Acidic pH modulation of Na+ channels in trigeminal mesencephalic nucleus neurons

Kang, In-Sik,Cho, Jin-Hwa,Choi, In-Sun,Kim, Do-Yeon,Jang, Il-Sung Wolters Kluwer Health | Lippincott Williams Wilkin 2016 NEUROREPORT - Vol.27 No.17

<P>Cell bodies of trigeminal mesencephalic nucleus (Vmes) neurons are located within the central nervous system, and therefore, peripheral as well as central acidosis can modulate the excitability of Vmes neurons. Here, we report the effect of acidic pH on voltage-gated Na+ channels in acutely isolated rat Vmes neurons using a conventional whole-cell patch clamp technique. Acidic pH (pH 6.0) slightly but significantly shifted both the activation and steady-state fast inactivation relationships toward depolarized potentials. However, acidic pH (pH 6.0) had a minor effect on the inactivation kinetics of voltage-gated Na+ channels. Less sensitivity of voltage-gated Na+ channels to acidic pH may allow Vmes neurons to transduce the precise proprioceptive information even under acidic pH conditions.Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.</P>

Enhanced activation of NAD(P)H: quinone oxidoreductase 1 attenuates spontaneous hypertension by improvement of endothelial nitric oxide synthase coupling via tumor suppressor kinase liver kinase B1/adenosine 5&vprime;-monophosphate-activated protein kina

Kim, Yong-Hoon,Hwang, Jung Hwan,Kim, Kyung-Shim,Noh, Jung-Ran,Gang, Gil-Tae,Oh, Won Keun,Jeong, Kyeong-Hoon,Kwak, Tae Hwan,Choi, Hueng-Sik,Lee, In-Kyu,Lee, Chul-Ho Wolters Kluwer Health | Lippincott Williams Wilkin 2014 Journal of Hypertension Vol.32 No.2

AIMS:: Guanosine 5&vprime;-triphosphate cyclohydrolase-1 (GTPCH-1) is a rate-limiting enzyme in de-novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) coupling. Adenosine 5&vprime;-monophosphate-activated protein kinase (AMPK) is crucial for GTPCH-1 preservation, and tumor suppressor kinase liver kinase B1 (LKB1), an upstream kinase of AMPK, is activated by NAD-dependent class III histone deacetylase sirtuin 1 (SIRT1)-mediated deacetylation. &bgr;-Lapachone has been shown to increase cellular NAD/NADH ratio via NAD(P)H:quinone oxidoreductase 1 (NQO1) activation. In this study, we have evaluated whether &bgr;-lapachone-induced NQO1 activation modulates blood pressure (BP) through preservation of GTPCH-1 in a hypertensive animal model. METHODS AND RESULTS:: Spontaneously hypertensive rats (SHRs), primary aortic endothelial cells, and endothelial cell line were used to investigate the hypotensive effect of &bgr;-lapachone and its action mechanism. &bgr;-Lapachone treatment dramatically lowered BP and vascular tension in SHRs and induced eNOS activation in endothelial cells. Consistent with these effects, &bgr;-lapachone treatment also elevated levels of both aortic cGMP and plasma nitric oxide in SHRs. Meanwhile, &bgr;-lapachone-treated SHRs showed significantly increased levels of aortic NAD, LKB1 deacetylation, and AMPK Thr phosphorylation followed by increased GTPCH-1 and tetrahydrobiopterin/dihydrobiopterin ratio. In-vitro study revealed that AMPK inhibition by overexpression of dominant-negative AMPK nearly abolished GTPCH-1 protein conservation. Enhanced LKB1 deacetylation and AMPK activation were also elicited by &bgr;-lapachone in endothelial cells. However, inhibition of LKB1 deacetylation by blocking of NQO1 or SIRT1 blunted AMPK activation by &bgr;-lapachone. CONCLUSION:: This is the first study demonstrating that eNOS coupling can be regulated by NQO1 activation via LKB1/AMPK/GTPCH-1 modulation, which is possibly correlated with relieving hypertension. These findings provide strong evidence to suggest that NQO1 might be a new therapeutic target for hypertension.

NT5C3 polymorphisms and outcome of first induction chemotherapy in acute myeloid leukemia

Cheong, Hyun Sub,Koh, Youngil,Ahn, Kwang-Sung,Lee, Chansu,Shin, Hyoung Doo,Yoon, Sung-Soo Wolters Kluwer Health | Lippincott Williams Wilkin 2014 PHARMACOGENETICS AND GENOMICS Vol.24 No.9

AIMS: The cytosolic 5&vprime;-nucleotidase-III (NT5C3) is involved in the metabolism of the nucleoside analog, cytosine arabinose (AraC), and the expression level of NT5C3 is correlated with sensitivity to AraC in acute myeloid leukemia (AML) patients. The current study examined whether the NT5C3 polymorphisms could affect chemotherapy outcomes in 103 Korean AML patients. METHODS: Forty-seven single nucleotide polymorphisms in NT5C3 were genotyped using the Illumina GoldenGate genotyping assay. The genetic effects of the polymorphisms on the outcome of chemotherapy were analyzed using &khgr; and logistic regression models. RESULTS: Although none of the NT5C3 polymorphisms was associated with a complete remission rate, a common single nucleotide polymorphism, rs3750117, showed a significant association with induction rate after the first course of chemotherapy (Pcorr=0.004 and odds ratio=11.28) in AML patients. In addition, NT5C3 expression levels were significantly increased in patients with risk allele homozygote. CONCLUSIONS: The data suggest that genotyping the NT5C3 polymorphism may have the potential to identify patients more likely to respond to AraC-based chemotherapy.

Naringenin ameliorates kainic acid-induced morphological alterations in the dentate gyrus in a mouse model of temporal lobe epilepsy

Park, Jungha,Jeong, Kyoung Hoon,Shin, Won-Ho,Bae, Young-Seuk,Jung, Un Ju,Kim, Sang Ryong Wolters Kluwer Health | Lippincott Williams Wilkin 2016 NEUROREPORT - Vol.27 No.15

<P>Granule cell dispersion (GCD) in the dentate gyrus (DG) of the hippocampus is a morphological alteration characteristic of temporal lobe epilepsy. Recently, we reported that treatment with naringin, a flavonoid found in grapefruit and citrus fruits, reduced spontaneous recurrent seizures by inhibiting kainic acid (KA)-induced GCD and neuronal cell death in mouse hippocampus, suggesting that naringin might have beneficial effects for preventing epileptic events in the adult brain. However, it is still unclear whether the beneficial effects of naringin treatment are mediated by the metabolism of naringin into naringenin in the KA-treated hippocampus. To investigate this possibility, we evaluated whether intraperitoneal injections of naringenin could mimic naringin-induced effects against GCD caused by intrahippocampal KA injections in mice. Our results showed that treatment with naringenin delayed the onset of KA-induced seizures and attenuated KA-induced GCD by inhibiting activation of the mammalian target of rapamycin complex 1 in both neurons and reactive astrocytes in the DG. In addition, its administration attenuated the production of proinflammatory cytokines such as tumor necrosis tumor necrosis factor- (TNF) and interleukin-1 (IL-1) from microglial activation in the DG following KA treatment. These results suggest that naringenin may be an active metabolite of naringin and help prevent the progression of epileptic insults in the hippocampus in vivo; therefore, naringenin may be a beneficial metabolite of naringin for the treatment of epilepsy.</P>

Starburst amacrine cells express parvalbumin but not calbindin and calretinin in rabbit retina

Lee, Eun-Shil,Jeon, Chang-Jin Wolters Kluwer Health | Lippincott Williams Wilkin 2013 NEUROREPORT - Vol.24 No.16

Calcium-binding proteins (CBPs) are important components in calcium-mediated cellular signal transduction. Among the many CBPs, at least three EF-hand CBPs, calbindin-D28K (CB), calretinin (CR), and parvalbumin (PV), have been extensively studied in the retina. In the present study, we investigated the expression patterns of these three CBPs in cholinergic starburst amacrine cells (SACs), which are the most important element for direction selectivity in the rabbit retina. Double-label immunocytochemical analysis of vibratome sections and single-cell injection after immunocytochemical analysis on whole mounts were carried out in rabbit retinas. We found that all SACs in the inner nuclear layer and the ganglion cell layer contained PV. However, none of the SACs in the inner nuclear layer or ganglion cell layer contained either CB or CR. These results suggest that PV, but not CR or CB, may act as a calcium-buffering protein in the SACs of the rabbit retina.

Hypoxia-inducible factor-1α upregulates tyrosine hydroxylase and dopamine transporter by nuclear receptor ERR&ggr; in SH-SY5Y cells

Lim, Juhee,Kim, Hyo-In,Bang, Yeojin,Seol, Wongi,Choi, Hueng-Sik,Choi, Hyun Jin Wolters Kluwer Health | Lippincott Williams Wilkin 2015 NEUROREPORT - Vol.26 No.6

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor relevant to the development of many mammalian organs including the brain. However, the molecular mechanisms by which signaling events mediate neuronal differentiation have not been fully elucidated. In the present study, we show for the first time that the orphan nuclear receptor estrogen-related receptor &ggr; (ERR&ggr;) is upregulated by HIF-1α and plays essential roles in HIF-1α-induced upregulation of dopaminergic marker molecules such as tyrosine hydroxylase and dopamine transporter. We found that deferoxamine upregulated HIF-1α and enhanced the dopaminergic phenotype and neurite outgrowth of SH-SY5Y cells. Deferoxamine activated transcription and protein expression of ERR&ggr;, and deferoxamine-induced upregulation of tyrosine hydroxylase and dopamine transporter was attenuated by using the ERR&ggr; inverse agonist or silencing ERR&ggr;. Altogether, these results suggest that HIF-1α can positively regulate the dopaminergic phenotype through ERR&ggr;. This study could provide new perspectives for understanding the mechanisms underlying the promotion of dopaminergic neuronal differentiation by hypoxia.

Pramipexole protects dopaminergic neurons through paraplegin against 6-hydroxydopamine

Kim, Mun ki,Park, Hyeon soo,Cho, Jea hyeon,Kim, Gon sup,Won, Chungkil Wolters Kluwer Health | Lippincott Williams Wilkin 2015 NEUROREPORT - Vol.26 No.2

The neurotransmitter dopamine (DA) regulates various physiological and psychological functions, such as movement, motivation, behavior, and learning. DA exerts its function through DA receptors and a series of studies have reported the role of DAergic receptors in preventing DAergic neuronal degeneration. Here, we studied the DA receptor-mediated neuroprotective effect of the D2-like receptor agonists against 6-hydroxydopamine (6-OHDA)-induced DAergic neurodegeneration. D2-like receptor agonists were administered in the substantia nigra in vivo and to primary cultured neurons. Treatment of 6-OHDA decreased tyrosine hydroxylase (TH) and paraplegin (mitochondrial regulation protein) immunoreactivity, whereas pretreatment with quinpirole (a full D2-like receptor agonist) preserved TH and paraplegin reactivity. This led us to test which DA receptors were necessary for the neuroprotective effect and whether paraplegin can be regulated by D2 or D3 receptor agonists. Pretreatment with the D2 receptor selective agonist, sumanirole, did not preserve TH and paraplegin reactivity from 6-OHDA. However, the D3 receptor agonist, pramipexole, protected TH reactivity and restored paraplegin expression to the control level in the presence of 6-OHDA. Interestingly, pretreatment with the D3 receptor antagonist GR103691 reduced TH and paraplegin expression levels. These results suggest that the D3 receptor agonist may protect DA neurons from the effect of 6-OHDA through the modulation of the mitochondrial regulation protein paraplegin.

Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics

Chung, Jae-Yong,Cho, Sung Kweon,Kim, Tae Hee,Kim, Kyoung Hee,Jang, Geun Hye,Kim, Choon Ok,Park, Eun-Mi,Cho, Joo-Youn,Jang, In-Jin,Choi, Ji Ha Wolters Kluwer Health | Lippincott Williams Wilkin 2013 Pharmacogenetics and genomics Vol.23 No.7

OBJECTIVE: Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. METHODS: We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. RESULTS: Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.−130G>A and haplotype 2 containing two polymorphisms, g.−609G>A and g.−396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539±76 (reference group) vs. 633±102 (variant group) ml/min; P=0.006] and secretion clearance [439±81 (reference group) vs. 531±102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. CONCLUSION: Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

Examining the resting-state vascular connectivity using fMRA in comparison with fMRI: a preliminary study

Park, Chan-A,Kang, Chang-Ki,Kim, Young-Bo,Cho, Zang-Hee Wolters Kluwer Health | Lippincott Williams Wilkin 2015 NEUROREPORT - Vol.26 No.11

This study examined resting-state functional connectivity in the vascular system of the brain using functional magnetic resonance angiography (fMRA) with an ultra-high-field 7 T MRI. Four healthy individuals participated in the functional imaging study using fMRA and functional MRI (fMRI) for determination of vascular and blood oxygenation level-dependent (BOLD) connectivity, respectively. We calculated voxel-wise connectivity maps and measured the correlation coefficients of the region of interest (ROI)-wise connectivity in the resting-state human brain. Z-map in the posterior cingulate cortex showed more correlated voxels in fMRA than fMRI. There was little or weak interhemispheric vascular connectivity using fMRA in the lateral parietal cortex and the lateral temporal cortex. In contrast, both vascular and BOLD interhemispheric correlations in the precentral gyrus were strong. Correlation coefficients for ROI-wise connectivity analysis were statistically different between fMRA and fMRI in the left and right lateral parietal cortex and lateral temporal cortex (P=0.029). Unlike BOLD connectivity, vascular connectivity showed little interhemispheric correlation in the default mode network. These results could provide the vascular connectivity on the basis of arterial response that can only be obtained by fMRA with an ultra-high-field environment along with further studies. Therefore, this method could provide additional and supplementary information for investigating the vascular effect in patients with cerebrovascular disease.

Functional topography of the primary motor cortex during motor execution and motor imagery as revealed by functional MRI

Makary, Meena M.,Eun, Seulgi,Soliman, Ramy S.,Mohamed, Abdalla Z.,Lee, Jeungchan,Park, Kyungmo Wolters Kluwer Health | Lippincott Williams Wilkin 2017 NEUROREPORT - Vol.28 No.12

<P>Controversy exists regarding the involvement of the primary motor cortex (M1) during motor imagery (MI) and also regarding the differential somatotopic representation of motor execution (ME) and mental simulation of movement, that is, MI within M1. Although some research reported clear M1 involvement during MI without overt motor output, others did not. However, possible somatotopic representation between execution and imagery has not been clearly investigated to date. The aim of the present study was to aid in the resolution of this controversy by investigating the possible involvement of M1 during MI, and the differential, within M1, somatotopic representation between execution and imagery by quantitatively assessing different location markers such as activation peak and center of mass as well as intensity differences between the two tasks in case of with and without the overlap between the two representations. Forty-one healthy volunteers participated in two functional MRI runs of mouth-stretching ME and MI tasks. Our findings suggest the clear involvement of M1 (BA 4) during MI with lower signal intensity compared with ME, and further showed distinct centers for each representation along the y-axis (anteroposterior plane), with MI showing more involvement of the anterior sector of M1 (BA 4a), whereas ME recruited more of the posterior sector (BA 4p). These results parallel the pioneering findings of a functional distinction between BA 4a and BA 4p, where BA 4a is more involved in the cognitive aspects of MI, whereas BA 4p is more related to executive function, promoting the idea of distinctive somatotopic mapping between execution and imagery within M1 sectors.</P>