J Neuroinflamm
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For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals. ⋯ The SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.
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Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. ⋯ Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases.
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The kinin B(1) receptor (B(1)R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B(1)R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B(1)R expression in the spinal cord dorsal horn, and the underlying mechanism. ⋯ This study highlights a new mechanism for B(1)R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.
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Tibia fracture in rats followed by cast immobilization leads to nociceptive, trophic, vascular and bone-related changes similar to those seen in Complex Regional Pain Syndrome (CRPS). Substance P (SP) mediated neurogenic inflammation may be responsible for some of the signs of CRPS in humans. We therefore hypothesized that SP acting through the SP receptor (NK1) leads to the CRPS-like changes found in the rat model. ⋯ Bone microarchitecture was measured using micro computed tomography (μCT). We observed that: (1) SP intraplantar injection induced mechanical allodynia, warmth and edema as well as the expression of nociceptive mediators in the hindpaw skin of normal rats, (2) LY303870 administered intraperitoneally after fracture attenuated allodynia, hindpaw unweighting, warmth, and edema, as well as cytokine and NGF expression, (3) LY303870 blocked fracture-induced epidermal thickening and BrdU incorporation after fracture, (4) anti-NGF antibody blocked SP-induced allodynia but not warmth or edema, and (5) LY303870 had no effect on bone microarchitecture. Collectively our data indicate that SP acting through NK1 receptors supports the nociceptive and vascular components of CRPS, but not the bone-related changes.
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The neuroinflammatory responses in the spinal cord following bone cancer development have been shown to play an important role in cancer-induced bone pain (CIBP). Lipoxins (LXs), endogenous lipoxygenase-derived eicosanoids, represent a unique class of lipid mediators that possess a wide spectrum of anti-inflammatory and pro-resolving actions. In this study, we investigated the effects of intrathecal injection with lipoxin and related analogues on CIBP in rats. ⋯ Taken together, the results of our study suggest that LXs and analogues exert strong analgesic effects on CIBP. These analgesic effects in CIBP are associated with suppressing the expression of spinal proinflammatory cytokines.