Propentofylline Prevents Sickness Behavior and Depressive-Like Behavior Induced by Lipopolysaccharide in Rats via Neuroinflammatory Pathway

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.

Fig 1. Body weight.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on the body weight of adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). *p < 0.05 and **p < 0.01, SAL+LPS vs. SAL+SAL; ^#p < 0.05, SAL+LPS vs. PPF+LPS; ⁺p < 0.05, SAL+SAL vs. PPF+SAL (two-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.

Fig 2. Open-field behavior.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on the open-field behaviors in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). ***p < 0.001, SAL+LPS vs. SAL+SAL; ^#p < 0.05 and ^##p < 0.01, SAL+LPS vs. PPF+LPS; ⁺⁺p < 0.01, SAL+SAL vs. PPF+SAL (two-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.

Fig 3. Anxiety-like behavior.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on the light-dark test in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). **p < 0.01 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.

Fig 4. Depressive-like behavior.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on the forced-swim test in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). *p < 0.05, **p < 0.01, ***p < 0.001 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.

Fig 5. TNF-α and BDNF.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on TNF-α and BDNF plasma levels in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). **p < 0.01 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.

Fig 6. GFAP photomicrographs.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on central glial fibrillary acidic protein (GFAP) expression. Photomicrographs of the medial prefrontal cortex, nucleus accumbens, and hippocampus analyzed by immunohistochemistry in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4.

Fig 7. GFAP expression.

Effects of LPS (1 mg/kg/day) and propentofylline (12.5 mg/kg/day) on glial fibrillary acidic protein (GFAP) expression in the medial prefrontal cortex, nucleus accumbens, and hippocampus, analyzed by immunohistochemistry in adult male rats. SAL+SAL, saline injection at days 1–5 and another saline injection 1 h later at days 3–4; SAL+LPS, saline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+LPS, propentofylline injection at days 1–5 and LPS injection 1 h later at days 3–4; PPF+SAL, propentofylline injection at days 1–5 and saline injection 1 h later at days 3–4 (n = 10 per group). *p < 0.05 and ***p < 0.0001 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± SEM.