European journal of pharmacology
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The astrocytic glutamate transporters GLAST/EAAT1 and GLT-1/EAAT2 are crucial for the removal of glutamate from the synaptic cleft and are essential for maintaining a low concentration of extracellular glutamate in the brain. Enhanced transporter expression is neuroprotective. In the present study, we tested the neuropotective effects of maslinic acid, a natural product from the Olea europaea plant, on cultures of primary neurons from the cerebral cortex. ⋯ Real-time PCR and western blot analysis revealed that maslinic acid pre-treatment significantly increased the expression of GLAST and GLT-1 at the protein and mRNA levels. In addition, this neuroprotection was abolished by the glutamate transporter inhibitor, L-Threohydroxy aspartate (THA), in a co-culture of astrocytes and neurons. These findings suggest that maslinic acid regulates the extracellular glutamate concentration by increasing the expression of astrocytic glutamate transporters, which may, in turn, provide neuroprotection.
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In addition to analgesia opioids may also enhance pain sensitivity. Opioid-induced hyperalgesia, typically associated with potent mu-opioid agonists (e.g. fentanyl, morphine, and heroin), may be of clinical importance due to the possible counteraction of analgesia and/or paradoxical enhancement of a pre-existing pain condition during opioid therapy. Buprenorphine, a potent opioid analgesic, has a complex pharmacology on mu and kappa receptors. ⋯ The antinociceptive effect of buprenorphine was diminished in rats, which previously exhibited hyperalgesia with buprenorphine. In summary, bimodal properties of buprenoprhine were separately demonstrated: pronociceptive at ultra-low dose and antinociceptive at higher doses. An NMDA-receptor mechanism was involved in hyperalgesia with buprenorphine.
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This study investigated the expression of A(1) and A(2A) receptors in the rat colonic neuromuscular compartment, and characterized their roles in the control of motility during inflammation. Colitis was induced by 2,4-dinitrobenzenesulfonic acid. A(1), A(2A) receptors, and ecto-5'-nucleotidase (CD73, adenosine producing enzyme) mRNA expression was examined by RT-PCR. ⋯ AOPCP enhanced electrically-induced contractions and prevented the contractile effects of 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, without interfering with DPCPX, both in normal and inflamed colons. These results indicate that, in normal colon, both A(1) and A(2A) receptors contribute to the inhibitory control of motor functions at neuronal level. Under bowel inflammation, A(1) receptor loses its modulating actions, while the recruitment of A(2A) receptor by CD73-dependent endogenous adenosine drives an enhanced inhibitory control of colonic neuromotility.
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Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. ⋯ In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of psoralidin via blocking IKK/IκB signaling propagation in LPS-stimulated RAW 264.7 macrophages.
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Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. ⋯ Pretreatment with tempol (a SOD mimetic, 50mg/kg) or co-enzyme Q(10) (50mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via superoxide overproduction and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.