Pharmacology/Drug Development

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).

KLS-13019, a novel devised cannabinoid-like compound, was explored for anti-inflammatory actions in dorsal root ganglion cultures relevant to chemotherapy-induced peripheral neuropathy (CIPN). Time course studies with 3 µM paclitaxel indicated > 1.9-fold increases in immunoreactive (IR) area for cell body GPR55 after 30 min as determined by high content imaging. To test for reversibility of paclitaxel-induced increases in GPR55, cultures were treated for 8 h with paclitaxel alone and then a dose response to KLS-13019 added for another 16 h. This "reversal" paradigm indicated established increases in cell body GPR55 IR areas were decreased back to control levels. Because GPR55 had previously reported inflammatory actions, IL-1β and NLRP3 (inflammasome-3 marker) were also measured in the "reversal" paradigm. Significant increases in all inflammatory markers were produced after 8 h of paclitaxel treatment alone that were reversed to control levels with KLS-13019 treatment. Accompanying studies using alamar blue indicated that decreased cellular viability produced by paclitaxel treatment was reverted back to control levels by KLS-13019. Similar studies conducted with lysophosphatidylinositol (GPR55 agonist) in DRG or hippocampal cultures demonstrated significant increases in neuritic GPR55, NLRP3 and IL-1β areas that were reversed to control levels with KLS-13019 treatment. Studies with a human GPR55-β-arrestin assay in Discover X cells indicated that KLS-13019 was an antagonist without agonist activity. These studies indicated that KLS-13019 has anti-inflammatory properties mediated through GPR55 antagonist actions. Together with previous studies, KLS-13019 is a potent neuroprotective, anti-inflammatory cannabinoid with therapeutic potential for high efficacy treatment of neuropathic pain.

This retrospective study analyzed the long-term effects of radiosynoviorthesis (RSO) with special emphasis to local joint pain in patients from 4 different RSO centers in Germany and Austria.

The pro-inflammatory cytokine TNFα is elevated in GI disease and sensitises colonic afferents via modulation of TRPA1 and Na 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα mediated colonic afferent sensitisation. Specifically, we show that: TNFα sensitises sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitisation of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitisation of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively this data supports the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in GI disease.

Clinical trials and observational studies with anti-calcitonin gene-related peptide antibodies poorly investigated their impact on migraine prodromal and accompanying symptoms. This information might help deciphering the biologics' pharmacodynamic and provide hints on migraine pathogenesis. Herein, we report the effects of erenumab, fremanezumab and galcanezumab on attack prodromal and accompanying symptoms and on neurological and psychiatric traits. .

Neuropathic pain (NP) is one of the most intractable diseases. The lack of effective therapeutic measures remains a major problem due to the poor understanding of the cause of NP. The aim of the present study was to investigate the effect of the long non‑coding RNA small nucleolar RNA host gene 5 (SNHG5) in NP and the underlying molecular mechanism in order to identify possible therapeutic targets. A chronic constriction injury (CCI) mouse model was used to investigate whether SNHG5 prevents NP and the inflammatory response. Luciferase and RNA pull‑down assays were used to detect the binding between SNHG5 and miR‑142‑5p as well as between miR‑142‑5p and CAMK2A. Western blot and qPCR were used to detect the RNA and protein expression. The results indicated that SNHG5 significantly inhibited CCI‑induced NP. In addition, SNHG5 inhibited the inflammatory response through decreasing the release and the mRNA expression of interleukin (IL)‑1β, IL‑6, IL‑10 and tumor necrosis factor‑α. Mechanistically, SNHG5 acted via sponging microRNA‑142‑5p, thereby upregulating the expression of calcium/calmodulin‑dependent protein kinase II α (CAMK2A). Further investigation indicated that CAMK2A knockdown also inhibited CCI‑induced NP and inflammation. In summary, the present study demonstrated that SNHG5 silencing could alleviate the neuropathic pain induced by chronic constriction injury via sponging miR‑142‑5p and regulating the expression of CAMK2A.

T helper 17 (Th17) lymphocytes play a critical role in the pathogenesis of autoimmune diseases, mainly by producing the pro-inflammatory cytokine interleukin-17 (IL-17). Therefore, Th17 lymphocytes have been considered a strategic target for drug discovery and development. In this study, we investigated the activity and possible mechanisms of action of a 4-phenyl coumarin isolated from propolis, named cinnamoyloxy-mammeisin (CNM), in Th17 cell differentiation and the development of experimental Th17-dependent autoimmune encephalomyelitis (EAE). Our data showed that in vitro Th17 cell differentiation was attenuated by CNM treatment in a concentration-dependent manner (1, 3, and 10 μM). This was associated with a reduction in the release of IL-17 (35% inhibition) and interleukin-22 (IL-22, 51% inhibition). Th17-differentiated cells exposed to CNM also downregulated the expression of Th17 hallmarked cell genes, such as RAR-related orphan receptor c (Rorc, 51% inhibition), and interleukin-23 receptor (Il23r, 64% inhibition), indicating possible upstream molecular mechanisms. Mechanistically, CNM significantly reduced the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) during in vitro Th17 cell differentiation. In vivo treatment with CNM (100 μg/kg) reduced the clinical signs of EAE, which was associated with a reduction in Central Nervous System demyelination, neuroinflammation, and Th17 response in the spinal cord and inguinal lymph nodes. Consistent with this, CNM also effectively attenuated human Th17 differentiation in vitro. Collectively, our results highlight the potential of CNM as a new molecule that can modulate Th17 cells via inhibition of STAT3 signaling and, as a result, reduce autoimmune inflammation.