Aim : Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI. Methods : The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing ( n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury. Results : Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment. Conclusion : Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.

No abstract

Neonatal sepsis and inflammation pose a potential source of morbidity and mortality in newborns, specifically in the first weeks of life. We have previously shown that vagus nerve stimulation modulates pro‐inflammatory cytokine expression in the Central Nervous System (CNS). The optimal vagus nerve stimulation (VNS) parameters to reduce inflammation have been unknown. In this study, we tested the hypothesis that vagus nerve stimulation reduces the expression of pro‐inflammatory cytokines in a lipopolysaccharide (LPS) model of airway inflammation. To test our hypothesis, we used intratracheal injections of LPS (0.5 mg/kg in 10 μL of saline) in neonatal Sprague Dawley rats (postnatal days 10 to 12) to induce pro‐inflammatory cytokine production. The P10–12 pups were anesthetized with isoflurane (2 to 4%) and then LPS was injected into the trachea to mimic airway inflammation. The experimental group was subjected to VNS at pre‐selected frequencies (ranging logarithmically from 10 to 10000 Hz) continuously for 30 minutes immediately after the LPS injection. Stimulation current was titrated down as needed to account for irregular breathing or apneas (typically approximately 0.5 mA). After recovery, each rat’s brainstem was collected and processed for cryosectioning and immunohistochemistry. We stained for and measured the expression of IL‐1 beta, TNF alpha, and HMGB1 in subjects with or without VNS (the positive control group received LPS without VNS). We then used ImageJ software and the particle analysis plug‐in to quantify the number of cells that expressed cytokines in the nucleus tractus solitarius (NTS). Using one‐way ANOVA analysis, our data showed a significant decrease (p < 0.05) in expression of IL‐1 beta, TNF alpha, and HMGB1 in LPS‐injected rats that underwent VNS compared to LPS‐injected rats that did not receive VNS. Frequencies of 10, 100, 1000, and 10000 Hz all resulted in significant decreases in cytokine expression. Cytokine expression in the LPS + VNS group was similar when compared to sham rats (no LPS injection or VNS). Our study showed that VNS significantly decreased the expression of the early inflammatory cytokines in LPS‐induced inflammation in neonatal rats. Blocking the early cytokine cascade may be associated with decreased inflammation and a concomitant reduction in associated symptoms in patients with sepsis. VNS used either alone or in conjunction with antibiotics may lead to improved outcomes in neonatal patients suspected to be affected by infection. Support or Funding Information This study was supported via a grant funded by the Pediatric Research Initiative at Loma Linda University.

No abstract

No abstract