Abstract
Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.
Highlights
Depression is a complex mood disorder, characterized by loss of interest or pleasure, anhedonia, apathy, poor concentration, low energy, disturbed sleep and appetite, reduced social and sexual interest, among other symptoms [1, 2]
Propentofylline treatment together with LPS (PPF+LPS group) prevented the body weight loss induced by LPS both at days 4 and 5, compared with SAL+LPS group, reaching the same levels exhibited by the doi:10.1371/journal.pone.0169446.g001
Propentofylline treatment together with LPS (PPF+LPS group) prevented the locomotion reduction and the immobility increase induced by LPS at day 4, compared with SAL+LPS group, reaching the same levels exhibited by the control group
Summary
Depression is a complex mood disorder, characterized by loss of interest or pleasure, anhedonia, apathy, poor concentration, low energy, disturbed sleep and appetite, reduced social and sexual interest, among other symptoms [1, 2]. Little is still known about the etiology and pathophysiology of depression. It is regarded as a disorder of multifactorial causes, including genetic factors, stressful events, diseases, hormonal imbalance, and drug abuse [2, 8]. Smith [10] proposed the macrophage theory of depression, which states that the excessive secretion of interleukin (IL)-1 and other products of macrophages are involved in the pathogenesis of depression In this sense,https://translate.google.com/?tr=t&hl=pt-BR some patients diagnosed with depression have increased levels of cytokines such as tumor necrosis factor (TNF-α) and IL-6 in the blood [11]. Even low doses of lipopolysaccharide (LPS) administered to volunteer subjects are able to increase serum levels of proinflammatory cytokines and induce anhedonia, which is one of the main symptoms of depression [13]. LPS is an endotoxin that mimics infection by gram-negative bacteria by activating the immune system to release cytokines, such as TNF-α, IL-1β, and IL-6 [14,15,16]
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