Methotrexate Neurotoxicity Is Related to Epigenetic Modification of the Myelination Process.

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.

Minocycline restores cognitive-relative altered proteins in young bile duct-ligated rat prefrontal cortex.

AIMS: Bile duct ligation (BDL) model is used to study hepatic encephalopathy accompanied by cognitive impairment. We employed the proteomic analysis approach to evaluate cognition-related proteins in the prefrontal cortex of young BDL rats and analyzed the effect of minocycline on these proteins and spatial memory. MAIN METHODS: BDL was induced in young rats at postnatal day 17. Minocycline as a slow-release pellet was implanted into the peritoneum. Morris water maze test and two-dimensional liquid chromatography-tandem mass spectrometry were used to evaluate spatial memory and prefrontal cortex protein expression, respectively. We used 2D/LC-MS/MS to analyze for affected proteins in the prefrontal cortex of young BDL rats. Results were verified with Western blotting, immunohistochemistry, and quantitative real-time PCR. The effect of minocycline in BDL rats was assessed. KEY FINDINGS: BDL induced spatial deficits, while minocycline rescued it. Collapsin response mediator protein 2 (CRMP2) and manganese-dependent superoxide dismutase (MnSOD) were upregulated and nucleoside diphosphate kinase B (NME2) was downregulated in young BDL rats. BDL rats exhibited decreased levels of brain-derived neurotrophic factor (BDNF) mRNA as compared with those by the control. However, minocycline treatment restored CRMP2 and NME2 protein expression, BDNF mRNA level, and MnSOD activity to control levels. SIGNIFICANCE: We demonstrated that BDL altered the expression of CRMP2, NME2, MnSOD, and BDNF in the prefrontal cortex of young BDL rats. However, minocycline treatment restored the expression of the affected mediators that are implicated in cognition.

Prenatal dexamethasone exposure in rats results in long-term epigenetic histone modifications and tumour necrosis factor-α production decrease.

Glucocorticoid (GC) is often given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, reports and related research regarding the prolonged effects of prenatal GC on the development of immunity are very limited. Some data, derived from infants whose mothers were given immunosuppressants during pregnancy for the treatment of autoimmune disorders, suggest that prenatal exposure to GC may have only a limited effect on the development of the immune system. What is unknown is whether the immune modulation effects of prenatal GC might appear at a later childhood stage and beyond. Here we evaluated the immune programming influenced by prenatal GC. Pregnant Sprague-Dawley rats received dexamethasone (DEX; 0.1 mg/kg/day) or saline at gestational days 14-20. Male offspring were killed at day 7 or day 120 after birth. Spleens were collected for immune study. Of the inflammation mediators, matrix metalloproteinase-9, tumour necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor mRNAs decreased in the prenatal DEX group at an early stage after birth. Upon concanavalin A stimulation, prenatal DEX treatment reduced TNF-α production, but not interferon-γ production, by splenocytes at day 120 after birth compared with the vehicle group. Decreased levels of active chromatin signs (acetylation of histone H3 lysines, H3K4me1/3, and H3K36me3) in TNF-α promoter were compatible with the expressions of TNF-α. Our results suggest that prenatal DEX has a profound and lasting impact on the developing immune system even to the adult stage. Epigenetic histone modifications regulate TNF-α expression following prenatal DEX in rats.

Sex differences of oxidative stress to cholestatic liver and kidney injury in young rats.

BACKGROUND: Sexual dimorphism plays a role in the liver and in renal injuries. However, whether sex is a risk factor in bile duct ligation (BDL) in young rats has never been examined. METHODS: Six male and six female rats treated with BDL were sacrificed 2 weeks after surgery and were designated as BDL-M and BDL-F groups. The other six male and six female rats that received sham ligation were designated as sham-M and sham-F groups. Plasma biochemistry and liver and kidney asymmetric dimethylarginine (ADMA)-related molecules were examined. RESULTS: Both BDL-M and BDL-F groups had elevated plasma aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, and transforming growth factor-ß1 levels. The BDL-F group had lower plasma AST and ALT levels than the BDL-M group. The BDL-M and BDL-F groups had elevated plasma ADMA levels. The cationic amino acid transporter 1 (CAT1) level was increased in the BDL-F group as compared to the sham-F group, whereas the CAT2 level was reduced in the both BDL-M and BDL-F groups. CONCLUSION: We found that young male rats were prone to higher degrees of biochemical liver and kidney injury to cholestasis. Sex differences in modulation of oxidative stress markers, such as ADMA, may play a role. Our results support careful monitoring and optimal treatment of cholestatic disease, especially in young male patients.

Use of spectral entropy monitoring in reducing the quantity of sevoflurane as sole inhalational anesthetic and in decreasing the need for antihypertensive drugs in total knee replacement surgery.

BACKGROUND: The use of spectral entropy for monitoring the depth of anesthesia or level of hypnosis in surgery or painful procedures can reduce the consumption of drugs and shorten the recovery time of total intravenous anesthesia such as by propofol. The aim of this study was to investigate: (1) the consumption of sevoflurane as the sole anesthetic; and (2) hemodynamic stability in orthopedic surgery with tourniquet inflation under the guidance of spectral entropy, in contrast with the conventional method. METHODS: Sixty-five patients, ASA I or II, scheduled to undergo total knee replacement were enrolled and randomized into an entropy-guided group or a conventionally-monitored group. In the conventional group, the depth of anesthesia was judged by the clinical experience of the anesthesia provider based on the hemodynamic response. In the entropy group, state entropy (SE) and response entropy (RE) were kept within the range of 35-45 and an adequate gradient of 5-10 intraoperatively. The overall consumption of sevoflurane (mL) was monitored by the GE Datex-Ohemda S/5 Anesthetic Delivery Unit System. The physiologic changes during five major events in sequence in total knee replacement surgery, i.e., intubation, tourniquet inflation, skin incision, deflation and extubation, were observed closely over the first 5 minutes after each individual event. Within the first 5 minutes of each event, antihypertensive drugs were prohibited. The rest of the time, changes were recorded at 5-minute intervals and the use of rescue medication was allowed in case of need. We compared the heart rate, mean arterial pressure, SE, RE, sevoflurane concentration and rescue drugs in both groups. RESULTS: The sevoflurane consumption was significantly lower in the entropy group than in the conventional group (27.79 +/- 7.4 mL vs. 31.42 +/- 6.9 mL; p < 0.05). During the first 5 minutes of each major event, there were no significant differences in hemodynamics between the two groups. In the ensuing time, entropy-guided anesthesia was associated with significantly less frequent need of antihypertensive drugs (0.94 vs. 1.48 times; p = 0.043), especially in the 45-60 minutes after tourniquet inflation (p = 0.012). CONCLUSION: Using spectral entropy monitoring for guiding the depth of sevoflurane anesthesia in total knee replacement surgery can reduce its consumption and the frequency of use of antihypertensive drugs.