Hyperalgesia, which often occurs in people suffering from alcohol use disorder, may drive excessive drinking and relapse. Emerging evidence suggests that the lateral habenula (LHb) may play a significant role in this condition. Previous research suggests that endocannabinoid signaling (eCBs) is involved in drug addiction and pain, and that the LHb contains core components of the eCBs machinery. We report here our findings in rats subjected to chronic ethanol vapor exposure. We detected a substantial increase in endocannabinoid-related genes, including Mgll and Daglb mRNA levels, as well as monoacylglycerol lipase (MAGL) protein levels, as well as a decrease in Cnr1 mRNA and type-1 cannabinoid receptor (CB1R) protein levels, in the LHb of ethanol-exposed rats. Also, rats withdrawing from ethanol exposure displayed hypersensitivity to mechanical and thermal nociceptive stimuli. Conversely, intra-LHb injection of the MAGL inhibitor JZL184, the fatty acid amide hydrolase inhibitor URB597, or the CB1R agonist WIN55,212-2 produced an analgesic effect, regardless of ethanol or air exposure history, implying that alcohol exposure does not change eCB pain responses. Intra-LHb infusion of the CB1R inverse agonist rimonabant eliminated the analgesic effect of these chemicals. Rimonabant alone elicited hyperalgesia in the air-, but not ethanol-exposed animals. Moreover, intra-LHb JZL184, URB597, or WIN55,212-2 reduced ethanol consumption in both homecages and operant chambers in rats exposed to ethanol vapor but not air. These findings suggest that LHb eCBs play a pivotal role in nociception and facilitating LHb eCBs may attenuate pain in drinkers.
C-Phycocyanin (C-PC), a kind of blue protein isolated from Spirulina platensis, can ameliorate hyperglycemia, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of C-PC on gluconeogenesis and glycogenesis in insulin resistant hepatocytes. Insulin resistance was induced by high glucose (HG) in human hepatocellular carcinoma (HepG2) cells. C-PC ameliorated glucose production and phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in HG-induced insulin resistant HepG2 cells. It also increased glucose uptake, glycogen content and glycogen synthase (GS) activation in HG-induced insulin resistant HepG2 cells. The data revealed the mechanism of C-PC in improving glucose homoeostasis via activating the IRS/PI3 K/Akt and SIRT1/LKB1/AMPK signaling pathway in insulin resistant hepatocytes. C-PC could be a promising leading compound for the development of a hypoglycemic agent.
Background
Astrocyte over-activation and extensive neuron loss are the main characteristic pathological features of spinal cord ischemia–reperfusion injury (SCII). Prior studies have placed substantial emphasis on the role of heat shock protein family A member 8 (HSPA8) on postischemic myocardial inflammation and cardiac dysfunction. However, it has never been determined whether HSPA8 participates in astrocyte activation and thus mediated neuroinflammation associated with SCII.
Methods
The left renal artery ligation-induced SCII rat models and oxygen–glucose deprivation and reoxygenation (OGD/R)-induced rat primary cultured astrocytes were established. The lentiviral vector encoding short hairpin RNA targeting HSPA8 was delivered to the spinal cord by intrathecal administration or to culture astrocytes. Then, the spinal neuron survival, gliosis, and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and its related pro-inflammatory cytokines were analyzed.
Results
SCII significantly enhanced the GFAP and HSPA8 expression in the spinal cord, resulting in blood–brain barrier breakdown and the dramatical loss of spinal neuron and motor function. Moreover, injury also increased spinal nuclear factor-kappa B (NF-κB) p65 phosphorylation, NLRP3 inflammasome-mediated caspase-1 activation, and subsequent interleukin (IL)-1β as well as IL-18 secretion. Silencing the HSPA8 expression efficiently ameliorated the spinal cord tissue damage and promoted motor function recovery after SCII, through blockade of the astrocyte activation and levels of phosphorylated NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Further in vitro studies confirmed that HSPA8 knockdown protected astrocytes from OGD/R-induced injury via the blockade of NF-κB and NLRP3 inflammasome activation.
Conclusion
Our findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.
Background: Chronic neuropathic pain often occurs with unclear mechanisms after brachial plexus root avulsion (BPRA) injuries. Emerging evidence suggests that the maladaptation of spinal glial glutamate transporter GLT-1 causes extracellular glutamate accumulation, contributing to central sensitization of chronic pain. Dexmedetomidine (DMET), an α2-adrenergic receptor (α2AR) agonist, widely used in the clinic as a sedative and analgesic drug, has been shown to inhibit glial activation. This study assessed DMET effects on BPRA induced pain and the possible involvement of GLT-1 regulation. Methods: The right C8 and T1 roots were avulsed to establish a lower trunk BPRA injury rat model and LPS-induced activation of rat primary cultured astrocytes. Then we used the molecular and behavioral assay combined with pharmacological manipulation to test the hypothesis that DMET attenuates the pain and neuroinflammation through restoring the GLT-1 function via PKA signaling.Results: The mechanical allodynia and thermal hyperalgesia appeared and reached the peak at 1-day post-injury (dpi) and persisted for at least 28 dpi. Notably, BPRA enhanced phosphorylated PKA levels, reduced GLT-1 expression, and caused an imbalance between anti- and proinflammatory cytokines in the affected spinal segments. Acute systemic or local DMET administration, at the un-sedative doses, demonstrated an analgesic effect. Moreover, a 3-days intrathecal DMET treatment ameliorated hyperalgesia and allodynia of BPRA injured rats by attenuating PKA phosphorylation, IL-1β, and IL-6, while restoring the levels of GLT-1, IL-4, and IL-10 in the spinal cord. Significantly, intrathecal administration of the selective PKA inhibitor H89 mimicked, but the PKA activator 8-Br-cAMP blocked DMET’s effects. Conclusion: Overall, these results suggest that PKA inactivation mediates DMET's analgesic effect for the pain induced by BPRA injury through the recovery of GLT-1 function.
Background: Chronic neuropathic pain often occurs with unclear mechanisms after brachial plexus root avulsion (BPRA) injuries. Emerging evidence suggests that the maladaptation of spinal glial glutamate transporter GLT-1 causes extracellular glutamate accumulation, contributing to central sensitization of chronic pain. Dexmedetomidine (DMET), an α2-adrenergic receptor (α2AR) agonist, widely used in the clinic as a sedative and analgesic drug, has been shown to inhibit glial activation. This study assessed DMET effects on BPRA induced pain and the possible involvement of GLT-1 regulation. Methods: The right C8 and T1 roots were avulsed to establish a lower trunk BPRA injury rat model and LPS-induced activation of rat primary cultured astrocytes. Then we used the molecular and behavioral assay combined with pharmacological manipulation to test the hypothesis that DMET attenuates the pain and neuroinflammation through restoring the GLT-1 function via PKA signaling.Results: The mechanical allodynia and thermal hyperalgesia appeared and reached the peak at 1-day post-injury (dpi) and persisted for at least 28 dpi. Notably, BPRA enhanced phosphorylated PKA levels, reduced GLT-1 expression, and caused an imbalance between anti- and proinflammatory cytokines in the affected spinal segments. Acute systemic or local DMET administration, at the un-sedative doses, demonstrated an analgesic effect. Moreover, a 3-days intrathecal DMET treatment ameliorated hyperalgesia and allodynia of BPRA injured rats by attenuating PKA phosphorylation, IL-1β, and IL-6, while restoring the levels of GLT-1, IL-4, and IL-10 in the spinal cord. Significantly, intrathecal administration of the selective PKA inhibitor H89 mimicked, but the PKA activator 8-Br-cAMP blocked DMET’s effects. Conclusion: Overall, these results suggest that PKA inactivation mediates DMET's analgesic effect for the pain induced by BPRA injury through the recovery of GLT-1 function.
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