研究者詳細 - 溝口　博之

論文 - 溝口　博之

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Chronic Hyponatremia Causes Neurologic and Psychologic Impairments Open Access

Fujisawa Haruki, Sugimura Yoshihisa, Takagi Hiroshi, Mizoguchi Hiroyuki, Takeuchi Hideyuki, Izumida Hisakazu, Nakashima Kohtaro, Ochiai Hiroshi, Takeuchi Seiji, Kiyota Atsushi, Fukumoto Kazuya, Iwama Shintaro, Takagishi Yoshiko, Hayashi Yoshitaka, Arima Hiroshi, Komatsu Yukio, Murata Yoshiharu, Oiso Yutaka

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 27 巻 ( 3 ) 頁： 766 - 780 2016年3月

Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction. 査読有り

Mouri A, Hoshino Y, Narusawa S, Ikegami K, Mizoguchi H, Murata Y, Yoshimura T, Nabeshima T

Psychoneuroendocrinology 48 巻頁： 147-161 2014年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor β (TRβ) gene. TRβ is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.

DOI： 10.1016/j.psyneuen.2014.05.021

Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin 査読有り Open Access

Doi Y, Takeuchi H, Mizoguchi H, Fukumoto K, Horiuchi H, Jin S, Kawanokuchi J, Parajuli B, Sonobe Y, Mizuno T, Suzumura A

PLoS One 9 巻 ( 7 ) 頁： e103458 2014年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.

DOI： 10.1371/journal.pone.0103458

Open Access

Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment. 査読有り

Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A.

Behav. Brain Res. 268 巻頁： 88-93 2014年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Alzheimer's disease is a progressive neurodegenerative disorder. Amyloid β, a neurotoxic protein, causes disruption of hippocampal synaptic plasticity, and induces cognitive impairment in Alzheimer's disease. We previously revealed that fingolimod, a new oral immunosuppressant used to treat multiple sclerosis, ameliorates oligomeric amyloid β-induced neuronal damage via up-regulation of neuronal brain-derived neurotrophic factor (BDNF). Here, we showed that oral administration of fingolimod ameliorated the impairment in object recognition memory and associative learning in mice injected with amyloid β. This effect was associated with restoration of normal BDNF expression levels in the cerebral cortices and hippocampi, suggesting that neuroprotection was mediated by up-regulation of neuronal BDNF levels. Therefore, fingolimod may provide therapeutic effects in patients with Alzheimer's disease.

DOI： 10.1016/j.bbr.2014.03.046

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice 査読有り Open Access

Ibi D, Nagai T, Nakajima A, Mizoguchi H, Kawase T, Tsuboi D, Kano S, Sato Y, Hayakawa M, Lange UC, Adams DJ, Surani MA, Satoh T, Sawa A, Kaibuchi K, Nabeshima T, Yamada K.

Glia 61 巻 ( 5 ) 頁： 679-693 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）

Interferon-induced transmembrane protein 3 (IFITM3) ıplays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long-lasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)-induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:C-ACM-induced neurodevelopmental abnormalities were alleviated by ifitm3(-/-) astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3(-) (/) (-) mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

DOI： 10.1002/glia.22461

Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures. 査読有り Open Access

Mizoguchi H, Yamada K.

Clinical Psychopharmacology and Neuroscience 11 巻 ( 2 ) 頁： 45-52 2013年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors, which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy.

DOI： 10.9758/cpn.2013.11.2.45

Open Access

Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. 査読有り

Nakamoto K, Kawasaki S, Kobori T, Fujita-Hamabe W, Mizoguchi H, Yamada K, Nabeshima T and Tokuyama S.

Eur J Pharmacol. 683 巻頁： 86-92 2012年

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

Takuma K, Mizoguchi H, Funatsu Y, Hoshina Y, Himeno Y, Fukuzaki E, Kitahara Y, Arai S, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T and Yamada K.

Neuroscience. 207 巻頁： 261-273 2012年

Placental extract improves hippocampal neuronal loss and fear memory impairment resulting from chronic restraint stress in ovariectomized mice. 査読有り

Takuma K, Mizoguchi H, Funatsu Y, Kitahara Y, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T and Yamada K.

J Pharmacol Sci. 120 巻 ( 2 ) 頁： 89-97 2012年

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice. 査読有り Open Access

Furukawa-Hibi Y, Alkam T, Nitta A, Matsuyama A, Mizoguchi H, Suzuki K, Moussaoui S, Yu QS, Greig NH, Nagai T, Yamada K.

Behav. Brain Res. 225 巻 ( 1 ) 頁： 222-229 2011年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ(1-40) or the control peptide Aβ(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.

DOI： 10.1016/j.bbr.2011.07.035

Low barometric pressure aggravates neuropathic pain in guinea pigs. 査読有り

Sato J, Itano Y, Funakubo M, Mizoguchi H, Itoh M, Mori R.

Neurosci. Lett. 503 巻 ( 2 ) 頁： 152-156 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Several clinical studies have demonstrated a consistent relationship between changes in meteorological factors, particularly barometric pressure, and pain intensity in subjects with chronic pain. We have previously demonstrated that exposure to artificially low barometric pressure (LP) intensifies pain-related behaviors in rats with neuropathic pain. In the present study, guinea pigs with unilateral L5 spinal nerve ligation (SNL) were placed in a pressure-controlled chamber and subjected to LP of 10 or 27hPa below the ambient pressure. The SNL surgery led to increased hindpaw withdrawal frequencies to 34-, 59-, and 239-mN von Frey filaments (VFFs). When the SNL animals were subjected to both LP exposures consecutively, the hindpaw withdrawal frequencies further increased; the effect was most significant when the animals were exposed to LP 27hPa below ambient pressure. In contrast, no change was seen in a group of sham-operated control animals. These results indicate that fluctuations in LP within the range of natural weather patterns can potentiate neuropathic pain in guinea pigs.

DOI： 10.1016/j.neulet.2011.08.030

Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity. 査読有り

Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A.

Am J Pathol. 179 巻 ( 4 ) 頁： 2016-2027 2011年10月

Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. 査読有り

Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J, Yamada K.

J Neurosci. 31 巻 ( 36 ) 頁： 12963-12971 2011年9月

Nicotine ameliorates impairment of working memory in methamphetamine-treated rats. 査読有り

Mizoguchi H, Ibi D, Takase F, Nagai T, Kamei H, Toth E, Sato J, Takuma K, Yamada K.

Behav Brain Res. 220 巻 ( 1 ) 頁： 159-163 2011年6月

Lowering barometric pressure aggravates depression-like behavior in rats. 査読有り

Mizoguchi H, Fukaya K, Mori R, Itoh M, Funakubo M, Sato J.

Behav Brain Res. 218 巻頁： 190-193 2011年3月

Pharmacologic treatment with GABAB receptor agonist of methamphetamine-induced cognitive impairment in mice._B_B_B 査読有り

Mizoguchi H, Yamada K.

Current Neuropharmacol. 9 巻 ( 1 ) 頁： 109-112 2011年3月

Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage. 査読有り

Shichi K, Fujita-Hamabe W, Harada S, Mizoguchi H, Yamada K, Nabeshima T, Tokuyama S.

J Pharmacol Exp Ther. 頁： in press 2011年

Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. 査読有り Open Access

Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, Li H, Zhou Y, Mori R, Yasuoka S, Li E, Parajuli B, Kawanokuchi J, Sonobe Y, Sato J, Yamanaka K, Sobue G, Mizuno T, Suzumura A.

PLoS One. 6 巻 ( 6 ) 頁： e21108 2011年

Matrix metalloproteinases contribute to neuronal dysfunction in animal models of drug dependence, Alzheimer's disease, and epilepsy. 招待有り

Mizoguchi H, Yamada K, Nabeshima T.

Biochem Res Internat. 頁： 681385 2011年

Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. 査読有り Open Access

Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T, Yamada K.

J Neurochem. 114 巻 ( 6 ) 頁： 1840-1851 2010年9月

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