Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Methamphetamine-associated cognitive decline is attenuated by neutralizing IL-1 signaling

Methamphetamine (METH) abusers are prone to develop a variety of comorbidities, including cognitive disabilities, and the immunological responses have been recognized as an important component involved in the toxicity of this drug. Cytokines are among the key mediators between systemic inflammatory status and tissue responses. One of these, interleukin 1 (IL-1), has been hypothesized to be involved in cognitive functions and also appears to play a pivotal role among inflammatory molecules. In the present study, we demonstrate that exposure of mice to METH markedly increased the protein level of IL-1β in hippocampal tissue. Additionally, METH administration induced a decline in spatial learning as determined by the Morris water maze test. We next evaluated the hypothesis that blocking IL-1β signaling can protect against METH-induced loss of cognitive functioning. The results indicated that METH-induced impaired spatial learning abilities were attenuated by co-administration of mouse IL-1 Trap, a dimeric fusion protein that incorporates the extracellular domains of both of the IL-1 receptor components required for IL-1 signaling (IL-1 receptor type 1 and IL-1 receptor accessory protein), linked to the Fc portion of murine IgG2a. This effect was associated with a decrease in hippocampal IL-1β level. The current study indicates for the first time that the loss of METH-related cognitive decline can be attenuated by neutralizing IL-1 signaling. Our findings suggest a potential new therapeutic pathway for treatment of altered cognitive abilities that occur in METH abusing individuals

Global Proteome Profiling of the Temporal Cortex of Female Rats Exposed to Chronic Stress and the Western Diet

The increasing consumption of highly processed foods with high amounts of saturated fatty acids and simple carbohydrates is a major contributor to the burden of overweight and obesity. Additionally, an unhealthy diet in combination with chronic stress exposure is known to be associated with the increased prevalence of central nervous system diseases. In the present study, the global brain proteome approach was applied to explore protein alterations after exposure to the Western diet and/or stress. Female adult rats were fed with the Western diet with human snacks and/or subjected to chronic stress induced by social instability for 12 weeks. The consumption of the Western diet resulted in an obese phenotype and induced changes in the serum metabolic parameters. Consuming the Western diet resulted in changes in only 5.4% of the proteins, whereas 48% of all detected proteins were affected by chronic stress, of which 86.3% were down-regulated due to this exposure to chronic stress. However, feeding with a particular diet modified stress-induced changes in the brain proteome. The down-regulation of proteins involved in axonogenesis and mediating the synaptic clustering of AMPA glutamate receptors (Nptx1), as well as proteins related to metabolic processes (Atp5i, Mrps36, Ndufb4), were identified, while increased expression was detected for proteins involved in the development and differentiation of the CNS (Basp1, Cend1), response to stress, learning and memory (Prrt2), and modulation of synaptic transmission (Ncam1, Prrt2). In summary, global proteome analysis provides information about the impact of the combination of the Western diet and stress exposure on cerebrocortical protein alterations and yields insight into the underlying mechanisms and pathways involved in functional and morphological brain alterations as well as behavioral disturbances described in the literature

Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats

Background: In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention. Methods: We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel-running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot). Results: Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel-running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein—Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)—enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel-running reversed this decline in the cortical levels of HK1 and MCT2. Conclusion: The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity

The Modification of the Ketogenic Diet Mitigates Its Stunting Effects in Rodents

The high fat and low carbohydrate ketogenic diet (HFKD) is extensively studied within the fields of numerous diseases, including cancer and neurological disorders. Since most studies incorporate animal models, ensuring the quality of ketogenic rodent diets is important, both in the context of laboratory animal welfare as well as for the accuracy of the obtained results. In this study we implemented a modification to a commonly-used ketogenic rodent chow by replacing non-resorbable cellulose with wheat bran. We assessed the effects of month-long treatment with either the unmodified or the modified HFKD on the growth and development of young male rats. Daily body weight, functional performance, and brain morphometric parameters were assessed to evaluate the influence of both applied diets on rodent development. Our results revealed that the unmodified ketogenic chow induced strong side effects that included weakness, emaciation, and brain undergrowth concomitant to growth inhibition. However, application of the ketogenic chow supplemented with wheat bran suppressed these adverse side effects, which was associated with the restoration of insulin-like growth factor 1 and a decrease in corticosterone levels. We have also shown that the advantageous results of the modified HFKD are not species- or sex-specific. Our data indicate that the proposed HFKD modification even allows for its application in young animals, without causing detrimental side effects.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Physical activity reduces anxiety and regulates brain fatty acid synthesis

Physical activity impacts brain functions, but the direct mechanisms of this effect are not fully recognized or understood. Among multidimensional changes induced by physical activity, brain fatty acids (FA) appear to play an important role; however, the knowledge in this area is particularly scarce. Here we performed global metabolomics profiling of the hippocampus and the frontal cortex (FC) in a model of voluntary running in mice. Examined brain structures responded differentially to physical activity. Specifically, the markers of the tricarboxylic acid (TCA) cycle were downregulated in the FC, whereas glycolysis was enhanced in the hippocampus. Physical activity stimulated production of myristic, palmitic and stearic FA; i.e., the primary end products of de novo lipogenesis in the brain, which was accompanied by increased expression of hippocampal fatty acid synthase (FASN), suggesting stimulation of lipid synthesis. The changes in the brain fatty acid profile were associated with reduced anxiety level in the running mice. Overall, the study examines exercise-related metabolic changes in the brain and links them to behavioral outcomes