Effects of dexmedetomidine on cognitive dysfunction and neuroinflammation via the HDAC2/HIF-1α/PFKFB3 axis in a murine model of postoperative cognitive dysfunction.

Inhibition of histone deacetylase (HDAC) may be a useful approach in the treatment of disorders characterized by cognitive dysfunction. Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has demonstrated neuroprotective effects. Here, we attempted to investigate the protective effects of DEX on postoperative cognitive dysfunction (POCD) involving HDAC2. Male C57BL/6 mice were selected to develop a POCD model, where HDAC2, HIF-1α, and PFKFB3 expression was quantified. DEX was administered before POCD modeling. Then the cognitive function of POCD mice was evaluated with the open field and Y-maze tests. Meanwhile, lipopolysaccharide (LPS) was employed to induce BV-2 microglial cells to simulate the inflammatory response. The contents of TNF-α, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) in mouse serum and BV-2 cell supernatant. Abundant expression of HDAC2, HIF-1α, and PFKFB3 was confirmed in POCD mice (p < 0.05). Cognitive dysfunction in POCD mice could be alleviated following pharmacological inhibition of HDAC2 by FK228 (p < 0.05). Mechanistically, HDAC2 upregulated HIF-1α and PFKFB3 and promoted the secretion of inflammatory factors in LPS-exposed BV-2 cells (p < 0.05). DEX attenuated neuroinflammation and the resulting cognitive dysfunction by decreasing HDAC2 expression and HIF-1α-dependent PFKFB3 upregulation in POCD mice (p < 0.05). In conclusion, DEX-regulated HDAC2 may play an inhibitory role in mice with POCD through regulation of the HIF-1α/PFKFB3 axis.

Erratum to "Ulinastatin alleviates traumatic brain injury by reducing endothelin-1".

[This corrects the article DOI: 10.1515/tnsci-2021-0001.].

Ulinastatin alleviates traumatic brain injury by reducing endothelin-1.

BACKGROUND: Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). METHODOLOGY: A rat model of TBI was established. Animals were randomly divided into 2 groups - one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood-brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. RESULTS: UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. CONCLUSION: UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

Analgesic effects of gabapentin on mechanical hypersensitivity in a rat model of chronic pancreatitis.

Gabapentin, an anticonvulsant, is widely accepted as an alternative therapeutic agent for neuropathic pain and has proved to produce analgesic effects in a mouse model of visceral pain. However, it is unknown whether gabapentin is also analgesically effective in chronic pancreatitis. The aim of the present study was to investigate the role and underlying mechanisms of gabapentin in a rat model of chronic pancreatitis. Chronic pancreatitis induced by dibutyltin dichloride (DBTC) produced a marked increase in mechanical sensitivity of the abdomen after the establishment of the model. During the first day to the sixth day in the fourth week, Gabapentin was administered intraperitoneally daily at a dose of 100mg/kg. The behavioral test began 1h after drug administration. The analgesic effect of gabapentin was not evident with a single injection, but gabapentin significantly reduced the responsive frequencies to mechanical stimulation in rats with chronic pancreatitis from the third day to the end of the experiment. To explore the underlying mechanisms, the expression of alpha(2)delta-1 calcium channel subunit was examined in the thoracic spinal cord (T8-11). There was no significant change in alpha(2)delta-1 level of T8-11 following the first injection. But after the sixth injection, the alpha(2)delta-1 level of T8-11 in rats with chronic pancreatitis was declined. Taken together, the present study suggested that repeated administration of gabapentin daily could reduce mechanical hypersensitivity in the upper abdomen and produce an analgesic effect in a rat model of chronic pancreatitis. The down-regulation of alpha(2)delta-1 calcium channel subunit might be one of the mechanisms underlying the analgesic effect of gabapentin.

Blood serum profiling of the rat spinal nerve ligation model using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

Peripheral nerve injury, which gives rise to persistent chronic pain, has become an area of intense research activity, largely because it represents a disorder with a high unmet medical need. In this study, serum biomarkers of the spinal nerve ligation model were successfully investigated with the metabolomic method. The regulatory effect of gabapentin, a novel clinical antineuralgia drug, on biomarker levels in serum was also investigated. Rat serum extract samples were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A method of supervised multivariate analysis, the partial least squares-discrimination analysis (PLS-DA), was used to validate metabolic changes. In addition, another multivariate method, the orthogonal partial least-squares analysis (OPLS), was used to monitor the real biological variability and to detect potential biomarkers in the spinal nerve ligation model. The results demonstrated that the spinal nerve ligation model had several discriminating ions compared with the control model. Among the detectable metabolites, levels of norepinephrine were increased in the spinal nerve ligation model and were decreased to control levels by gabapentin.