Baicalein Protects 6-OHDA-induced Neuronal Damage by Suppressing Oxidative Stress

Heh-In Im,Eunjoo Nam,Eun-sun Lee,Yu-jin Hwang,Yong Sik Kim 대한생리학회-대한약리학회 2006 The Korean Journal of Physiology & Pharmacology Vol.10 No.6

The protective effects of baicalein, one of the flavonoids in Scutellaria baicalensis Georgi, were evaluated against 6-hydroxydopamine (6-OHDA)-induced neuronal damage in mice and cultured human neuroblastoma cells. Nigrostriatal damage was induced by stereotaxically injecting 6-OHDA into the right striatum. Baicalein was administered intraperitoneally 30 min before and 90 min after lesion induction. Animals received a further daily injection of baicalein for 3 consecutive days. Two weeks after 6-OHDA injection, contralateral rotational asymmetry was observed by apomorphine challenge in lesioned mice. Tyrosine hydroxylase (TH) immunohistochemistry revealed a significant loss of terminals in lesioned striatum and the reduction of the numbers of TH-positive cell in the ipsilateral substantia nigra (SN). In addition, the levels of dopamine (DA) and DA metabolites were reduced and lipid peroxidation was increased in lesioned striatum. However, baicalein treatment reduced apomorphine-induced rotational behavior in 6-OHDA-lesioned mice, and increased TH immunoreactivity in the striatum and SN, and DA levels in lesioned striatum. Lipid peroxidation induced by 6-OHDA was also inhibited by baicalein treatment. Furthermore, when SH-SY5Y human neuroblastoma cells were treated with baicalein, 6-OHDA-induced cytotoxicity and reactive oxygen species (ROS) production were significantly reduced. These results indicate that baicalein effectively protects 6-OHDA-induced neuronal damage through antioxidant action.

Brain Reward Circuits in Morphine Addiction

Heh-In Im,Juhwan Kim,Suji Ham,Heeok Hong,Changjong Moon 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.9

Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symp-toms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences.

Baicalein Protects 6-OHDA-induced Neuronal Damage by Suppressing Oxidative Stress

Im, Heh-In,Nam, Eun-Joo,Lee, Eun-Sun,Hwang, Yu-Jin,Kim, Yong-Sik The Korean Society of Pharmacology 2006 The Korean Journal of Physiology & Pharmacology Vol.10 No.6

The protective effects of baicalein, one of the flavonoids in Scutellaria baicalensis Georgi, were evaluated against 6-hydroxydopamine (6-OHDA)-induced neuronal damage in mice and cultured human neuroblastoma cells. Nigrostriatal damage was induced by stereotaxically injecting 6-OHDA into the right striatum. Baicalein was administered intraperitoneally 30 min before and 90 min after lesion induction. Animals received a further daily injection of baicalein for 3 consecutive days. Two weeks after 6-OHDA injection, contralateral rotational asymmetry was observed by apomorphine challenge in lesioned mice. Tyrosine hydroxylase (TH) immunohistochemistry revealed a significant loss of terminals in lesioned striatum and the reduction of the numbers of TH-positive cell in the ipsilateral substantia nigra (SN). In addition, the levels of dopamine (DA) and DA metabolites were reduced and lipid peroxidation was increased in lesioned striatum. However, baicalein treatment reduced apomorphine-induced rotational behavior in 6-OHDA-lesioned mice, and increased TH immunoreactivity in the striatum and SN, and DA levels in lesioned striatum. Lipid peroxidation induced by 6-OHDA was also inhibited by baicalein treatment. Furthermore, when SH-SY5Y human neuroblastoma cells were treated with baicalein, 6-OHDA-induced cytotoxicity and reactive oxygen species (ROS) production were significantly reduced. These results indicate that baicalein effectively protects 6-OHDA-induced neuronal damage through antioxidant action.

Intravenous morphine self-administration alters accumbal microRNA profiles in the mouse brain

Kim, Juhwan,Im, Heh-In,Moon, Changjong Medknow PublicationsMedia Pvt Ltd 2018 Neural regeneration research Vol.13 No.1

<P>A significant amount of evidence indicates that microRNAs (miRNAs) play an important role in drug addiction. The nucleus accumbens (NAc) is a critical part of the brain's reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of miRNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine (0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion) and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered miRNAs and their putative target mRNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway mapping and CyTargetLinker. We found that 62 miRNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine (receptor internalization/endocytosis). The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.</P>

Serum Exosomal MicroRNA-137 Predicts Repeated Psychostimulant Exposure after Prolonged Abstinence

( Byung Sun Kim ),( Heh In Im ) 한국감성과학회 2015 추계학술대회 Vol.2015 No.-

Background: Repeated exposure to psychostimulant results in various chronic alterations after a period of prolonged abstinence. However, method for determining the repeated exposure to psychostimulant after long-term abstinence (months to years) has been absent. MicroRNAs (miRNAs) can cross blood-brain barrier, either in free or exosome-enwrapped form, and a significant amount of exosomal miRNAs circulates within blood serum. Considering that striatum is an epicenter of long-term changes underlying addiction, the striatum-derived miRNAs in bloodstream may prove to be a suitable biomarker for detecting repeated psychostimulant exposure after prolonged abstinence. Methods and Results: Based on the miRNA expression profiling studies, we selected two candidate miRNAs (miR-137 and -132) that are evolutionarily conserved, brain-enriched and specific to cocaine addiction in terms of striatal expression changes and role in neuroplasticity. Between the candidate miRNAs, we demonstrate that miR-137 is concordantly diminished in striatum and serum exosome of mice after weeks of abstinence from repeated cocaine exposure, and that the striatal and serum exosomal miR-137 levels display strong correlation during the prolonged abstinence. Additionally, we show that the reduction in human serum exosomal miR-137 can effectively distinguish methamphetamine-addicted patients after several months to years of abstinence. Finally, we provide evidences that RNAs of striatal origin can be found in serum exosome, suggesting that the circulating brain-enriched miR-137 may be directly derived from striatum. Conclusions: Overall, our study indicates serum exosomal miR-137 as a potentially non-invasive, sensitive and reliable biomarker reflecting long-term striatal changes after the prolonged abstinence from repeated psychostimulant exposure. Acknowledgement: This research was funded by the Korea Institute of Science and Technology Intramural Funding (No. 2E25210) and Center for Women In Science, Engineering, and Technology (WISET) grant funded by the Korea government (MEST) (No. 2N38873).

Effects of Fetal Mesencephalic Cell Grafts on the Intrastriatal 6-hydroxydoapmine Lesioned Rats

Wan Seok Joo,Eunjoo Nam,Heh-In Im,Jin Ah Jung,Eun Sun Lee,Yu-Jin Hwang,Yong Sik Kim 대한생리학회-대한약리학회 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

The effects of fetal mesencephalic cell grafts on the restoration of nigrostriatal dopaminergic function were studied in the intrastriatal 6-hydroxydopamine-lesioned rats. Four weeks after lesioning, transplantation of ventral mesencephalic cells from embryonic day 14 fetuses showed the number of tyrosine hydroxylase (TH) positive cells and fiber outgrowth in the grafted striatum, and significantly ameliorated symptomatic motor behavior of the animals, as determined by apomorphine-induced rotation. Furthermore, in substantia nigra pars compacta (SNc), the numbers of TH⁢ cells and fibers were markedly restored. Dopamine content of ipsilateral SNc was close to that of contralateral SNc (91.9⁑9.8%) in the transplanted animals, while the ratio was approximately 32% in sham-grafted animals. These results indicate that grafted cells restored the activity for the dopaminergic neurons located in SNc, although they were transplanted into striatum. In addition, we showed that the implanted fetal cells expressed high level of glial cell line-derived neurotrophic factor (GDNF), suggesting that the transplanted fetal cells might serve as a dopamine producer and a reservoir of neurotrophic factors. These results may be helpful in consideration of the therapeutic transplantation at early stage of PD.

Effects of Fetal Mesencephalic Cell Grafts on the Intrastriatal 6-hydroxydoapmine Lesioned Rats

Joo, Wan Seok,Nam, Eun-Joo,Im, Heh-ln,Jung, Jin-Ah,Lee, Eun-Sun,Hwang, Yu-Jin,Kim, Yong-Sik The Korean Society of Pharmacology 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

The effects of fetal mesencephalic cell grafts on the restoration of nigrostriatal dopaminergic function were studied in the intrastriatal 6-hydroxydopamine-lesioned rats. Four weeks after lesioning, transplantation of ventral mesencephalic cells from embryonic day 14 fetuses showed the number of tyrosine hydroxylase (TH) positive cells and fiber outgrowth in the grafted striatum, and significantly ameliorated symptomatic motor behavior of the animals, as determined by apomorphine-induced rotation. Furthermore, in substantia nigra pars compacta (SNc), the numbers of TH + cells and fibers were markedly restored. Dopamine content of ipsilateral SNc was close to that of contralateral SNc $(91.9{\pm}9.8%)$ in the transplanted animals, while the ratio was approximately 32% in sham-grafted animals. These results indicate that grafted cells restored the activity for the dopaminergic neurons located in SNc, although they were transplanted into striatum. In addition, we showed that the implanted fetal cells expressed high level of glial cell line-derived neurotrophic factor (GDNF), suggesting that the transplanted fetal cells might serve as a dopamine producer and a reservoir of neurotrophic factors. These results may be helpful in consideration of the therapeutic transplantation at early stage of PD.

Brain Reward Circuits in Morphine Addiction

Kim, Juhwan,Ham, Suji,Hong, Heeok,Moon, Changjong,Im, Heh-In Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.9

Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate's innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences.

Multiplexed on-chip real-time PCR using hydrogel spot array for microRNA profiling of minimal tissue samples

Jung, Seungwon,Kim, Bong Kyun,Lee, Sangjoon,Yoon, Seungmin,Im, Heh-In,Kim, Sang Kyung Elsevier 2018 Sensors and actuators. B Chemical Vol.262 No.-

<P><B>Abstract</B></P> <P>Since microRNAs (miRNAs) have been considered as regulators of messenger RNA (mRNA) translation, the development of the simple, multiplex, and quantitatively precise miRNA profiling techniques becomes more significant. Here, an on-chip multiplex real-time quantitative polymerase chain reaction (qPCR) for miRNA profiling is demonstrated with a primer-immobilized network (PIN) array, which consists of hundreds of hydrogel spots. The array renders highly dense reaction cells of 20 × 20 in 1 cm<SUP>2</SUP>. Uniform performance of the 400 real-time PCR reservoirs was achieved through our fabrication process. The amplicons and their fluorescent signals were isolated in each hydrogel spot, whose detection limit was measured to 16 aM, covering a seven-log concentration range. With the PIN spots of different primers, multiple miRNAs could be quantified in a single reaction out of very limited amount of RNA. For proof of concept, ten different miRNAs from the medial habenula of a mouse which is small region of the brain were successfully analyzed.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We achieved 400 hydrogel spots array in 1 cm<SUP>2</SUP> with excellent structural and functional uniformity. </LI> <LI> We developed the multiplex qPCR array chip for fast and simple workflow. </LI> <LI> This qPCR chip successfully detected as low as 16 aM of miRNA with a wide dynamic range of seven logs. </LI> <LI> Ten miRNAs from medial habenula of mouse brain were profiled at once in a 10 × 10 array. </LI> </UL> </P>

Big Data Analysis of Genes Associated With Neuropsychiatric Disorders in an Alzheimer’s Disease Animal Model

Ham, Suji,Kim, Tae K.,Hong, Heeok,Kim, Yong S.,Tang, Ya-Ping,Im, Heh-In Frontiers Media S.A. 2018 Frontiers in neuroscience Vol.12 No.-

<P>Alzheimer’s disease is a neurodegenerative disease characterized by the impairment of cognitive function and loss of memory, affecting millions of individuals worldwide. With the dramatic increase in the prevalence of Alzheimer’s disease, it is expected to impose extensive public health and economic burden. However, this burden is particularly heavy on the caregivers of Alzheimer’s disease patients eliciting neuropsychiatric symptoms that include mood swings, hallucinations, and depression. Interestingly, these neuropsychiatric symptoms are shared across symptoms of bipolar disorder, schizophrenia, and major depression disorder. Despite the similarities in symptomatology, comorbidities of Alzheimer’s disease and these neuropsychiatric disorders have not been studied in the Alzheimer’s disease model. Here, we explore the comprehensive changes in gene expression of genes that are associated with bipolar disorder, schizophrenia, and major depression disorder through the microarray of an Alzheimer’s disease animal model, the forebrain specific PSEN double knockout mouse. To analyze the genes related with these three neuropsychiatric disorders within the scope of our microarray data, we used selected 1207 of a total of 45,037 genes that satisfied our selection criteria. These genes were selected on the basis of 14 Gene Ontology terms significantly relevant with the three disorders which were identified by previous research conducted by the Psychiatric Genomics Consortium. Our study revealed that the forebrain specific deletion of Alzheimer’s disease genes can significantly alter neuropsychiatric disorder associated genes. Most importantly, most of these significantly altered genes were found to be involved with schizophrenia. Taken together, we suggest that the synaptic dysfunction by mutation of Alzheimer’s disease genes can lead to the manifestation of not only memory loss and impairments in cognition, but also neuropsychiatric symptoms.</P>