagy in this brain region) of mice and alleviated behavioral aberrations of mice in models of neurodegeneration.…”

“…Several experimental models have been proposed for studies on Type 2 diabetes pathogenesis, among them db/db mice, which feature a leptin receptor deficiency [ 5 ]. New preventive measures and therapeutic agents have been suggested and developed for normalizing the glycemic profile in patients with Type 2 diabetes [ 6 , 7 , 8 , 9 ], including autophagy inducer trehalose, which is also effective in the db/db mouse model of diabetes [ 10 ]. The main mechanisms underlying the beneficial (hepatoprotective) action of trehalose were suggested recently and include: suppression of inflammatory signaling, enhancement of antioxidant defense, and induction of autophagy [ 11 ], although this topic needs further study.…”