BackgroundDexmedetomidine (Dex) can improve neuronal viability and protect the spinal cord from ischemia–reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. This study investigated the effects of dexmedetomidine on the toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NF-κB) inflammatory system and caspase-3 dependent apoptosis induced by spinal cord ischemia–reperfusion injury.MethodsTwenty-four rabbits were divided into three groups: I/R, Dex (10 µg/kg/h prior to ischemia until reperfusion), and Sham. Abdominal aortic occlusion was carried out for 30 min in the I/R and Dex groups. Hindlimb motor function was assessed using the Tarlov scoring system for gait evaluation. Motor neuron survival and apoptosis in the ventral grey matter were assessed by haematoxylin–eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling staining. The expression and localisation of ionised calcium-binding adaptor molecule 1, TLR4, NF-κB and caspase-3 were assessed by immunoreactivity analysis. The levels of interleukin 1β and tumour necrosis factor α were assessed using enzyme-linked immunosorbent assays.ResultsPerioperative treatment with dexmedetomidine was associated with a significant preservation of locomotor function following spinal cord ischemia–reperfusion injury with increased neuronal survival in the spinal cord compared to control. In addition, dexmedetomidine suppressed microglial activation, inhibited the TLR4-mediated NF-κB signalling pathway, and inhibited the caspase-3 dependent apoptosis.ConclusionsDexmedetomidine confers neuroprotection against spinal cord ischemia–reperfusion injury through suppression of spinal cord inflammation and neuronal apoptosis. A reduction in microglial activation and inhibition of both the TLR4-mediated NF-κB signalling pathway and caspase-3 dependent apoptosis are implicated.
Background Retrospective studies indicate that the use of regional anaesthesia causes a reduction in cancer recurrence after oncological surgery, which could be due to anaesthetic’s negating effect on immunosuppression related to the surgical stress response. Local anaesthetics may also exert direct suppressive effects on malignant cells, an area where further investigation is urgently needed. Methods Human colon cancer cells and human melanoma cells were cultured and then treated with 1 mM bupivacaine or levobupivacaine for up to 24 or 48 h. Their migratory ability was measured by scratch assay, proliferation determined with Ki67 immunofluorescence staining, and apoptosis accessed with annexin V and PI staining on flow cytometry. The effects of bupivacaine and levobupivacaine on cellular signaling and molecular response, specifically, on endoplasmic reticulum stress (ERS), were studied with immunostaining and western blot. Results In colon cancer cells, treatment with bupivacaine and levobupivacaine significantly inhibited cell migration (** p < 0.01, *** p < 0.001; n = 4) and proliferation (** p < 0.01; n = 4), while increasing the expression of CHOP (*** p < 0.001; n = 4) and decreased the expression of Grp78 (* p < 0.05; n = 4). These effects were not mirrored by melanoma cells, such that no significant increase in apoptosis was seen in either melanoma cell lines following treatment. Conclusion These in vitro data suggested that both bupivacaine and levobupivacaine suppress colorectal adenocarcinoma cell proliferation and migration, which are concurrent with increased endoplasmic reticulum stress. Conversely, melanoma cells are more resilient to these two commonly used local anaesthetics. Further in vivo studies or clinical trials are needed.
Background: Previous studies suggest that dexmedetomidine has a protective effect against local anaesthetic-induced nerve injury in regional nerve blocks. Whether this potentially protective effect exists in the context of diabetes mellitus is unknown. Methods: A diabetic state was established in adult male SpragueeDawley rats with intraperitoneal injection of streptozotocin. Injections of ropivacaine 0.5%, dexmedetomidine 20 mg kg À1 (alone and in combination), or normal saline (all in 0.2 ml) were made around the sciatic nerve in control and diabetic rats (n¼8 per group). The duration of sensory and motor nerve block and the motor nerve conduction velocity (MNCV) were determined. Sciatic nerves were harvested at post-injection day 7 and assessed with light and electron microscopy or used for pro-inflammatory cytokine measurements. Results: Ropivacaine and dexmedetomidine alone or in combination did not produce nerve fibre damage in control nondiabetic rats. In diabetic rats, ropivacaine induced significant nerve fibre damage, which was enhanced by dexmedetomidine. This manifested with slowed MNCV, decreased axon density, and decreased ratio of inner to outer diameter of the myelin sheath (G ratio). Demyelination, axon disappearance, and empty vacuoles were also found using electron microscopy. An associated increase in nerve interleukin-1b and tumour necrosis factor-a was also seen. Conclusions: Ropivacaine 0.5% causes significant sciatic nerve injury in diabetic rats that is greatly potentiated by highdose dexmedetomidine. Although the dose of dexmedetomidine used in this study is considerably higher than that used in clinical practice, our data suggest that further studies to assess ropivacaine (alone and in combination with dexmedetomidine) use for peripheral nerve blockade in diabetic patients are warranted.
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