Minocycline Pretreatment Prevents Blood–Brain Barrier Disruption in Septic Rats

Abstract

Introduction:The aim of the study was to explore the mechanism by which minocycline protects the bloodebrain barrier (BBB) in septic rats.Methods: A sepsis rat model was generated in healthy, male SpragueeDawley rats by cecal ligation and puncture (CLP). The rats were randomly divided into four groups and treated as follows: sham-operated plus normal saline (Sham þ S group), CLP plus normal saline (CLP þ S group), CLP plus minocycline pretreatment (CLP þ M1 group), and CLP plus minocycline treatment (CLP þ M2 group). Rats in the CLP þ M1 group received 45 mg/kg minocycline by intraperitoneal injection every 12 h for 72 h. Rats in the Sham þ S and CLP þ S groups were injected with the same volume of normal saline every 12 h for 72 h.Rats in the CLP þ M2 group were intraperitoneally injected with 45 mg/kg minocycline immediately after CLP and once every 12 h for 72 h. All rats were sacrificed at 72 h after operation. Tumor necrosis factor a and interleukin 6 levels, the expression of ionized calcium-binding adaptor molecule-1 (Iba-1), and the permeability of the BBB were measured. The expression of matrix metalloproteinases-9 (MMP-9) and the tight junction proteins zonula occludens-1 (ZO-1) and occludin was detected by Western blot. In addition, Evans blue (EB) staining, immunohistochemistry, and ELISA analysis were carried out.Results: Minocycline pretreatment significantly inhibited microglial activation, decreased the sepsis-induced expression of MMP-9, increased the expression of ZO-1 and occludin, and improved the permeability of the BBB. Minocycline treatment failed to inhibit microglial activation, decrease the sepsis-induced expression of MMP-9, increase the expression of ZO-1 or occluding, or improve the permeability of the BBB.Conclusions: Minocycline pretreatment can effectively improve the altered permeability of the BBB caused by sepsis. The mechanism may be related to the inhibition of microglial activation and MMP-9 expression and increased expression of ZO-1 and occludin.

Minocycline Mitigates Sepsis-Induced Neuroinflammation and Promotes Recovery in Mice: Insights into Neuroprotection and Inflammatory Modulation

“…The beneficial effects of minocycline against acute and chronic brain injuries have been reported in previous studies in various models. In the CLP model of sepsis, minocycline has been shown to prevent oxidative stress, production of inflammatory cytokines (Michels et al, 2015), long-term potentiation impairment (Hoshino et al, 2017), and blood-brain barrier permeability (Yang et al, 2022). Moreover, the neuroprotective effects of minocycline against traumatic brain injury (Lu et al, 2022), epilepsy-induced brain inflammation (Wang et al, 2015), and ischemic stroke-induced brain inflammation and injury (Camargos et al, 2020) have been previously reported.…”

“…Mice received intraperitoneal injection of bacterial lipopolysaccharide (LPS from E. coli O55:B5, Sigma Aldrich) in 5 mg/kg dose or an equivalent volume of saline (in the control group) to induce sepsis (Anderson et al, 2015;Salmani et al, 2022;Zhao et al, 2020). Minocycline was administered in three distinct doses (12.5, 25, and 50 mg/kg) via gavage, starting three days before LPS injection and continuing until the day of sepsis induction (Hoshino et al, 2017;Yang et al, 2022). The control and sepsis groups received the same volume of the vehicle (10% DMSO).…”

Antibiotics and mental health: The good, the bad and the ugly

“…Having penetrated the blood–brain barrier, minocycline shows considerable activity, especially in impacting microglia [ 58 ]. Two polar opposite phenotypes of microglia have been described: pro‐inflammatory (M1) and anti‐inflammatory (M2).…”

Minocycline in depression not responding to first-line therapy: A systematic review and meta-analysis

“…Here, it is seen to suppress microglial activation. [ 42 ] Depression involves an imbalance between the pro-inflammatory M1 microglia and the anti-inflammatory M2 microglia. Minocycline suppresses M1-phenotypic microglia, restores neurogenesis, and corrects the neuroinflammatory markers.…”