Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models on neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of LTP. These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.
MicroRNAs are small non-coding RNA regulatory molecules that play an important role in the development and function of immune cells. MicroRNA-26a (miR-26a) exhibits anti-inflammatory immune effects on immune cells. However, the exact mechanism by which miR-26a plays an anti-inflammatory role remains unclear. Here, we report that miR-26a reduces inflammatory response via inhibition of prostaglandin E2 (PGE2) production by targeting cyclooxygenase-2 (COX-2). We found that miR-26a was downregulated
in vitro
and
in vivo
. The miR-26a mimic significantly decreased COX-2 protein levels, further inhibiting pro-inflammatory cytokine production in LPS-stimulated macrophages. We predicted that miR-26a could potentially target COX-2 in LPS-stimulated macrophages. Computational algorithms showed that the 3′-UTR of COX-2 mRNA contains a binding site for miR-26a. This putative targeting relationship between miR-26a and COX-2 was further confirmed by a dual-reporter gene assay. The anti-inflammatory effects of the miR-26a mimic were diminished by PGE2 supplementation. Importantly, miR-26a mimics protected mice from lethal endotoxic shock and attenuated pro-inflammatory cytokine production. Collectively, these results suggest that miR-26a may function as a novel feedback negative regulator of the hyperinflammatory response and as a drug target for the progression of inflammation.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10753-022-01631-2.
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