• 생물정신의학
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• 제25권2호
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• pp.38-43
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• 2018

Objectives Dopamine dysregulation has been regarded as one of the core pathologies in patients with schizophrenia. Since dopamine synthesis capacity has found to be inconsistent in patients with schizophrenia, current classification of patients based on clinical symptoms cannot reflect the neurochemical heterogeneity of the disease. Here we performed new subtyping of patients with first-episode psychosis (FEP) through biotype-based cluster analysis. We specifically suggested basal ganglia structural changes as a biotype, which deeply involves in the dopaminergic circuit. Methods Forty FEP and 40 demographically matched healthy participants underwent 3T T1 MRI. Whole brain parcellation was conducted, and volumes of total 6 regions of basal ganglia have been extracted as features for cluster analysis. We used K-means clustering, and external validation was conducted with Positive and Negative Syndrome Scale (PANSS). Results K-means clustering divided 40 FEP subjects into 2 clusters. Cluster 1 (n = 25) showed substantial volume decrease in 4 regions of basal ganglia compared to Cluster 2 (n = 15). Cluster 1 showed higher positive scales of PANSS compared with Cluster 2 (F = 2.333, p = 0.025). Compared to healthy controls, Cluster 1 showed smaller volumes in 4 regions, whereas Cluster 2 showed larger volumes in 3 regions. Conclusions Two subgroups have been found by cluster analysis, which showed a distinct difference in volume patterns of basal ganglia structures and positive symptom severity. The result possibly reflects the neurobiological heterogeneity of schizophrenia. Thus, the current study supports the importance of paradigm shift toward biotype-based diagnosis, instead of phenotype, for future precision psychiatry.

• Journal of Ginseng Research
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• 제42권3호
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• pp.379-388
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• 2018

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. KRGE (37.5 mg/ kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2-related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood-brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood-brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD.

• Animal cells and systems
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• 제4권1호
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• pp.71-76
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• 2000

The aim of this study was to investigate expression patterns of the prolactin (PRL) and c-fos genes by 17$\beta$-estradiol (17$\beta$-E) and stress in the mouse pituitary. In the pituitary, the levels of PRL mRNA were found high with some fluctuation at 30, 50, and 90 min whereas the levels of PRL mRNA were low at 120 min when ovariectomized female mice were injected with 17$\beta$-E or vehicle. PRL mRNA levels began to increase again at 4 h and remained high up to 24 h only in the 17$\beta$-E- treated mice. The overall changes in c-fos mRNA by 17$\beta$-E were very similar to those in PRL mRNA in the pituitary. Subsequent study revealed that these high initial levels of PRL and c-fos mRNAs were caused by stress during Injection, not by 17$\beta$-E, since vehicle injection alone into the ovariectomized mice could increase the levels of PRL and c-fos mRNAs. The stress-induced elevations of PRL and c-fos mRNAs were inhibited by bromocriptin, a dopamine agonist, suggesting that the dopaminergic system is involved in the action route of injection stress. In addition, the induced levels of c-fos mRNA by 17$\beta$-E and stress in the pituitary were very low compared with those in the uterus. The time course changes in c-fos mRNA level were different between the pituitary and uterus. Taken together, these data indicate that PRL and c-tos gene expression in the pituitary are regulated by 17$\beta$-E and stress in a parallel manner, supporting the notion that c-Fos plays a role in regulation of PRL gene expression.

• Toxicological Research
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• 제12권1호
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• pp.69-79
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• 1996

Primary culture of cerebellar neuronal cells derived from 8-day old Long-Evans rats was used. Pure granule cells, astrocytes or mixed cells culture systems were prepared. These cells were differentiated and developed synaptic connections. And the astrocytes were identified by immunostaining with glial fibrillary acidic protein (GFAP). Methamphetamine (MAP), which acts on dopaminergic system and cadmium (Cd), a toxic heavy metal, were applied and biochemical assays and electrophysiological studies were performed. $LC_50$ values estimated by MTT assay of MAP and Cd were 3 mM and 2$\mu M$ respectively. Cells were treated with 1 mM or 2 mM MAP and 1$\mu M$ $CdCl_2$ for 48 hour, and the incubation media were analyzed for the content of released LDH. MAP (2 mM) and Cd significantly increased the LDH release. Cell viability was decreased in both groups and some cytopathological changes like cell swelling or vacuolization were seen. The cerebellar granule cells were used for measuring membrane currents using whole-cell clamp technique. Sodium and potassium currents were not affected by MAP neither Cd, but calcium current was significantly reduced by Cd but not affected by MAP. Therefore, in vitro neurotoxicity test system using neuronaI cells and astrocytes cultures were established and can be used in screening of potential neurotoxic chemicals.

• Toxicological Research
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• 제30권4호
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• pp.267-276
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• 2014

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.

• Biomolecules & Therapeutics
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• 제22권6호
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• pp.558-562
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• 2014

Tramadol is an opioid analgesic agent that has been the subject of a series of case reports suggesting potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive in Korea. In this study, we examined the dependence potential and abuse liability of tramadol as well as its effect on the dopaminergic and serotonergic systems in rodents. In animal behavioral tests, tramadol did not show any positive effects on the experimental animals in climbing, jumping, and head twitch tests. However, in the conditioned place preference and self-administration tests, the experimental animals showed significant positive responses. Taken together, tramadol affected the neurological systems related to abuse liability and has the potential to lead psychological dependence.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2005년도 창립30주년기념 추계 학술대회 및 정기총회
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• pp.41-63
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• 2005

Ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. CTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, wehypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum (${\mu}$-receptors) and mouse vas deferens(${\delta}$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H (${\kappa}$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced CAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• Toxicological Research
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• 제35권1호
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• pp.83-91
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• 2019

Nanoparticles (NPs) have been recognized as both useful tools and potentially toxic materials in various industrial and medicinal fields. Previously, we found that zinc oxide (ZnO) NPs that are neurotoxic to human dopaminergic neuroblastoma SH-SY5Y cells are mediated by lipoxygenase (LOX), not cyclooxygenase-2 (COX-2). Here, we examined whether human bone marrow-derived mesenchymal stem cells (MSCs), which are different from neuroblastoma cells, might exhibit COX-2- and/or LOX-dependent cytotoxicity of ZnO NPs. Additionally, changes in annexin V expression, caspase-3/7 activity, and mitochondrial membrane potential (MMP) induced by ZnO NPs and ZnO were compared at 12 hr and 24 hr after exposure using flow cytometry. Cytotoxicity was measured based on lactate dehydrogenase activity and confirmed by trypan blue staining. Rescue studies were executed using zinc or iron chelators. ZnO NPs and ZnO showed similar dose-dependent and significant cytotoxic effects at concentrations ${\geq}15{\mu}g/mL$, in accordance with annexin V expression, caspase-3/7 activity, and MMP results. Human MSCs exhibited both COX-2 and LOX-mediated cytotoxicity after exposure to ZnO NPs, which was different from human neuroblastoma cells. Zinc and iron chelators significantly attenuated ZnO NPs-induced toxicity. Conclusively, these results suggest that ZnO NPs exhibit both COX-2- and LOX-mediated apoptosis by the participation of mitochondrial dysfunction in human MSC cultures.

• Biomolecules & Therapeutics
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• 제27권2호
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• pp.178-184
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• 2019

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether ${\beta}-Lapachone$ (${\beta}-LAP$), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. ${\beta}-LAP$ reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, ${\beta}-LAP$ protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether ${\beta}-LAP$ induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that ${\beta}-LAP$ increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, ${\beta}-LAP$ increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). ${\beta}-LAP$ also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that ${\beta}-LAP$ exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.

• 동의신경정신과학회지
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• 제32권2호
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• pp.111-127
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• 2021

Objectives: To review and analyze clinical and preclinical evidence of effectiveness, safety, and underlying mechanisms of yokukansan (YKS), a herbal medicine, in alleviating aggression. Methods: Classical records on YKS were searched in the Korean Traditional Medicine Knowledge Database (KTMKD). By searching five electronic databases, prospective clinical studies and preclinical studies of YKS for alleviating aggression/agitation published up to March 30, 2021 were included. Results: Only two classical records on YKS were found from the KTMKD. A total of 11 clinical studies and 15 preclinical studies were found from the five electronic databases. Among 11 clinical studies, seven enrolled patients with dementia and four enrolled patients with other neuropsychiatric disorders. Most clinical studies reported significant improvement in one or more outcomes related to aggression in the YKS group after treatment. Among 15 preclinical studies, all studies except two reported a significant decrease in aggression/agitation-related behavior of YKS or yokukansankachimpihange. Suggested underlying mechanisms of YKS or yokukansankachimpihange for aggression/agitation in these studies included regulation of serotonin receptor, amelioration of abnormal glucocorticoid level related to the hypothalamic-pituitary-adrenal axis, regulation of orexin secretion, amelioration of degeneration in brain cells including glia cells, and suppression of excessive glutamatergic or dopaminergic activity. Conclusions: There were some clinical and preclinical evidence supporting the effectiveness and safety of YKS for alleviating aggression. Given that aggression is the most frequent and destructive symptoms of behavioral and psychological symptoms of dementia, applicability of YKS as a herbal medicine should be further investigated in future high-quality research.