No abstract

Nigella glandulifera seeds are used as a spice or remedy for the treatment of various inflammatory diseases. This study aimed to investigate analgesic (writhing test), anti-inflammatory (ear-induced edema, vascular permeability test), antioxidant, and antitumor activities of total saponins from this plant (TSN). TSN (6, 12, and 24 mg/kg) were exhibited analgesic and anti-inflammatory activities in a dose-dependent manner (P < 0.05). In D-galactose-induced ageing model, TSN significantly increased the plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities (P < 0.05) and decreased the malondialdehyde (MDA) level compared to control group (P < 0.05). DPPH radical scavenging effect of TSN was also found. Moreover, TSN (20 mg/mL) showed 86.75% and 88.26% inhibition of the growth on Bel-7402 and Hela cells, respectively. Five compounds were further isolated and identified from TSN as Nigella A, B, C, D, and nigeglanoside, of which the content of Nigella A was 60.36 ± 1.25 g/100 g TSN by HPLC-ELSD method. Altogether, these results suggest that TSN could be considered as a potential analgesic, anti-inflammatory, antitumor, and antioxidant agent.

Little is known about the impact of the blood-nerve barrier (BNB) on drug distribution into peripheral nerves. In this study, we examined the peripheral nerve penetration in rats of 11 small-molecule drugs possessing diverse physicochemical and transport properties and ProTx-II, a tarantula venom peptide with molecular mass of 3826 Daltons. Each drug was administered as constant rate intravenous infusion for 6 hours (small molecules) or 24 hours (ProTx-II). Blood and tissues including brain, spinal cord, sciatic nerve, and dorsal root ganglion (DRG) were collected for drug concentration measurements. Unbound fractions of a set of compounds were determined by equilibrium dialysis method in rat blood, brains, spinal cords, sciatic nerves, and DRG. We also investigated the influence of -[4-[2-(6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10-acridine-4-carboxamide (GF120918), a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor, on the peripheral nerve and central nervous system (CNS) tissue penetration of imatinib. We found that: 1) the unbound fraction in brain tissue homogenate highly correlates with that in the spinal cord, sciatic nerve, and DRG for a set of compounds and thus provides a good surrogate for spinal cord and peripheral nerve tissues, 2) small-molecule drugs investigated can penetrate the DRG and sciatic nerve, 3) P-gp and BCRP have a limited impact on the distribution of small-molecule drugs into peripheral nerves, and 4) DRG is permeable to ProTx-II, but its distribution into sciatic nerve and CNS tissues is restricted. These results demonstrate that small-molecule drugs investigated can penetrate peripheral nerve tissues, and P-gp/BCRP may not be a limiting factor at the BNB. Biologics as large as ProTx-II can access the DRG but not sciatic nerve and CNS tissues.

Neuropathic pain is elicited after a serious disorder of the nervous system and is along with the neural damage. It is usually chronic and challenging to treat. Transcription factor 4 (TCF4) is a key transcription factor of Wnt signaling system. Recent studies have shown that TCF4 interacts with β-catenin in the Wnt signaling pathway and coactivates downstream target genes in diverse systems. However, it is not well elucidated in the pathogenesis of neuropathic pain. In the present study, we investigated the role of TCF4 in the maintenance of neuropathic pain after chronic constriction injury (CCI) in rats. CCI induced persistent TCF4 upregulation in the dorsal root ganglion and spinal cord. Interestingly, TCF4 was mainly colocalized with neurons in the injured dorsal root ganglion and spinal cord on CCI day 7. Moreover, the expression patterns of β-catenin and glycogen synthase kinase-3β (GSK-3β) were parallel with that of TCF4 in vivo studies. Intrathecal injection of Wnt/β-catenin pathway inhibitor IWR-1-endo and TCF4 small interfering RNA (siRNA) significantly attenuated CCI-induced mechanical allodynia and heat hyperalgesia. The results suggest that TCF4 in the dorsal root ganglion and spinal cord is involved in the maintenance of CCI-induced neuropathic pain. Targeting TCF4 or Wnt/β-catenin signaling may be a potential treatment for chronic neuropathic pain.