Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo

This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPSinduced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders.

Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells

Large doses of acetaminophen (APAP) could cause oxidative stress and tissue damage through production of reactive oxygen/nitrogen (ROS/RNS) species and quinone metabolites of APAP. Although ROS/RNS are known to modify DNA, the effect of APAP on DNA modifications has not been studied systematically. In this study, we investigate whether large doses of APAP can modify the nuclear DNA in C6 glioma cells used as a model system, because these cells contain cytochrome P450-related enzymes responsible for APAP metabolism and subsequent toxicity (Geng and Strobel, 1995). Our results revealed that APAP produced ROS and significantly elevated the 8-oxo- deoxyguanosine (8-oxodG) levels in the nucleus of C6 glioma cells in a time and concentration dependent manner. APAP significantly reduced the 8- oxodG incision activity in the nucleus by decreasing the activity and content of a DNA repair enzyme, Ogg1. These results indicate that APAP in large doses can increase the 8-oxodG level partly through significant reduction of Ogg1 DNA repair enzyme.

Distribution of Neuropeptide mRNA-Containing Neurons and Changes of Their Gene Expression in the Rat Periaqueductal Gray in a Neuropathic Pain Model / 대한해부학회지

The distribution of enkephalin, dynorphin, substance P and neurotensin in the periaqueductal gray[PAG] has been well established by immunohistochemical methods. However, there is little information about the regional distribution of these neuropeptide mRNA-containing neurons in the PAG. The present study was undertaken [1] to elucidate the distribution of these neuropeptide mRNA-containing neurons and to determine of the PAG, [2] to know how peptide expression relates to the proposed functional subdivisions of the PAG and [3] to know how neuropeptide mRNA levels in the PAG change following peripheral neuropathy The results obtained are as follows ; 1. Preproenkephalin[pENK] mRNA-containing neurons are found mostly in the ventrolateral portion at all levels of the PAG. 2. Prodynorphin[pDYN] mRNA-containing neurons are concentrated mostly in the ventrolateral portion at the caudal level of the PAG. 3. Preprotachykinin[pTAK] mRNA-containing neurons are localized mainly in the ventrolateral portion at all levels of the PAG. There is small numbers of pTAK mRNA-containing neurons in the dorsolateral and dorsal portion at all levels of the PAG. 4. Proneurotensin[pNT] mRNA-containing neurons are concentrated mostly in the medial part of ventrolateral portion of the caudal and mid PAG. 5. Peripheral neuropathy induces an increase of pNT mRNA levels in the PAG, while pENK, pDYN and pTAK mRNAs levels show no change. The present results indicate that the pENK, pDYN, pTAK or pNT mRNA-containing neurons are found mainly in the ventrolateral PAG, the area where analgesia is most easily produced and that neurotensin in the PAG may play an important role in modulating chronic neuropathic pain.