Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice.

BACKGROUND: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern-induced cognitive decline. METHODS: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. RESULTS: Damage-associated molecular pattern-induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1ß: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1ß: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. CONCLUSIONS: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline.

Outcomes of 23-gauge pars plana vitrectomy combined with phacoemulsification and capsulotomy without intraocular lens implantation in rhegmatogenous retinal detachment associated with choroidal detachment.

Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a special type of complex retinal detachment, and usually has a poor prognosis. This study aimed to assess the anatomical outcomes of 23-gauge pars plana vitrectomy (23G PPV) combined with phacoemulsification (phaco) and capsulotomy without intraocular lens (IOL) implantation in patients with RRDCD.Seventy-six consecutive patients with RRDCD, who underwent retinal repair surgery from January 2010 to December 2014, were retrospectively analyzed. Forty patients underwent 23G PPV + phaco + IOL implantation, and 36 underwent 23G PPV + phaco + capsulotomy without IOL implantation (i.e., aphakia). All cases were filled with silicone oil. The follow-up time was 6 months after silicone oil was removed. Multivariate logistic regression analysis was the statistical method used.The overall retinal anatomical reattachment rate was 58% (44/76): 40% (16/40) of patients receiving 23G PPV + phaco + IOL implantation; and 78% (28/36) of patients receiving 23G PPV + phaco + capsulotomy + aphakia (P = .007).Surgical repair using 23G PPV + phaco + capsulotomy without IOL implantation can improve anatomical reattachment rates in patients with RRDCD.

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice.

Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2+ leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.

Exercise Prevents Enhanced Postoperative Neuroinflammation and Cognitive Decline and Rectifies the Gut Microbiome in a Rat Model of Metabolic Syndrome.

INTRODUCTION: Postoperative cognitive decline (PCD) can affect in excess of 10% of surgical patients and can be considerably higher with risk factors including advanced age, perioperative infection, and metabolic conditions such as obesity and insulin resistance. To define underlying pathophysiologic processes, we used animal models including a rat model of metabolic syndrome generated by breeding for a trait of low aerobic exercise tolerance. After 35 generations, the low capacity runner (LCR) rats differ 10-fold in their aerobic exercise capacity from high capacity runner (HCR) rats. The LCR rats respond to surgical procedure with an abnormal phenotype consisting of exaggerated and persistent PCD and failure to resolve neuroinflammation. We determined whether preoperative exercise can rectify the abnormal surgical phenotype. MATERIALS AND METHODS: Following institutional approval of the protocol each of male LCR and male HCR rats were randomly assigned to four groups and subjected to isoflurane anesthesia and tibia fracture with internal fixation (surgery) or anesthesia alone (sham surgery) and to a preoperative exercise regimen that involved walking for 10 km on a treadmill over 6 weeks (exercise) or being placed on a stationary treadmill (no exercise). Feces were collected before and after exercise for assessment of gut microbiome. Three days following surgery or sham surgery the rats were tested for ability to recall a contextual aversive stimulus in a trace fear conditioning paradigm. Thereafter some rats were euthanized and the hippocampus harvested for analysis of inflammatory mediators. At 3 months, the remainder of the rats were tested for memory recall by the probe test in a Morris Water Maze. RESULTS: Postoperatively, LCR rats exhibited exaggerated cognitive decline both at 3 days and at 3 months that was prevented by preoperative exercise. Similarly, LCR rats had excessive postoperative neuroinflammation that was normalized by preoperative exercise. Diversity of the gut microbiome in the LCR rats improved after exercise. DISCUSSION: Preoperative exercise eliminated the metabolic syndrome risk for the abnormal surgical phenotype and was associated with a more diverse gut microbiome. Prehabilitation with exercise should be considered as a possible intervention to prevent exaggerated and persistent PCD in high-risk settings.