Brain research
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The anticoagulant activated protein C (APC) protects neurons and vascular cells from injury through its direct cytoprotective effects that are independent of its anticoagulant action. Wild-type recombinant murine APC (wt-APC) exerts significant neuroprotection in mice if administered early after traumatic brain injury (TBI). Here, we compared efficacy and safety of a late therapy for TBI with wt-APC and 3K3A-APC, an APC analog with approximately 80% reduced anticoagulant activity but normal cytoprotective activity, using a controlled cortical impact model of TBI. ⋯ Three days post-TBI, the hemoglobin levels in the injured brain were increased by approximately 3-fold after wt-APC treatment compared to saline indicating an increased risk for intracerebral bleeding. In contrast, comparable levels of brain hemoglobin in 3K3A-APC-treated and saline-treated mice suggested that 3K3A-APC treatment did not increase risk for bleeding after TBI. Thus, compared to wt-APC, 3K3A-APC is more efficacious and safer therapy for TBI with no risk for intracerebral hemorrhage.
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Molecular mechanisms underlying bone cancer pain are poorly understood. Recently, p38 mitogen-activated protein kinase (MAPK) activation was shown to play a major role not only in the production of proinflammatory cytokines but also in the progression of inflammatory and neuropathic pain. We have demonstrated that tactile allodynia and spontaneous pain of female rats with tibia tumors were correlated with the increase of both phosphorylated-p38MAPK (p-p38MAPK) and proinflammatory cytokines (IL-1beta and TNF-alpha) in the spinal cord 6 days after Walker 256 cells' inoculation. ⋯ To characterize the cellular events upstream of p38MAPK, we have examined the role of the toll-like receptor 4 (TLR4), which had been suggested to be involved in pain hypersensitivity. We found that prolonged knockdown of TLR4 during the 3-day administration of TLR4 small interfering RNA (siRNA; 2 microg/rat/day, i.t.) could attenuate hyperalgesia developed by Walker 256 cells' inoculation and decrease the phosphorylation of p38 as well as the increase of IL-1beta and TNF-alpha expression. These results demonstrate that TLR4-dependent phosphorylation of p38MAPK in spinal cord of rats might contribute to the development and maintenance of bone cancer pain, and p38MAPK and TLR4 would possibly be the potential targets for pain therapy.
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The study was aimed to investigate the protective effects of rosuvastatin on spinal cord ischemia in rats and to determine the effects of this agent on the expressions of nitric oxide synthase (NOS). Spinal cord ischemia was induced in male Sprague-Dawley rats by occluding the descending thoracic aorta. Experimental groups (n=30 per group) were as follows: sham operation, control (receiving only normal saline), rosuvastatin (5 mg/kg/day for 10 days before occlusion), and rosuvastatin-mevalonate (5 mg/kg/day rosuvastatin and 5 mg/kg/day mevalonate for 10 days before occlusion). ⋯ However, rosuvastatin had no influence on nNOS mRNA and protein expression. Administrations of mevalonate completely reversed the changes caused by rosuvastatin. These results indicate that rosuvastatin can protect rat spinal cord against ischemia injury by modulation of NOS expressions.
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Endothelins as pronociceptive mediators of the rat trigeminal system: role of ETA and ETB receptors.
The trigeminal nerve is comprised of three main divisions, ophthalmic, maxillary and mandibular, each providing somatosensory innervation to distinct regions of the head, face and oral cavity. Recently, a role for endothelins in nociceptive signaling in the trigeminal system has been proposed. The present study aimed to gain better insight into the participation of the endothelin system in trigeminal nociceptive transmission. ⋯ Our behavioral data showed that ET-1 (3 to 30 pmol/site) induced overt nociceptive responses after injection into the upper lip or temporomandibular joint (TMJ) and hyperalgesic actions when applied to the eye, while ET-3 and the selective ET(B) receptor agonist IRL-1620 (each at 3 to 30 pmol/site) showed only the first two effects. Injection of BQ-123, but not BQ-788 (ET(A) and ET(B) receptor antagonists, respectively, 10 nmol/site each, 30 min beforehand), into the ipsilateral upper lip abolished ET-1 induced facial grooming, but both antagonists markedly reduced the nociceptive responses induced by ET-1 injected into the TMJ. Taken together, these findings suggest that endothelins, acting through ET(A) and/or ET(B) receptors, may play an important role in mediating pain resulting from activation of most trigeminal nerve branches.
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The olfactory bulbectomized (OBX) rat model is an animal model of depression. The deregulation of the serotonergic (5-HT) system is implicated in the pathophysiology of depression. Buspirone is a partial agonist of 5-HT(1A) receptors and is used in the treatment of depression and anxiety. ⋯ The receptors and 5-HTT densities were quantified in 38 brain regions as well as the pineal body. Chronic treatment with buspirone produced the following: 1) a decrease in the 5-HT(1B) densities, which was more pronounced in the Sham rats; 2) an increase in the 5-HT(2A) receptor densities, which was more pronounced in the Sham rats; and 3) an decrease in 5-HTT densities in both groups. The results indicate differential effects of chronic antidepressant treatment on the 5-HT system regulation in the OBX model of depression and normal rats.