Protection Against Electroshock- and Pentylenetetrazol-induced Seizures by the Water Extract of Rehmannia glutinous can be Mediated through GABA Receptor-chloride Channel Complexes

김미경,김희진,김성목,June Bryan de la Peña,Irene Joy dela Peña,Chrislean Jun Botanas,우태선,이용수,류종훈,정재훈 한국생약학회 2017 Natural Product Sciences Vol.23 No.1

Epilepsy is a brain disorder that affects millions of people worldwide. It is characterized by recurrent and unpredictable seizures that are usually controlled with antiepileptic/anticonvulsive drugs. However, most antiepileptic drugs produce various side effects such as tolerance and sedation. Thus, there is a growing interest for alternative anticonvulsive drugs, preferably from natural or herbal sources. In this study, we evaluated the anticonvulsive effects of Rehmannia glutinosa (RG). The anticonvulsive effect of RG extract was evaluated using electroshock- and chemical-induced seizure tests in mice. To identify its probable mechanism of action, the effects of RG extract on Cl- influx was measured in vitro. We found that RG extract has anticonvulsive effects against electroshock-induced seizures, as indicated by an increased seizure threshold in mice. The RG extract also decreased the percentage of seizure responses induced by the GABAergic antagonist, pentylenetetrazole. These results suggest that the anticonvulsive effects of RG extract are mediated through a GABAergic mechanism. In support of this mechanism, our in vitro test showed that RG extract increases intracellular Cl- influx. Furthermore, RG extract did not show sedative and/or muscle relaxant effects in the open-field and rota-rod tests. Altogether, these results confirm that RG extract could be a herbal anticonvulsant and a potential alternative for clinical use.

Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2

김미경,June Bryan de la Peña,정재훈,김희진 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.4

Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS.

Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Raly James Perez Custodio,Chrislean Jun Botanas,윤성순,June Bryan de la Peña,Irene Joy dela Peña,김미경,우태선,서정욱,장춘곤,권용호,김남용,이용섭,김희진,정재훈 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

The psychopharmacological activities of Vietnamese ginseng in mice: characterization of its psychomotor, sedativeehypnotic, antistress, anxiolytic, and cognitive effects

Irene Joy I. dela Peña,김희진,Chrislean Jun Botanas,June Bryan de la Peña,Thi Hong Van Le,Minh Duc Nguyen,박정힐,정재훈 고려인삼학회 2017 Journal of Ginseng Research Vol.41 No.2

Background: Panax vietnamensis Ha et Grushv. or Vietnamese ginseng (VG) is a recently discovered ginseng species. Studies on its chemical constituents have shown that VG is remarkably rich in ginseng saponins, particularly ocotillol saponins. However, the psychopharmacological effects of VG have not been characterized. Thus, in the present study we screened the psychopharmacological activities of VG in mice. Methods: VG extract (VGE) was orally administered to mice at various dosages to evaluate its psychomotor (open-field and rota-rod tests), sedativeehypnotic (pentobarbital-induced sleeping test), antistress (cold swimming test), anxiolytic (elevated plus-maze test), and cognitive (Y-maze and passiveavoidance tests) effects. Results: VGE treatment increased the spontaneous locomotor activity, enhanced the endurance to stress, reduced the anxiety-like behavior, and ameliorated the scopolamine-induced memory impairments in mice. In addition, VGE treatment did not alter the motor balance and coordination of mice and did not potentiate pentobarbital-induced sleep, indicating that VGE has no sedative-hypnotic effects. The effects of VGE were comparable to those of the Korean Red Ginseng extract. Conclusion: VG, like other ginseng products, has significant and potentially useful psychopharmacological effects. This includes, but is not limited to, psychomotor stimulation, anxiolytic, antistress, and memory enhancing effects.

A transgenic mouse showing sustained hyperactivity; a possible animal model of ADHD

DE LA PEÑ,A June Bryan,DELA PEÑ,A Irene Joy,KIM Hee Jin,SHIN Chan Young,CHEONG Jae Hoon 한국특수교육학회 2014 한국특수교육학회 학술대회 Vol.2014 No.-

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>

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>

Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms

Botanas, Chrislean Jun,Bryan de la Peñ,a, June,Custodio, Raly James,Joy dela Peñ,a, Irene,Kim, Mikyung,Woo, Taeseon,Kim, Hee Jin,Kim, Hye In,Chang Cho, Min,Lee, Yong Sup,Cheong, Jae Hoon Pergamon Press 2017 Neuropharmacology Vol.126 No.-

<P><B>Abstract</B></P> <P>Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MXE produced rapid and sustained antidepressant effects. </LI> <LI> Antidepressant effects MXE were blocked by NBQX, an AMPA receptor antagonist. </LI> <LI> Ketanserin, a 5HT2 receptor antagonist, attenuated antidepressant effects of MXE. </LI> <LI> MXE altered hippocampal glutamatergic and serotonergic-related gene expression. </LI> <LI> MXE's effects likely mediated by glutamertergic and serotonergic systems. </LI> </UL> </P>

Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice

Custodio, Raly James Perez,Botanas, Chrislean Jun,de la Peñ,a, June Bryan,dela Peñ,a, Irene Joy,Kim, Mikyung,Sayson, Leandro Val,Abiero, Arvie,Ryoo, Zae Young,Kim, Bung-Nyun,Kim, Hee Jin,C Elsevier 2018 NEUROSCIENCE Vol.390 No.-

<P><B>Abstract</B></P> <P>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 8–12% of children globally. Factor analyses have divided ADHD symptoms into two domains: inattention and a combination of hyperactivity and impulsivity. The identification of domain-specific genetic risk variants may help uncover potential genetic mechanisms underlying ADHD. We have previously identified that thyroid hormone-responsive (THRSP) gene expression is upregulated in spontaneously hypertensive rats (SHR/NCrl) and Wistar-Kyoto (WKY/NCrl) rats which exhibited inattention behavior. Thus, we established a line of THRSP overexpressing (OE) mice and assessed their behavior through an array of behavioral tests. The gene and protein overexpression of THRSP in the striatum (STR) was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The THRSP OE mice exhibited inattention in the novel-object recognition and Y-maze test, but not hyperactivity in the open-field test and impulsivity in the cliff-avoidance and delay-discounting task. We have also found that expression of dopamine-related genes (dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptors) in the STR increased. Treatment with methylphenidate (5 mg/kg), the most commonly used medication for ADHD, improved attention and normalized expression levels of dopamine-related genes in THRSP OE mice. Our findings suggest that THRSP plays a role in the inattention phenotype of ADHD and that the THRSP OE mice may be used as an animal model to elucidate the genetic mechanisms of the disorder.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Thyroid-hormone responsive (THRSP) overexpressing (OE) mice exhibits inattention, but not hyperactivity and impulsivity. </LI> <LI> THRSP OE mice have elevated striatal dopamine-related gene (DAT, TH, and dopamine D1 and D2 receptors) expression levels. </LI> <LI> Methylphenidate improves attention in THRSP OE mice. </LI> <LI> Methylphenidate normalizes the expression levels of dopaminergic-related genes in the striatum of THRSP OE mice. </LI> <LI> THRSP OE mice can be a potential mouse model for ADHD-inattentive type. </LI> </UL> </P>