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October 25, 2016
10/25/2016 3:15:00 PM - 10/25/2016 5:15:00 PM
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Dexmedetomidine can Prevent Cognitive Dysfunction Following Abdominal Surgery in Aged Rats
Tsuyoshi Koyama, M.D., Takashi Kawano, M.D., Hideki Iwata, M.D., Daiki Yamanaka, M.D., Fabricio M. Locatelli, M.D., Masataka . Yokoyama, MD, Masataka . Yokoyama, MD, Masataka Yokoyama, M.D.
Kochi Medical School, Kochi, Japan
Disclosures:  T. Koyama: None. T. Kawano: None. H. Iwata: None. D. Yamanaka: None. F.M. Locatelli: None. M. Yokoyama: None.
Background: Post-operative cognitive dysfunction (POCD) is a common complication for geriatric surgical patients. Although the exact mechanism underlying POCD remains unclear, emerging evidence suggests that neuroinflammation, which includes microglia activation and increases in the levels of pro-inflammatory cytokines in the brain, plays a pivotal role in POCD development. Dexmedetomidine (DEX) has been widely used in clinical practice as a perioperative sedative agent. Previous research has shown that DEX can reduce the risk of perioperative cognitive outcomes in critical care or postoperatively. In addition, DEX has exhibited peripheral anti-inflammatory effects in patients with severe sepsis. In the present study, we investigated whether peri-operative DEX administration could regulate surgery-induced, microglia-mediated neuroinflammation and be effective for POCD in aged rats.

Methods: Aged rats, 20-25 months and weighing 500-680 g underwent abdominal or sham surgery, which were each divided into two groups, vehicle (saline) and DEX treatment (n=12 in each group). The abdominal surgery was performed under isoflurane anesthesia (1.5-2.0%) through a 2-cm midline incision, and small intestine was manipulated with fingers for 3 min. Sham control animals were only anesthetized and given analgesia in the same manner as surgical rats. In all the experiments, duration of isoflurane inhalation was strictly standardized at 10 min. Either vehicle or DEX (10 µg/kg) was administered intraperitoneally (i.p) either 1 hour prior to surgery and then every 6 hour for 3 days. Fourteen days after surgery, cognitive function was assessed using novel object recognition test, followed by measurement of hippocampal cytokines. In another experiment, microglia were isolated from hippocampus of naïve aged rats, and the effects of DEX on lipopolysaccharide (LPS)-induced cytokines release form hippocampal microglia were also tested. Differences between the data sets were evaluated by performing repeated-measure one-way analysis of variance test, followed by Bonferroni post hoc tests. Results with p<0.05 were considered statistically significant.

Results: During the period of isoflurane anesthesia, no differences in arterial oxygen saturation level, pulse rate, and body temperature were observed among groups. The administration of DEX produced a minimum spontaneous activity but intact righting reflex, which represents the clinical condition of conscious sedation. At the testing phase in novel object recognition test, the sham/vehicle-treated rats spent more time exploring the novel object than the familiar object, indicating intact recognition memory. On the other hand, the surgery/vehicle-treated rats exhibited significantly impaired novel object recognition performance. However, such impairment was not observed in the surgery/DEX-treatment group. In vehicle-treatment group, the levels of hippocampal TNF-α and IL-1β were significantly higher in surgery group than in sham group. However, these surgery-induced increases in cytokines were significantly decreased by the DEX-treatment. In another ex vivo experiment, LPS (10 nM) alone markedly induced IL-1β and TNF-α release from microglia compared with baseline. Pre-treatment with DEX (0.1-100 µM) significantly inhibited LPS-induced cytokines release in a dose-dependent manner.

Conclusion: The present results demonstrated that perioperative treatment with DEX at a sedative dose can inhibit the development of hippocampal inflammation and related memory deficits after abdominal surgery via inhibiting microglial activation. Since efficiency and safety profile of perioperative DEX has been established, our results warrant further study with respect to translational potential in the clinical management.

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