Asimadoline

Pain after spinal cord injury (SCI) can be difficult to treat. Drugs that target the opioid receptor (OR) outside the central nervous system (CNS) have gained increasing interest in pain control owing to their low risk of central side effects. Asimadoline and ICI-204448 are believed to be peripherally restricted KOR agonists withlimited access to the CNS. This study examined whether they can attenuate pain hypersensitivity in mice subjected to a contusive T10 SCI. Subcutaneous (s.c.) injection of asimadoline (5, 20 mg/kg) and ICI-204448 (1, 10 mg/kg) inhibited heat hypersensitivity at both doses, but only attenuated mechanical hypersensitivity at the high dose. However, the high-dose asimadoline adversely affected animals' exploratory performance in SCI mice and caused aversion, suggesting CNS drug penetration. In contrast, high-dose ICI-204448 did not impair exploration and remained effective in reducing both mechanical and heat hypersensitivities after SCI. Accordingly, we chose to examine the potential peripheral neuronal mechanism for ICI-204448-induced pain inhibition by conducting in vivo calcium imaging of dorsal root ganglion (DRG) in Pirt-GCaMP6s^+/- mice. High-dose ICI-204448 (10 mg/kg, s.c.) attenuated the increased fluorescence intensity of lumbar DRG neurons activated by a noxious pinch (400 g) stimulation in SCI mice. In conclusion, systemic administration of ICI-204448 achieved SCI pain inhibition at doses that did not induce notable side effects and attenuated DRG neuronal excitability which may partly contribute to its pain inhibition. These findings suggest that peripherally restricted KOR agonists may be useful for treating SCI pain, but the therapeutic window must be carefully examined.

The bioconversion of onion extracts with P. acidilactici MNL5 enhances the metabolites and has a synergistic lipid-reduction impact that is beneficial for anti-obesity studies. The 48 h fermented onion extracts (FOE) demonstrated an enhanced inhibitory activity against pancreatic lipase (89.5 ± 1.25 %) as compared to the raw onion extract (ROE) (33.4 ± 0.86 %). The antioxidant properties of FOE significantly increased compared to the ROE inhibitory effect on DPPH (99.5 ± 2.40 mg vitamin C equiv./mg, DW FOE), and ABTS (104.5 ± 2.32 mg vitamin C equiv./mg, DW FOE). Based on FOE's higher antioxidant activity, UHPLC-Q-TOF-MS/MS demonstrated dramatic changes in the untargeted metabolite profile as compared to ROE. Moreover, C. elegans supplemented with FOE and quercetin exhibited an enhanced lifespan activity, lipid reduction, and decreased triglycerides. FOE can lower cholesterol and enhance quercetin to promote pancreatic lipase activity for synergistic anti-obesity effects.