Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors.

Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1ß, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.

Increased Renal Clearance of Rocuronium Compensates for Chronic Loss of Bile Excretion, via upregulation of Oatp2.

Requirement for rocuronium upon surgery changes only minimally in patients with end-stage liver diseases. Our study consisted of both human and rat studies to explore the reason. The reduction rate of rocuronium infusion required to maintain neuromuscular blockade during the anhepatic phase (relative to paleohepatic phase) was examined in 16 children with congenital biliary atresia receiving orthotopic liver transplantation. Pharmacodynamics and pharmacokinetics of rocuronium were studied based on BDL rats. The role of increased Oatp2 and decrease Oatp1 expressions in renal compensation were explored. The reduction of rocuronium requirements significantly decreased in obstructively jaundiced children (24 ± 9 vs. 39 ± 11%). TOF50 in BDL rats was increased by functional removal of the kidneys but not the liver, and the percentage of rocuronium excretion through urine increased (20.3 ± 6.9 vs. 8.6 ± 1.8%), while that decreased through bile in 28d-BDL compared with control group. However, this enhanced renal secretion for rocuronium was eliminated by Oatp2 knock-down, rather than Oatp1 overexpression (28-d BDL vs. Oatp1-ShRNA or Oatp2-ShRNA, 20.3 ± 6.9 vs. 17.0 ± 6.6 or 9.3 ± 3.2%). Upon chronic/sub-chronic loss of bile excretion, rocuronium clearance via the kidneys is enhanced, by Oatp2 up-regulation.

Protective effect of stellate ganglion block on delayed cerebral vasospasm in an experimental rat model of subarachnoid hemorrhage.

Stellate ganglion block (SGB) is a blockade of sympathetic ganglia innervating the head and neck, and is known to function through vasodilation of the target region. However, the effectiveness of SGB in relieving cerebral vasospasm (CVS) through dilation of intracerebral vessels has not been evaluated. The aim of the present study is to investigate the therapeutic effects of SGB in a rat model of subarachnoid hemorrhage (SAH) complicated by delayed CVS, and explore the underlying mechanisms. The SAH model was established by double injection of autologous arterial blood into the cisterna magna. We simulated SGB by transection of the cervical sympathetic trunk (TCST), and measured changes in the diameter, perimeter and cross-sectional area of the basilar artery (BA) and middle cerebral artery (MCA) to evaluate its vasodilatory effect. To investigate the underlying mechanisms, we determined the expression level of vasoactive molecules endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in the plasma, and apoptotic modulators Bcl-2 and Bax in the hippocampus. We found a significant increase in the diameter, perimeter and cross-sectional area of the BA and right MCA in SAH rats subjected to TCST. Application of SGB significantly reduced the expression of ET-1 while increasing that of CGRP in SAH rats. We also found a significant increase in the expression of Bcl-2 and decrease in the expression of Bax in the hippocampus of SAH rats subjected to TCST, when compared to untreated SAH rats. The mechanism of action of SGB is likely mediated through alterations in the ratio of ET-1 and CGRP, and Bax and Bcl-2. These results suggest that SGB can alleviate the severity of delayed CVS by inducing dilation of intracerebral blood vessels, and promoting anti-apoptotic signaling. Our findings provide evidence supporting the use of SGB as an effective and well-tolerated approach to the treatment of CVS in various clinical settings.

Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and -apoptosis actions in aged mice.

Although the underlying mechanisms of isoflurane-induced cognitive impairments remain largely to be determined, neuronal inflammation and apoptosis are thought to be major contributors. Resveratrol is a naturally available herbal compound for the treatment of inflammatory and neurodegenerative diseases. We therefore aimed to investigate the effects of resveratrol on the isoflurane-induced cognitive impairments and the associated hippocampal inflammation responses and neuronal apoptosis in the aged mice. Fifteen-month-old male C57BL/6 mice received 2 h of 1.5 % isoflurane or oxygen exposure 24 h after the intraperitoneal injection of resveratrol or saline daily for 7 consecutive days. Here, we showed that the isoflurane anesthesia decreased the freezing time to context significantly at 48 h after the isoflurane exposure in the fear conditioning test. The hippocampal levels of IL-1ß, TNF-α, NLRP3, cleaved caspase-3, and Bax increased significantly while the hippocampal levels of IkBα and Bcl-2 decreased significantly at 6 and/or 48 h after the isoflurane anesthesia. All these effects induced by isoflurane were attenuated by resveratrol pretreatment. However, the isoflurane anesthesia had no significant effect on the hippocampal Sirt1. In conclusion, our results suggest that resveratrol attenuates the hippocampus-dependent cognitive impairment induced by isoflurane anesthesia through its anti-inflammation and anti-apoptosis effects in aged mice.

Isoflurane preserves energy balance in isolated hepatocytes during in vitro anoxia/reoxygenation.

AIM: To investigate the protective effect of isoflurane on energy balance in isolated hepatocytes during in vitro anoxia/reoxygenation, and to compare isoflurane with halothane. METHODS: Hepatocytes freshly isolated from fed rats were suspended in Krebs-Henseleit buffer, and incubated in sealed flasks under O(2)/CO(2) or N(2)/CO(2) (95%/5%, V/V) for 30 or 60 min, followed by 5 or 10 min of reoxygenation, with an added volatile anesthetic or not. ATP, ADP, and adenosine monophosphate in hepatocytes were determined by high performance liquid chromatography, and energy charge was calculated. RESULTS: During 30 min of anoxia, the energy charge and total adenine nucleotide steadily increased with the isoflurane dose from 0 to 2 minimum alveolar anesthetic concentration (MAC), then decreased from 2 to 3 MAC. In short incubations (30-35 min) at 1 MAC isoflurane, energy charge modestly decreased during anoxia, which was partially prevented by isoflurane and completely reversed by reoxygenation, and total adenine nucleotide did not decrease. In long incubations (60-70 min), both energy charge and total adenine nucleotide greatly decreased during anoxia, with partial and no reversal by reoxygenation, respectively. Isoflurane partly prevented decreases in both energy charge and total adenine nucleotide during anoxia and reoxygenation. In addition, 1 MAC isoflurane obviously increased ATP/ADP, which could not be changed by 1 MAC halothane. CONCLUSION: Isoflurane partially protects isolated hepatocytes against decreases in both energy charge and total adenine nucleotide during short (reversible) or long (irreversible) anoxia.