Neuropsychopharmacological Understanding for Therapeutic Application of Morphinans

신은주,Jau-Shyong Hong,김형춘 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.10

Morphinans are a class of compounds containing the basic structure of morphine. It is wellknown that morphinans possess diverse pharmacological effects on the central nervous system. This review will demonstrate novel neuroprotective effects of several morphinans such as, dextromethorphan, its analogs and naloxone on the models of multiple neurodegenerative disease by modulating glial activation associated with the production of a host of proinflammatory and neurotoxic factors, although dextromethorphan possesses neuropsycotoxic potentials. The neuroprotective effects and the therapeutic potential for the treatment of excitotoxic and inflammatory neurodegenerative diseases, and underlying mechanism of morphinans are discussed.

Effects of Chronic Dextromethorphan Administration on the Cellular Immune Responses in Mice

Kim, Hyoung-Chun,Jhoo, Wang-Kee,Kwan, Myung-Sang,Hong, Jau-Shyong The Pharmaceutical Society of Korea 1995 Archives of Pharmacal Research Vol.18 No.4

We examined the chronic effect of dextromethorphan(DM) on the cellular immune responses in mice. T cell simulator, phytohemagglutinin did not show singificant effect on lymphocyte proliferation. Costimulator of T and B cell, pokeweed mitogen, and B cell stimulator, lipopolysaccharide exhibited DM-induced decreased lymphocyte proliferation. Singificantly suppressed natural killer (NR) cell cytotoxicity was evidenced following 6 months DM exposure. These results suggest that chronic DM administration pertub B cell functioning and NK cell cytotoxicity. In addition, prenatal DM exposure did not potentiate the immunomodulation in postnatal effect induced by chronic DM.

PKCδ-dependent p47<i>phox</i> activation mediates methamphetamine-induced dopaminergic neurotoxicity

Dang, Duy-Khanh,Shin, Eun-Joo,Kim, Dae-Joong,Tran, Hai-Quyen,Jeong, Ji Hoon,Jang, Choon-Gon,Ottersen, Ole Petter,Nah, Seung-Yeol,Hong, Jau-Shyong,Nabeshima, Toshitaka,Kim, Hyoung-Chun PERGAMON PRESS 2018 FREE RADICAL BIOLOGY AND MEDICINE Vol.115 No.-

<P><B>Abstract</B></P> <P>Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX <I>in vivo</I> remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47<I>phox</I>, and facilitated phosphorylation and membrane translocation of p47<I>phox</I>. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47<I>phox</I> or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47<I>phox</I> or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ <B>[</B>i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)<B>]</B>, or genetic inhibition of p47<I>phox</I> (i.e., p47<I>phox</I> KO or p47<I>phox</I> ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47<I>phox</I>. Therefore, we suggest that PKCδ is a critical regulator for p47<I>phox</I> activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47<I>phox</I>, is important for dopaminergic protection against MA insult.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Interplay between PKC and PHOX <I>in vivo</I> in the neurotoxic condition remains unclear. </LI> <LI> PKCδ co-immunoprecipitated with p47<I>phox</I> and facilitated the potential of p47<I>phox.</I> </LI> <LI> Methamphetamine-induced Nrf-2 system was mitigated by inhibition of p47<I>phox</I> or PKCδ. </LI> <LI> BSO potentiated microgliosis and apoptotic changes, leading to dopaminergic losses. </LI> <LI> PKCδ is a critical regulator for p47<I>phox</I> activation induced by methamphetamine. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

A pivotal role of matrix metalloproteinase‐3 activity in dopaminergic neuronal degeneration via microglial activation

Kim, Yoon Seong,Choi, Dong Hee,Block, Michelle L.,Lorenzl, Stefan,Yang, Lichuan,Kim, Youn Jung,Sugama, Shuei,Cho, Byung Pil,Hwang, Onyou,Browne, Susan E.,Kim, Soo Yul,Hong, Jau‐,Shyong,Flint Bea Federation of American Society for Experimental Bi 2007 The FASEB Journal Vol.21 No.1

<P>Recent studies have demonstrated that activated microglia play an important role in dopamine (DA) neuronal degeneration in Parkinson disease (PD) by generating NADPH-oxidase (NADPHO)-derived superoxide. However, the molecular mechanisms that underlie microglial activation in DA cell death are still disputed. We report here that matrix metalloproteinase-3 (MMP-3) was newly induced and activated in stressed DA cells, and the active form of MMP-3 (actMMP-3) was released into the medium. The released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3) led to microglial activation and superoxide generation in microglia and enhanced DA cell death. cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed culture of wild-type (WT) mice, but this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, nigrostriatal DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These results indicate that actMMP-3 released from stressed DA neurons is responsible for microglial activation and generation of NADPHO-derived superoxide and eventually enhances nigrostriatal DA neuronal degeneration. Our results could lead to a novel therapeutic approach to PD.</P>

Dextromethorphan Protect the Valproic Acid Induced Downregulation of Neutrophils in Patients with Bipolar Disorder

Ru-Band Lu,Yun-Hsuan Chang,Sheng-Yu Lee,Tzu-Yun Wang,Shu-Li Cheng,Po See Chen,Yen Kuang Yang,Jau-Shyong Hong,Shiou-Lan Chen 대한정신약물학회 2020 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.18 No.1

Objective: Valproic acid (VPA) is an anticonvulsant and commonly long term used as a mood stabilizer for patients with mood disorders. However its chronic effects on the hematological changes were noticed and need to be further evaluated. In this study, we evaluated, in Taiwanese Han Chinese patients with bipolar disorders (BD), the chronic effects of VPA or VPA plus dextromethorphan (DM) on the hematological molecules (white blood cell [WBCs], red blood cells [RBCs], hemoglobin, hematocrit, and platelets). Methods: In a 12-week, randomized, double-blind study, we randomly assigned BD patients to one of three groups: VPA plus either placebo (VPA+P, n = 57) or DM (30 mg/day, VPA+DM30, n = 56) or 60 mg/day (VPA+DM60, n = 53). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate symptom severity, and the hematological molecules were checked. Results: Paired t test showed that the WBC, neutrophils, platelets and RBCs were significantly lowered after 12 weeks of VPA+P or VPA+DM30 treatment. VPA+DM60 represented the protective effects in the WBCs, neutrophils, and RBCs but not in the platelets. We further calculated the changes of each hematological molecules after 12 weeks treatment. We found that combination use of DM60 significantly improved the decline in neutrophils induced by the long-term VPA treatment. Conclusion: Hematological molecule levels were lower after long-term treatment with VPA. VPA+DM60, which yielded the protective effect in hematological change, especially in the neutrophil counts. Thus, DM might be adjunct therapy for maintaining hematological molecules in VPA treatment.

ALDH2 Gene: Its Effects on the Neuropsychological Functions in Patients with Opioid Use Disorder Undergoing Methadone Maintenance Treatment

Po-Wei Lee,Tzu-Yun Wang,Yun-Hsuan Chang,Sheng-Yu Lee,Shiou-Lan Chen,Ze-Cheng Wang,Po See Chen,Chun-Hsien Chu,San-Yuan Huang,Nian-Sheng Tzeng,I Hui Lee,Kao Chin Chen,Yen Kuang Yang,Jau-Shyong Hong,Ru-B 대한정신약물학회 2020 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.18 No.1

Objective: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase 2 (ALDH2 ) gene has been associated with OUD and ALDH2 gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether ALDH2 genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT). Methods: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. ALDH2 gene polymorphisms were genotyped. Connors’ Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the ALDH2 genotypes and performance on the CPTs and WMS-R. Results: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the ALDH2 *1/*2+*2/*2 (ALDH2 inactive) genotypes had significantly higher commission error T-scores (p = 0.03), significantly lower hit reaction time T-scores (p = 0.04), and significantly lower WMS-R visual memory index scores (p = 0.03) than did patients with the ALDH2 1 */*1 (ALDH2 active) genotype. Conclusion: OUD patients with the ALDH2 inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the ALDH2 active genotype. We conclude that the ALDH2 gene is important in OUD and is associated with neuropsychological performance after MMT.