The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD

dela Peñ,a, Irene Joy I.,Botanas, Chrislean Jun,de la Peñ,a, June Bryan,Custodio, Raly James,dela Peñ,a, Ike,Ryoo, Zae Young,Kim, Bung-Nyun,Ryu, Jong Hoon,Kim, Hee Jin,Cheong, Jae Ho Elsevier 2019 Progress in neuro-psychopharmacology & biological Vol.88 No.-

<P><B>Abstract</B></P> <P>Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (<I>Atxn7</I>) as a hyperactivity-associated gene. Here, we generated Atxn7 overexpressing (Atxn7 OE) mice to investigate whether the increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We previously found that Atxn7 is associated with ADHD-like behaviors. </LI> <LI> We generated mice that overexpresses Atxn7 in the brain (Atxn7 OE). </LI> <LI> The Atxn7 OE mice show hyperactivity and impulsivity, but not inattention. </LI> <LI> Atomoxetine attenuates the hyperactive and impulsive behavior of the Atxn7 OE mice. </LI> <LI> The Atxn7 OE mice may represent the hyperactive-impulsive subtype of ADHD. </LI> </UL> </P>

Transcriptional profiling of SHR/NCrl prefrontal cortex shows hyperactivity‐associated genes responsive to amphetamine challenge

dela Peñ,a, I. J. I.,dela Peñ,a, I.,de la Peñ,a, J. B.,Kim, H. J.,Sohn, A.,Shin, C. Y.,Han, D. H.,Kim, B.‐,N.,Ryu, J. H.,Cheong, J. H. Blackwell Publishing Ltd 2017 Genes, brain, and behavior Vol.16 No.7

<P>Several studies suggest a strong genetic component of attention‐deficit/hyperactivity disorder (ADHD), a complex neurodevelopmental disorder characterized by inappropriate levels of hyperactivity, impulsivity and inattention. Determining specific genetic risk variants for each symptom dimension of ADHD may aid in the identification of the biological risk factors of the disorder. In this study, we explored the potential genetic underpinnings of the hyperactive phenotype of ADHD. To this end, we examined differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of SHR/NCrl, an animal model of ADHD, compared with its genetic control, the Wistar Kyoto (WKY/NCrl) rat and the Wistar rat, strain used to represent the ‘normal’ heterogeneous population. Relative to WKY/NCrl and Wistar controls, SHR/NCrl showed hyperactivity in the open‐field test. Treatment with the ADHD drug, amphetamine (AMPH) reduced hyperactivity in SHR/NCrl. Meanwhile, AMPH increased locomotor activity in WKY/NCrl and Wistar rats. Gene expression analysis found 21 common upregulated and 36 downregulated genes in the PFC of drug‐naive SHR/NCrl when compared with WKY/NCrl and Wistar rats. Of these DEGs, expression levels of two genes, <I>Atxn7</I> and <I>Per2,</I> which are involved in transcription and circadian rhythm, respectively, were downregulated following AMPH treatment in SHR/NCrl. Quantitative real‐time‐polymerase chain reaction analyses verified expression patterns of these genes in the PFC of drug‐naïve and AMPH‐treated SHR/NCrl. The present findings indicate genetic risk variants that may be associated with the hyperactive phenotype in ADHD. Further studies are warranted to establish the roles of <I>Atxn7</I> and <I>Per2</I> in mediating hyperactivity.</P>

Propofol pretreatment induced place preference and self-administration of the tiletamine-zolazepam combination: implication on drug of abuse substitution

de la Peñ,a, June Bryan,Ahsan, Hafiz Muhammad,dela Peñ,a, Irene Joy,Park, Hyun Bin,Kim, Hee Jin,Sohn, Aeree,Kim, Yun Tai,Cheong, Jae Hoon Informa Healthcare USA, Inc. 2014 The American journal of drug and alcohol abuse Vol.40 No.4

<P><I>Background</I>: Propofol and the tiletamine-zolazepam combination are anesthetics with both sedative-hypnotic and hallucinogenic effects. In South Korea, propofol is controlled while the tiletamine-zolazepam combination is not. Thus, there is a possibility that this drug combination might be used as a substitute drug by propofol-abusers. <I>Objective</I>: In the present study we evaluated whether repeated pre-exposure to propofol predisposes to the use/abuse of the tiletamine-zolazepam combination. <I>Methods</I>: Rats (8-10 animals/group) were pre-treated with saline (control) or propofol at different dosages (10, 30, 60 mg/kg, i.p.), for 14 days, then conditioned place preference (CPP) and self-administration (SA) for the tiletamine-zolazepam combination were evaluated. <I>Results</I>: Rats pretreated with saline exhibited neither CPP nor SA for the tiletamine-zolazepam combination. On the other hand, rats pretreated with propofol, in all dosages, demonstrated significant CPP and SA for the tiletamine-zolazepam combination. <I>Conclusion</I>: These results suggest that tiletamine-zolazepam combinations might be used as a “substitute drug” by abusers of propofol. The careful use, dispensation, and monitoring of tiletamine-zolazepam combinations are advocated.</P>

Common prefrontal cortical gene expression profiles between adolescent SHR/NCrl and WKY/NCrl rats which showed inattention behavior

dela Peñ,a, Ike,Bang, Minji,Lee, Jinhee,de la Peñ,a, June Bryan,Kim, Bung-Nyun,Han, Doug Hyun,Noh, Minsoo,Shin, Chan Young,Cheong, Jae Hoon Elsevier 2015 Behavioural brain research Vol.291 No.-

<P><B>Abstract</B></P> <P>Factor analyses of attention-deficit/hyperactivity (ADHD) symptoms divide the behavioral symptoms of ADHD into two separate domains, one reflecting inattention and the other, a combination of hyperactivity and impulsivity. Identifying domain-specific genetic risk variants may aid in the discovery of specific biological risk factors for ADHD. In contrast with data available on genes involved in hyperactivity and impulsivity, there is limited information on the genetic influences of inattention. Transcriptional profiling analysis in animal models of disorders may provide an important tool to identify genetic involvement in behavioral phenotypes. To explore some of the potential genetic underpinnings of ADHD inattention, we examined common differentially expressed genes (DEGs) in the prefrontal cortex of SHR/NCrl, the most validated animal model of ADHD and WKY/NCrl, animal model of ADHD-inattentive type. In contrast with Wistar rats, strain representing the “normal” heterogeneous population, SHR/NCrl and WKY/NCrl showed inattention behavior in the Y-maze task. The common DEGs in the PFC of SHR/NCrl and WKY/NCrl vs. Wistar rats are those involved in transcription (e.g. <I>Creg1</I>, <I>Thrsp</I>, <I>Zeb2</I>), synaptic transmission (e.g. <I>Atp2b2</I>, <I>Syt12</I>, <I>Chrna5</I>), neurological system process (e.g. <I>Atg7</I>, <I>Cacnb4</I>, <I>Grin3a</I>), and immune response (e.g. <I>Atg7</I>, <I>Ip6k2</I>, <I>Mx2</I>). qRT-PCR analyses validated expression patterns of genes representing the major functional gene families among the DEGs (<I>Grin3a</I>, <I>Thrsp</I>, <I>Vof-16</I> and <I>Zeb2</I>). Although further studies are warranted, the present findings indicate novel genes associated with known functional pathways of relevance to ADHD which are assumed to play important roles in the etiology of ADHD-inattentive subtype.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We describe novel genes associated with inattention in SHR/NCrl and WKY/NCrl. </LI> <LI> These are genes involved in transcription, synapse transmission, immune system, etc. </LI> <LI> qRT-PCR validated expression patterns of <I>Grin3a, Zeb2, Vof-16</I> and <I>Thrsp</I>. </LI> <LI> Further studies are needed to determine their roles in ADHD inattentive subtype. </LI> </UL> </P>

Democracy and the Human Development Sequence

Jairo Acuñ,a–,Alfaro 연세대학교 빈곤문제국제개발연구원 2012 Journal of Poverty Alleviation and International D Vol.3 No.2

This paper provides a parsimonious empirical test of the relationship between democracy and HD, using time-series cross-sectional data on 164 countries from 1972 to 2002. The paper specifies a similar partial model to those found in the global comparative literature on democracy and development in an effort to replicate earlier findings and advance the proposition that there are strong reciprocal connections between HD and democratization that form two chains which reinforce one another cumulatively over time. The statistical analysis aims to show that the causal relationship forms two chains that run in both directions. This gives rise to virtuous and vicious circles, with good or bad performance on human development and democracy reinforcing each other. Cross-country partial regressions show a significant relationship in both directions. Yet evidence over time has strong sequential implications, and where a choice is necessary, democracy should be given sequencing priority over HD and economic growth, respectively. The discussion is relevant in lieu of ongoing debates about post 2015 Millennium Development Goals in regards to governance and democratization.

Stabilization of NaNO₃-Promoted Magnesium Oxide for High-Temperature CO₂ Capture

Triviñ,o, Monica Louise T.,Hiremath, Vishwanath,Seo, Jeong Gil ACS AMERICAN CHEMICAL SOCIETY 2018 Environmental science & technology Vol.52 No.20

Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate

dela Peñ,a, Ike,Jeon, Se Jin,Lee, Eunyoung,Ryu, Jong Hoon,Shin, Chan Young,Noh, Minsoo,Cheong, Jae Hoon Springer-Verlag 2013 Psychophamacology Vol.230 No.3

Lactobacillus aquaticus sp. nov., isolated from a Korean freshwater pond.

Mañ,es-Lá,zaro, Rosario,Song, Jaeho,Pardo, Isabel,Cho, Jang-Cheon,Ferrer, Sergi Society for General Microbiology 2009 International journal of systematic and evolutiona Vol.59 No.9

<P>A Lactobacillus strain, IMCC1736T, was isolated recently from a Korean freshwater pond following an extensive study of the microbial community in this ecosystem. Its 16S rRNA gene was sequenced and phylogenetic analysis placed this strain within the Lactobacillus salivarius group, closely related to Lactobacillus satsumensis NRIC 0604T, with 97.9% sequence similarity. In the present work, the taxonomic status of strain IMCC1736T has been re-evaluated. It was characterized phylogenetically, genotypically and phenotypically and, based on DNA-DNA hybridization values, this strain represents a novel Lactobacillus species. Strain IMCC1736T can be differentiated genotypically from its closest relatives by randomly amplified polymorphic DNA analysis and ribotyping patterns; phenotypically, it can be distinguished by its inability to grow in 5% NaCl and at pH 3.3 and by certain carbohydrate fermentations. Strain IMCC1736T is Gram-positive, catalase-negative and microaerophilic. Cells are motile rods and show homofermentative metabolism. The name Lactobacillus aquaticus sp. nov. is proposed, with strain IMCC1736T (=CECT 7355T=DSM 21051T) as the type strain.</P>

The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation

Muñ,oz-Fuentes, Violeta,Cacheiro, Pilar,Meehan, Terrence F.,Aguilar-Pimentel, Juan Antonio,Brown, Steve D. M.,Flenniken, Ann M.,Flicek, Paul,Galli, Antonella,Mashhadi, Hamed Haseli,Hrabě,de Springer Netherlands 2018 Conservation genetics Vol.19 No.4

<P>The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1007/s10592-018-1072-9) contains supplementary material, which is available to authorized users.</P>

Traditional oriental medicine for sensorineural hearing loss: Can ethnopharmacology contribute to potential drug discovery?

Castañ,eda, Rodrigo,Natarajan, Sathishkumar,Jeong, Seo Yule,Hong, Bin Na,Kang, Tong Ho Elsevier 2019 Journal of Ethnopharmacology Vol.231 No.-

<P><B>Abstract</B></P> <P><B>Ethnopharmacological relevance</B></P> <P>In Traditional Oriental Medicine (TOM), the development of hearing pathologies is related to an inadequate nourishment of the ears by the kidney and other organs involved in regulation of bodily fluids and nutrients. Several herbal species have historically been prescribed for promoting the production of bodily fluids or as antiaging agents to treat deficiencies in hearing.</P> <P><B>Aim of review</B></P> <P>The prevalence of hearing loss has been increasing in the last decade and is projected to grow considerably in the coming years. Recently, several herbal-derived products prescribed in TOM have demonstrated a therapeutic potential for acquired sensorineural hearing loss and tinnitus. Therefore, the aims of this review are to provide a comprehensive overview of the current known efficacy of the herbs used in TOM for preventing different forms of acquired sensorineural hearing loss and tinnitus, and associate the traditional principle with the demonstrated pharmacological mechanisms to establish a solid foundation for directing future research.</P> <P><B>Methods</B></P> <P>The present review collected the literature related to herbs used in TOM or related compounds on hearing from Chinese, Korean, and Japanese herbal classics; library catalogs; and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct).</P> <P><B>Results</B></P> <P>This review shows that approximately 25 herbal species and 40 active compounds prescribed in TOM for hearing loss and tinnitus have shown <I>in vitro</I> or <I>in vivo</I> beneficial effects for acquired sensorineural hearing loss produced by noise, aging, ototoxic drugs or diabetes. The inner ear is highly vulnerable to ischemia and oxidative damage, where several TOM agents have revealed a direct effect on the auditory system by normalizing the blood supply to the cochlea and increasing the antioxidant defense in sensory hair cells. These strategies have shown a positive impact on maintaining the inner ear potential, sustaining the production of endolymph, reducing the accumulation of toxic and inflammatory substances, preventing sensory cell death and preserving sensory transmission. There are still several herbal species with demonstrated therapeutic efficacy whose mechanisms have not been deeply studied and others that have been traditionally used in hearing loss but have not been tested experimentally. In clinical studies, <I>Ginkgo biloba</I>, <I>Panax ginseng</I>, and <I>Astragalus propinquus</I> have demonstrated to improve hearing thresholds in patients with sensorineural hearing loss and alleviated the symptoms of tinnitus. However, some of these clinical studies have been limited by small sample sizes, lack of an adequate control group or contradictory results.</P> <P><B>Conclusions</B></P> <P>Current therapeutic strategies have proven that the goal of the traditional oriental medicine principle of increasing bodily fluids is a relevant approach for reducing the development of hearing loss by improving microcirculation in the blood-labyrinth barrier and increasing cochlear blood flow. The potential benefits of TOM agents expand to a multi-target approach on different auditory structures of the inner ear related to increased cochlear blood flow, antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective activities. However, more research is required, given the evidence is very limited in terms of the mechanism of action at the preclinical <I>in vivo</I> level and the scarce number of clinical studies published.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>