Background: Depression and diabetes mellitus are increasingly recognized as comorbid chronic diseases. The relationship between diabetes and depression, argued to be bidirectional. Evidence is growing that depression and type 2 diabetes share biological origins, particularly overactivation of innate immunity leading to a cytokine-mediated inflammatory response, and potentially through dysregulation of the hypothalamic-pituitary-adrenal axis. Neuroinflammation forms the background for the induction of multiple cellular pathways which can lead to the complications of diabetes mellitus that the most debilitating ones is depression. Some studies suggest that regular moderate physical exercise has beneficial effects on the brain. It is believed that regular exercise decreases the levels of pro-inflammatory cytokines in the CNS, and therefore reduces cellular damage. 

Aim: Taking into account the above-mentioned facts, the present study is undertaken to evaluate whether physical activity (wheel running) could alleviate neuroinflammation in the rat’s brain and suppress depressive-like behavior of streptozotocin- induced diabetic rats.

Methods: 24 adult male Wistar rats (180-200 g) were randomly divided into four groups (n=6): Control group (CG), exercised group (EG), diabetic group (DG) and diabetic-exercised group (DEG). Diabetes was induced by injection of single dose of streptozotocin (35 mg/ kg, i.v.) in male rats. All rats in the trained groups, run on the running wheel for four weeks. At the end of the 4th week, sucrose preference test (SPT) and forced swim test (FST) were applied to all animals. After the tests the rats were decapitated and the hippocampi of animals were immediately removed on ice and kept frozen. The light supernatant was taken and stored at -80°C. They were used for determination of pro-inflammatory cytokine IL-1beta levels with sandwich ELISA.

Results:

    The influence of physical activity on the forced swimming test FST. 
 Physical activity in the running wheel significantly increase the climbing and swimming period and decrease immobility time in animals from DEG-group compared to DG-group (p<0.05), in forced swim test (FST). On the other hand there was no statistically significant differences between DEG-group and EG-group of animals (P>0.05). 



1.	The influence of physical activity on the sucrose preference test (SPT).
At 24h-SPT-test, preference index for sucrose was significantly higher in DEG-group (124±2,3%), compared to DG-group rats (90±1,4%), p<0.05. These results suggest that rats from DG-group have an anhedonik-like phenotype, unlike animals from the trained DEG-group.


2.	The influence of physical activity on levels of proinflammatory cytokine IL-1beta, measured by sandwich ELISA.
The influence of physical activity on the level of neuroinflammation, follows the same tendency. The lowest levels of IL-1beta were measured in EG-group of rats. DG-rats showed highest level of this cytokine. The statistically significant difference between those two groups was *** (p<0.001). The levels of IL-1beta was in the DEG-group were comparable with EG-group and statistically different (p<0.05) compared with DG-group.

   Discussion
In summary, the present study demonstrated that physical activity prevented enhancement of the levels of pro-inflammatory cytokines the diabetic rat hippocampus and ameliorates depression-like behaviors. Physical activity during 4 weeks, successfully restores the balance of cytokines in the brains of diabetic rats and in this way exert antidepressant effect. Our study demonstrated that neuroinflammation is the basis for depressive symptoms in the experimental animals with diabetes. On our knowledge, this is first study which investigated the effectiveness of exercise training on the depression of diabetic rats and its relation to the increased levels of pro-inflammatory cytokines.

Effects of physical activity on diabetes-induced depressive behavior and neuroinflammation in rats