Pifithrin-μ Attenuates Acute Sickness Response to Lipopolysaccharide in C57BL/6J Mice

Abstract

Sickness behavior is a coordinated set of behavioral changes that happen as a response to acute infectious pathogens. Its well-known benefit is to reorganize the organism's priorities to cope with infection, but the uncontrolled development of sickness behavior may trigger negative feelings or chronic depressive events. This study aims at investigating the potential effect of pifithrin-μ, an inhibitor of heat shock protein 70 substrate binding activity, on lipopolysaccharide (LPS)-induced sickness response. C57BL/6J mice were submitted to the forced swimming test (FST), tail suspension test (TST), open field test (OFT) and light-dark box test. Food intake and body weight were also evaluated. The serum corticosterone level was measured using an ELISA kit. Treatment of mice with LPS (0.33 mg/kg, i.p.) markedly increased the floating and immobility time in the FST and TST, respectively, and depressed locomotor activity in the OFT. LPS administration prolonged the latency to first transition and reduced the total number of transitions in the light-dark box test. In addition, LPS induced anorexia and increased serum corticosterone levels. Pretreatment with pifithrin-μ (1 or 5 mg/kg) attenuated behavioral changes induced by LPS in the FST, TST, OFT and light-dark box test. Pifithrin-μ also prevented the formation of anorexia as well as the increase in serum corticosterone levels in LPS-treated mice. Our previous studies showed that pifithrin-μ prevents the production of pro-inflammatory factors in both microglia and macrophages. These findings presented here extend the role of pifithrin-μ beyond an anti-inflammatory molecule to a modulator of sickness behavior.

Pifithrin‐μ modulates microglial activation and promotes histological recovery following spinal cord injury

“…The mechanism of action of PFTμ has been associated with both the inhibition of mitochondria translocation of p53, and the inhibition of heat shock protein 70 (Hsp70). 17,31,46,47 In our experiments, PFTμ results in a shift of the polarization of microglia/macrophages from an "M1-like" to an "M2-like" phenotype, consistent with studies in peripheral models demonstrating that PFTμ reduces the expression of inflammatory markers, such as TNFα, IL-6, and iNOS, through inhibition of Hsp70. 48 These results also corroborate the findings that PFTμ has direct anti-inflammatory effects on the BV2 microglia cell line.…”

“…Foot prints were collected in sham mice and in SCI mice at 7 and 30 dpi (Figure B). Rear track width has been described previously as a sensitive measure of balance and posture, and as a measure of functional outcome in wild‐type mice following SCI . SCI mice treated with PFT‐μ exhibited a significant increase in rear track width over vehicle‐treated animals at 7 dpi, indicating moderate functional recovery (Figures B,C); however, this was not statistically significant at 30 dpi, despite an increasing trend toward improved functional outcome.…”

“…[58][59][60] PFTμ has also shown to have favorable effects, beyond its anti-inflammatory and HSP70 inhibition properties. 46 Together, we suggest that PFTμ should be considered as an adjunct to other therapies for SCI, as well as in conjunction with rehabilitation therapy.…”

Microglia Loss Contributes to the Development of Major Depression Induced by Different Types of Chronic Stresses

“…However, the fact is not like that. Activation of microglia by LPS and/or M-CSF treatment has been reported to promote the development of depressivelike symptoms [20,51]. Thus, these must be more sophisticated reasons for the differential effect of LPS and/or M-CSF treatment on depressive symptoms at the condition of with or without chronic stresses, and this is also the key point that we should resolve in the future.…”

Tauroursodeoxycholic Acid Ameliorates Lipopolysaccharide-Induced Depression Like Behavior in Mice via the Inhibition of Neuroinflammation and Oxido-Nitrosative Stress

“…The TST and FST were performed according to our previous studies [17,18]. For TST, the mice were individually suspended 50 cm above the floor for 6 min by adhesive tape placed approximately 1 cm from the tip of the tail.…”