Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.

Neuropathic pain is a major symptom of multiple sclerosis (MS) with up to 92% of patients reporting bodily pain, and 85% reporting pain severe enough to cause functional disability. None of the available therapeutics target MS pain. Toll-like receptors 2 and 4 (TLR2/TLR4) have emerged as targets for treating a wide array of autoimmune disorders, including MS, as well as having demonstrated success at suppressing pain in diverse animal models. The current series of studies tested systemic TLR2/TLR4 antagonists in males and females in a low-dose Myelin oligodendrocyte glycoprotein (MOG) experimental autoimmune encephalomyelitis (EAE) model, with reduced motor dysfunction to allow unconfounded testing of allodynia through 50+ days post-MOG. The data demonstrated that blocking TLR2/TLR4 suppressed EAE-related pain, equally in males and females; upregulation of dorsal spinal cord proinflammatory gene expression for TLR2, TLR4, NLRP3, interleukin-1ß, IkBα, TNF-α and interleukin-17; and upregulation of dorsal spinal cord expression of glial immunoreactivity markers. In support of these results, intrathecal interleukin-1 receptor antagonist reversed EAE-induced allodynia, both early and late after EAE induction. In contrast, blocking TLR2/TLR4 did not suppress EAE-induced motor disturbances induced by a higher MOG dose. These data suggest that blocking TLR2/TLR4 prevents the production of proinflammatory factors involved in low dose EAE pathology. Moreover, in this EAE model, TLR2/TLR4 antagonists were highly effective in reducing pain, whereas motor impairment, as seen in high dose MOG EAE, is not affected.

Correlates of injection-related wounds and skin infections amongst persons who inject drugs and use a syringe service programme: A single center study.

Risk factors associated with wounds and skin infections amongst persons who inject drugs may have changed in the era of fentanyl and now stimulant coinjection. We assessed the number of injection site wounds and skin infections and associated factors amongst 675 persons who inject drugs in a syringe services programme. Of this sample, 173 participants reported a total of 307 wounds and skin infections. Significant factors associated with increased number of wounds and skin infections were age 30 or older, female gender, ever experiencing homelessness, cocaine injection, and injecting between 5 and 10 years. Wounds and skin infections were common amongst syringe services programme clients and are associated with certain risk factors that may help to design effective interventions. Given the high prevalence of wounds in syringe services programme clients, wound care clinicians can make a significant difference and improve outcomes. We also shed light on correlates of wounds and skin infections in persons who inject drugs in order to spur further research to devise efficacious interventions for this underserved group.

A single peri-sciatic nerve administration of the adenosine 2A receptor agonist ATL313 produces long-lasting anti-allodynia and anti-inflammatory effects in male rats.

Neuropathic pain is a widespread problem which remains poorly managed by currently available therapeutics. Peripheral nerve injury and inflammation leads to changes at the nerve injury site, including activation of resident and recruited peripheral immune cells, that lead to neuronal central sensitization and pain amplification. The present series of studies tested the effects of peri-sciatic nerve delivery of single doses of adenosine 2A receptor (A2aR) agonists on pain and neuroinflammation. The data provide converging lines of evidence supportive that A2aR agonism at the site of peripheral nerve injury and inflammation is effective in suppressing ongoing neuropathic pain. After A2aR agonism resolved neuropathic pain, a return of pain enhancement (allodynia) was observed in response to peri-sciatic injection of H-89, which can inhibit protein kinase A, and by peri-sciatic injection of neutralizing antibody against the potent anti-inflammatory cytokine interleukin-10. A2aR agonist actions at the nerve injury site suppress neuroinflammation, as reflected by decreased release of interleukin-1ß and nitric oxide, as well as decreased sciatic expression of markers of monocytes/macrophages and inducible nitric oxide synthase. Taken together, the data are supportive that A2aR agonists, acting at the level of peripheral nerve injury, may be of therapeutic value in treating chronic pain of neuroinflammatory origin.

HPTLC method for simultaneous determination of piperine, embeline, and carvone in the ayurvedic formulation Catpusphadhya churna.

Churnas are an important group of formulations used by traditional physicians to treat various types of diseases. The principle of using a churna is based on the fact that the therapeutic value of most substances greatly increases when they are reduced to a very fine state of subdivision. Catpusphadhya churna, as per the Ayurvedic system of Indian medicine, is used for acute rheumatoid arthritis. In the present study, an attempt was made to develop an HPTLC method for the quantitative determination of piperine, embeline, and carvone in a laboratory-prepared formulation. Raw materials used in formulations were obtained from two different suppliers and were subjected to methanol extractions by using a Soxhlet apparatus. Piperine, embeline, and carvone were quantified in the extracts by using HPTLC. The detection and quantification were performed at 254 nm. The formulation contained 2.35% (w/w) of piperine, 4.86% (w/w) of embeline, and 1.48% (v/w) of carvone. Linearity studies indicated that piperine, embeline, and carvone were in the linear ranges, while the recovery studies revealed a recovery of 99.32% (w/w) of piperine, 101.82% (w/w) of embeline, and 100.09% (v/w) of carvone, thus proving the accuracy of the analysis. The developed HPTLC method resolved and quantified piperine, embeline, and carvone effectively, so it could be an important method for the QC of polyherbal formulations.