European journal of pharmacology
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Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 protein-induced lung injury. ⋯ Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 protein-triggered acute lung injury.
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The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. ⋯ AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α-induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)-WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors.
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Capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, has been reported to protect against ischemia-reperfusion injury in various organs, including the brain, heart, and kidney, whereas activation of TRPV1 was also reported to contribute to neurodegeneration, including pressure-induced retinal ganglion cell death in vitro. We histologically investigated the effects of capsaicin and SA13353, TRPV1 agonists, on retinal injury induced by intravitreal N-methyl-d-aspartic acid (NMDA; 200 nmol/eye) in rats in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection. ⋯ Cg-TgN(Thy1-CFP)23Jrs/J transgenic mice that express the enhanced cyan fluorescent protein in retinal ganglion cells in the retina. These results suggested that activation of TRPV1 protects retinal neurons from the injury induced by intravitreal NMDA in rats in vivo. Activation of CGRP and tachykinin NK1 receptors is possibly involved in underlying protective mechanisms.
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K(+) channels play important functional roles in excitable cells, as neurons and muscle cells. The activation or inhibition of K(+) channels hyperpolarizes or depolarizes the cell membrane, respectively. These effects determine in the smooth muscle decrease or increase in Ca(2+) influx through voltage-gated Ca(2+) (CaV1.2) channels and relaxation or contraction, respectively. ⋯ Therefore, KV7 channel activators could be used to relax the smooth muscle and relieve symptoms in diseases such as functional dyspepsia and irritable bowel syndrome with prevalent diarrhea. The discovery of activators selective for the channel subtypes present in the smooth muscle, mainly KV7.4 and 7.5, would allow avoiding adverse cardiac and nervous system effects. A further step forward would be characterizing putative differences among the KV7 channel subtypes expressed in the various smooth muscles and synthesizing molecules specific for the gastrointestinal smooth muscle.
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The present study has been undertaken to explore the potential of liver X receptor (LXR) modulator, T0901317, in dementia induced by streptozotocin (STZ) and cholesterol enriched diet. Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] and high fat diet (HFD, administered for 90 days) were used to induce dementia in separate groups of Swiss albino mice. The Morris water maze (MWM) test was used to evaluate the effect on cognitive functions. ⋯ T0901317 treatment significantly attenuated STZ and HFD-induced memory deficits, biochemical and histopathological alterations as well as HFD induced rise in cholesterol content. Hence the study indicates the potential role of liver X receptors in the pathophysiology of dementia. Therefore, the results demonstrate the defensive role of T0901317 in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative, anti-inflammatory and cholesterol lowering effects.