Journal of pharmacological sciences
-
We examined whether deletion of inducible nitric oxide synthase (iNOS) could prevent lipid infusion-induced insulin resistance in iNOS-knockout and wild-type mice with the in vivo euglycemic-hyperinsulinemic clamp technique. Plasma NO metabolites were increased in lipid-infused wild-type mice, while they were not increased in iNOS-knockout mice. Plasma tumor necrosis factor-α levels were increased in both wild-type and iNOS-knockout by lipid-infusion. ⋯ The mRNA levels of inflammatory cytokines were also increased in the gastrocnemis of wild-type and iNOS-knockout mice by lipid infusion. Nitrotyrosine level in the gastrocnemius was increased in lipid-infused wild-type mice but it was not increased in iNOS-knockout mice. These results suggest that lack of iNOS prevents lipid infusion-induced skeletal muscle insulin resistance without attenuating cytokine levels.
-
The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. ⋯ In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1β- or bradykinin-induced prostaglandin E(2) production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.10319FP].
-
Oxidative stress plays pivotal roles in aging, neurodegenerative disease, and pathological conditions such as ischemia. We investigated the effect of sulforaphane and 6-(methysulfinyl) hexyl isothiocyanate (6-HITC), a naturally occurring isothiocyanate, on oxidative stress-induced cytotoxicity using primary neuronal cultures of rat striatum. Pretreatment with sulforaphane and 6-HITC significantly protected against H(2)O(2)- and paraquat-induced cytotoxicity in a concentration-dependent manner. ⋯ In contrast, sulforaphane and 6-HITC increased heme oxygenase-1 (HO-1) expression in neurons. However, zinc-protophorphyrin IX, a competitive inhibitor of HO-1, did not influence the protective effects of sulforaphane and 6-HITC. These results suggest that sulforaphane and 6-HITC prevent oxidative stress-induced cytotoxicity in rat striatal cultures by raising the intracellular glutathione content via an increase in γ-GCS expression induced by the activation of the Nrf2-antioxidant response element pathway.
-
Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor-mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. ⋯ BD1047, a σ-1-receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a σ-1 agonist. Haloperidol, a σ-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of σ receptors.
-
DJ-1, Parkinson's disease PARK7, acts as an oxidative stress sensor in neural cells. Recently, we identified the DJ-1 modulator UCP0054278 by in silico virtual screening. However, the effect of the peripheral administration of UCP0054278 on an in vivo Parkinson's disease (PD) model is unclear. ⋯ In addition, 6-OHDA- or rotenone-induced neural cell death and the production of reactive oxygen species were significantly inhibited by UCP0054278 in normal SH-SY5Y cells, but not in DJ-1-knockdown cells. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then produces antioxidant and neuroprotective responses in both in vivo and in vitro models of PD. The present study raises the possibility that DJ-1 stimulatory modulators, such as UCP0054278, may be a new type of dopaminergic neuroprotective drug for the treatment of PD.