Department of Neuropsychopharmacology and Hospital Pharmacy

1.Faculty Member/Staff

Department of Neuropsychopharmacology (2015.01.01)
Faculty Member/Staff
Professor:
     Kiyofumi Yamada, Ph.D.
Associate Professor:
     Taku Nagai, Ph.D.
Designated Assistant Professor:
     Norimichi Ioth, Ph.D.
Graduate Student:
     Yuki Aoyama (D-4)
Kazuya Ichikawa (D-4)
     Yasutaka Fujino (D-4)
     Yasuo Kumakura (D-4)
     Ali Bin Saifullah (D-3, from Bangladesh)
     Hiroshi Kato (D-2)
Wei Shan (D-2, from China)
     Akira Sobue (D-1)
Bolati Wulaer (D-1, from China)
 Wang Tian (D-1, from China)
Technician:
 Eri Arata
Tomoko Yamaguchi
Visiting Professor:
     Yukihiro Noda, Ph.D. (Meijo Univ.)
Visiting Researcher:
     Akihiro Mouri, Ph.D. (Meijo Univ.)
Hiroyuki Kamei, Ph.D. (Meijo Univ.)
Keiko Yamamura, Ph.D. (Aichi Gakuin Univ.)
     Takayoshi Mamiya , Ph.D. (Meijo Univ.)
Research Student:
Tsuyoshi Mugishima (Fukuoka Prefectural Univ.)

Department of Hospital Pharmacy (2015.01.01)
Director:
     Kiyofumi Yamada E, O, P, Ph.D.
Vice Director:
     Taku Nagai, Ph.D.
     Isao Muraoka, Ph.D.
     Kazuhiro Ishikawa K, Ph.D.
     Masato Yamamoto F, P, Ph.D.
     Koji Yano J, O, P, Ph.D.
Chief Pharmacist:
     Noriko Tamaoki
     Saori Ohta
     Kumiko Shimizu D
     Koji Senzaki H, N, O, P
     Satoko Mori P, MSc.
     Mayumi Torimoto C, P, MSc.
     Yasuhiro Miyagawa P, Ph.D.
     Masayuki Miyazaki B, O, P, L, Q, Ph.D.
     Yasuo Kumakura L, MSc.
     Masako Ishizuka J, L
     Yusuke Sakai, MSc. J
     Tomomi Kataoka K, P, L, Q, MSc.
     Aki Kubota A, MSc.
     Norimichi Itoh, Ph.D.
Pharmacist:
     Yoshiaki Kato G, Ph.D.
     Noriko Kiriyama M, N, P, Q, MSc.
     Yosuke Niwa, MSc.
     Yoko Morita A
     Ayano Tojima
     Akane Kurachi
     Mako Ito
     Hiroshi Kato I, P, Q, MSc.
     Mika Ohara
     Chikako Yamada
     Noriko Tanaka
     Kazuya Ichikawa, MSc.
     Yasutaka Fujino, MSc.
     Rina Kishi, MSc.
     Ikumi Yata
     Yoko Hibi P, Ph.D.
     Yuko Kitahara, MSc.
     Hidetaka Iwamizu, MSc.
     Noriko Takeuchi, Ph.D.
     Hidehiro Nomura, Ph.D.
     Toshiki Motegi, MSc.
     Runa Asada
     Noriko Kono
     Tomoya Sugimoto, MSc.
     Kazuyo Takahashi, MSc.
     Kiyomi Hirose, MSc.
     Minako Watanabe, MSc.
     Yuichi Koyama, Ph.D.
     Ai Maeda, MSc.
     Risa Araki, MSc.
     Masashi Tomiyasu, MSc.
     Saori Kinoshita
     Hatsue Kume
     Kazusa Sano
     Ai Okajima
     Ayaka Tsuchiya
     Kazuhiro Hada, MSc.
     Shota Fukuzawa, MSc.
     Maiko Kondo
     Yuki Watanabe
     Mayumi Oba
     Yoshinori Tsuruta D, J
     Shogo Hotta
     Kazuyo Hosokawa
     Mariko Hiraiwa
     Masami Sasaki
     
     Mariko Nabekura
     Takayuki Inagaki B, G, P, Ph.D.
     Ai Hattori B, Ph.D.
     Takahiro Ueno, Ph.D.
     Kanako Kobayashi, Ph.D.
     Aya Sugimoto
     Machiko Ito
     Naoko Hirata
     Yuki Kawarada
     Ayaka Ito
     Chizuru Muramatsu
     Yukari Inoue, MSc.
     Kanako Kitagawa, MSc.

Resident:
     Koji Suzuki
     Miki Iwano
     Eri Yamada
     Airi Iwasaki
     Sayaka Ishii
     Ami Matsunaga
     Shota Aoki
     Yuta Sugano
     Saeko Takase

Administrator:
     Yuriko Nakayama
     Kikuko Yogo
     Mari Kodama
     Mayumi Mizutani

Pharmacy Specialties
I. Certification Board for Diabetes Educators in Japan (CBDEJ)
Certified Diabetes Educator of Japan (CDEJ) ・・・A
II. Japan Anti-Doping Agency (JADA)
Sports Pharmacist ・・・B
III. Japan Pharmacists Education Center (JPEC)
JPEC Certified Pharmacist in Pediatric Pharmacotherapy (JSDPT) ・・・C
IV. Japanese Society of Clinical Pharmacology and Therapeutics (JSCPT)
Certified Clinical Research Coordinator (CCRC) ・・・D
Board Certified Clinical Pharmacist (BCCP) ・・・E
V. Japanese Society of Hospital Pharmacists (JSHP)
Board Certified Infection Control Pharmacy Specialist (BCICPS) ・・・F
Board Certified Pharmacist in Infection Control (BCPIC) ・・・G
Board Certified Pharmacist in Psychiatric Pharmacy (BCPPP) ・・・H
VI. Japanese Society of Nephrology and Pharmacotherapy (JSNP)
Certified nephrology pharmacist ・・・I
VII. Japanese Society of Parental & Enteral Nutrition (JSPEN)
JSPEN-certified Pharmacist in Nutritional Support ・・・J
VIII. Japanese Society of Pharmaceutical Health Care and Science (JSPHCS)
JSPHCS-certified Senior Oncology Pharmacist (JSOP) ・・・K
JSPHCS-certified Oncology Pharmacist (JOP) ・・・L
JSPHCS-certified Senior Pharmacotherapy Pharmacist ・・・M
JSPHCS-certified Pharmacotherapy Pharmacist ・・・N
JSPHCS-certified Senior Pharmacist ・・・O
JSPHCS-certified Pharmacist ・・・P
IX. Japanese Society for Pharmaceutical Palliative Care and Sciences (JPPS)
Board Certified Pharmacist in Palliative Pharmacy (BCPPP) ・・・Q

2.Introduction of Research

Department of Neuropsychopharmacology
 Introduction of Research
The brain controls all body activities, ranging from heart rate to memory. Each brain function is operated by particular neural circuits made by synapses. The most important feature of synapses is the activity-dependent plasticity. The long-term objective in our laboratory is twofold. One is to define the molecular and cellular mechanisms that regulate synaptic plasticity associated with learning and memory. In particular, we are interested in molecular and cellular mechanisms that are responsible for working/short-term memory and reference/long-term memory. The other is to define the pathogenesis/pathophysiology of neuropsychiatric brain disorders, including Alzheimer’s disease, schizophrenia and drug addiction. Our current efforts have been focused on the following projects.

(1) Schizophrenia, drug addiction, and other mental disorders
Both genetic and environmental factors play a role in the pathology of schizophrenia. Recently, genetic susceptibility factors for the disorder have become available, which include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Epidemiological studies have identified environmental factors for schizophrenia, and maternal viral infection during pregnancy is regarded as the most promising one. Viral infection in the second trimester of pregnancy in humans increases the risk of subsequently developing schizophrenia in adolescence/adulthood. A possible interaction between environmental and genetic susceptibility factors, especially during neurodevelopment, is proposed for the disease etiology.


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We focus on phenotypic analyses at behavioral, neurochemical and neuroanatomical levels in mice with mutant schizophrenia susceptibility genes such as DISC1. We also study a possible interaction of genetic and environmental factors in schizophrenia by using a genetically-engineered mouse models under exposure to the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid [polyI:C, a toll-like receptor 3 (TLR3) ligand that induces strong innate immune response]. PolyI:C has been used to mimic a viral infection during neurodevelopment for modeling schizophrenia in mice (Fig. 1).


Drug addiction/dependence is defined as a chronically relapsing disorder that is characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The positive reinforcing/rewarding effects of drugs primarily depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens while the craving for drugs is associated with activation of the prefrontal cortex. The chronic intake of drugs causes homeostatic molecular and functional changes in synapses, which may be critically associated with the development of drug dependence. We have demonstrated that various cytokines such as TNF-β and GDNF


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and proteinases such as tissue plasminogen activator (tPA) and matrix metalloproteinase (MMP-2/MMP-9) are produced in the brain on treatment with drugs of abuse, and play a role in drug dependence. These endogenous modulators of drug dependence are classified into two groups, pro-addictive and anti-addictive factors. We have proposed that an imbalance between pro-addictive and anti-addictive factors contributes to the development and relapse of drug dependence. Targeting these endogenous modulators would provide new therapeutic approaches to the treatment of drug dependence (Fig. 2).  

Decision-making is a key activity of everyday life. Consequently, disturbances in the ability to make appropriate decisions or anticipate their possible consequences can result in massive social, medical, and financial problems. Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders have impairments in decision-making, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using an originally developed gambling test for rodents, we demonstrated that methamphetamine (METH)-dependent rats choose a high-risk/high-reward option more frequently, and assign higher subjective value to high returns, than control rats, suggesting that decision-making is impaired in the drug-dependent animals. We seek to clarify the underlying neural mechanism for the impairment of decision-making in methamphetamine-dependent rats.

(2)Alzheimer’s disease and other neurodegenerative disorders
Alzheimer’s disease (AD) is a progressive neurodegenerative process characterized by senile plaques, neurofibrillary tangles and neuronal loss. A pathologic hallmark of AD is deposition of amyloid-β peptide (Aβ), a 39-43-amino acid peptide derived from the transmembrane amyloid precursor protein (APP). Fibrillar Aβ deposits are found in extracellular senile plaque cores and are associated with neurodegeneration in later stages of AD. We study the mechanisms underlying the Aβ-induced neurotoxicity in vivo, by directly injecting Aβ into the lateral ventricle. We have already discovered novel compounds to prevent the Aβ-induced neurotoxicity.
Seizures cause brain injury via a number of mechanisms, potentially contributing to neurologic and cognitive deficits in epilepsy patients. Although seizures induce neuronal death in some situations, they also can produce nonlethal pathophysiologic effects on neuronal structures and functions. Kindling is an experimental epilepsy model in which repeated electrical or chemical stimulation of certain forebrain structures triggers progressively more intense electroencephalographic and behavioral seizure activity. Once established,


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kindling results in a permanent state of seizure susceptibility, which may manifest as spontaneous epileptiform seizures. Kindling has recently been shown to induce a variety of permanent structural changes in the brain, including sprouting of the mossy fiber pathway that originates from hippocampal dentate gyrus granule cells and neuronal loss in the hippocampus. Using a pentylenetetrazole (PTZ)-induced kindling model in mice, we have been exploring the neuronal mechanism for seizure susceptibility leading to variety of permanent structural changes (Fig. 3).


(3) Basic mechanisms of learning/memory and other brain functions 
Recognition memory is a fundamental facet of ability to remember, and an integral component of the class of memory lost in amnesia. The ability to discriminate familiar from novel stimuli is supported by this form of memory and is widely used as an assay in animals. Recent work highlights a major role in recognition memory for the perirhinal cortex because lesions or transient inactivation of perirhinal cortex consistently disrupt performance on familiarity discrimination tasks with object in both primates and rats. We have previously demonstrated that the activation of ERK1/2 following stimulation of dopamine D1 receptors in the prefrontal cortex is necessary for the protein synthesis-dependent long-term retention of recognition memory. Now, we focus on the possible interaction between dopamine and glutamate systems in protein synthesis-dependent long-term retention of recognition memory. Furthermore, we look for target genes of the dopamine D1 receptor-ERK1/2 signaling which are responsible for long-term recognition memory.
It has been widely believed that the synaptic plasticity in hippocampal neurons is related to the formation of various memories. Synaptic plasticity refers to the ability of synapses to vary their efficacy of chemical or electrical transmission over time in response to activities. Regulation of synaptic transmission and strength may be mediated by several events including changes in expression of synaptic surface receptors and neurotransmitters, altered neurite conductance, receptor subunit phosphorylation, postsynaptic calcium release and cytoskeletal remodeling. Neurotrophins are also considered powerful molecular mediators in synaptic plasticity. For example, brain-derived neurotrophic factor (BDNF) as well as its receptor TrkB have emerged as key molecules in the neurobiological mechanisms related to learning and memory. TrkB is known to activate Ras/extracellular signal-regulated kinase (ERK), phospholipase C-? (PLC-?) pathways and phosphatidylinositol 3-kinase (PI3-K)/Akt. Serine/threonine kinase Akt has been linked to brain development, ageing, and neurodegenerative and psychiatric disorders via the phosphorylation of a wide variety of its substrates.
Girdin (also known as APE, GIV, HkRP1) has been identified as an actin-binding Akt substrate that has been


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reported to regulate migration of various cells. We have recently demonstrated that Girdin S1416 was phosphorylated in an activity-dependent manner, and this phosphorylation was essential for spine morphogenesis, maintenance of hippocampal LTP and memory formation. Furthermore, Girdin interacts with Src and NR2B subunit of NMDA receptors, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that activity-dependent Girdin phosphorylation at S1416 induced by Akt is crucial for NMDA receptor activation associated with neuronal plasticity underlying hippocampal memory formation (Fig. 4).


Department of Hospital Pharmacy
1.Divisions
Dispensing section (Injections/Oral medicines)
Drug Purchase/Inventory Management
Pharmaceutical Manufacturing (PM) I/PM II/PM III
Clinical Pharmacy Service (CPS) I/CPS II/CPS III
MICU/SICU/NICU
Drug Information
Narcotic Drug Control
Drug Safety Management
Therapeutic Drug Monitoring (TDM)

2.Pharmacy Specialty Training Programs
We provide appropriate and certified training programs for preparing examinations for JSHPCS-certified Pharmacist, JSHPCS-certified Oncology Pharmacist, JSHPCS-certified Pharmacotherapy Pharmacist, and Board Certified Pharmacist in Oncology Pharmacy (BCPOP ) by JSHP. We also provide a 1-day training program for JSDPT JPEC Certified Pharmacist in Pediatric Pharmacotherapy.

3.Residency programs
The residency programs prepare pharmacists to be skilled clinical practitioners, researchers and educators. We offer both Postgraduate Year 1 (PGY1) and Postgraduate Year 2 (PGY2) pharmacy practice residency programs in the following settings:
PGY1: Basic pharmacotherapy program (3 out of 22 wards, each for 3 months) under the supervision by experienced clinical pharmacists.
PGY2: Advanced Pharmacotherapy, Oncology, NST or ICT program under the supervision by experienced clinical pharmacists with JSHPCS/JSHP certified Pharmacy Specialty.

4. Pharmacist-managed clinics for patient education and counseling
To improve the adherence to and knowledge about pharmacotherapy in outpatients and to maximize the efficacy and minimize the adverse drug events, the first pharmacist-managed clinic (PMC) in Japan was established for anticoagulation therapy at Nagoya University Hospital in 2000. We now operate 7 PMCs at NUH, such as for anticoagulation therapy, asthma/chronic obstructive pulmonary disease (COPD), donepezil outpatient consultation service (DOCS), palliative care, chronic kidney disease, molecular-targeted drugs, and continuous ambulatory peritoneal dialysis. Some of them are run in collaboration with schools of pharmacy. A PMC for DOCS is an example of such hospital pharmacist/faculty pharmacist collaboration. The DOCS provides pharmaceutical education and counseling about the pathophysiology of Alzheimer’s disease and drug therapy with donepezil and other drugs to outpatients and their family members.

5.Research Activity
We conduct a large variety of clinical and basic researches to provide better pharmaceutical care, in collaboration with clinical departments at NUH. Those include human pharmacokinetics in specific subpopulations such as infants, aged patients or patients with liver/kidney dysfunction, pharmacogenetics, cross-sectional pre- to post-intervention studies of patient education and counseling by pharmacists, retrospective factor analyses for better response/adverse drug reactions, and the basic researches in animal models to elucidate the mechanism of actions of therapeutic drugs.

3.Representative publications (2000- )

Department of Neuropsychopharmacology
Schizophrenia, drug addiction, and other mental disorders
1. Miyamato Y, Yamada K, Noda Y, Mori H, Mishina M and Nabeshima T: Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking NMDA receptor ?1 subunit. J. Neurosci. 21, 750-757, 2001.
2. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M and Nabeshima T: Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ?4 subunit. J. Neurosci. 22, 2335-2342, 2002.
3. Miyamoto Y, Yamada K, Nagai T, Mori, H, Mishina M, Furukawa H, Noda Y and Nabeshima T: Behavioral adaptations to addictive drugs in mice lacking NMDA receptor ?1 subunit. Eur. J. Neurosci. 19, 151-158, 2004.
4. Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, Nitta A, Mizuno M, Tran MH, Seto A, Yoshimura M, Kitaichi K, Hasegawa T, Saito K, Yamada Y, Seishima M, Sekikawa K, Kim HC and Nabeshima T: Role of TNF-? in methamphetamine-induced drug dependence and neurotocicity. J. Neurosci. 24, 2212-2225, 2004.
5. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto M, Hashimoto K, Noda Y, Nitta A and Nabeshima T: Tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc. Natl. Acad. Sci. U.S.A. 101, 3650-3655, 2004.
6. Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Noda Y, Nitta A and Nabeshima T: Regulation of methamphetamine reward by extracellualr signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mol. Pharmacol. 65, 1293-1301, 2004.
7. Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T and Yamada K: Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK 1/2 activation in the prefrontal cortex. Biol. Psychiatry 59, 75-84, 2006.
8. Nagai T, Ito M, Nakamichi N, Mizoguchi H, Kamei H, Fukakusa A, Nabeshima T, Takuma K and Yamada K: The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1. J. Neurosci., 26, 12374-12383, 2006.
9. Mizoguchi H, Yamada K, Niwa M, Mouri A, Mizuno T, Noda Y, Nitta A, Itohara S, Banno Y and Nabeshima T: Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9 deficient mice. J. Neurochem. 100, 1579-1588, 2007.
10. Yan Y, Yamada K, Niwa M, Nagai T, Nitta A and Nabeshima T: Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice. FASEB J. 21, 1994-2004, 2007.
11. Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T, Fujita K, Takasawa S, Yokoyama S, Koizumi K, Shiraishi Y, Tanaka S, Hashii M, Yoshihara T, Higashida K, Islam MS, Yamada N, Hayashi K, Noguchi N, Kato I, Okamoto H, Matsushima A, Salmina A, Munesue T, Shimizu N, Mochida S, Asano M and Higashida H: CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41-45, 2007.
12. Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y, Kamei H, Nagai T, Yoneda Y, Nabeshima T and Yamada K: Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J. Neurochem. 105, 921-932, 2008.
13. Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Takahashi K, Kamei H, Nabeshima T and Yamada K: Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. Neuropsychopharmacology 33, 3164-3175, 2008.
14. Ibi D, Nagai T, Kitahara Y, Mizoguchi H, Koike H, Shiraki A, Takuma K, Kamei H, Noda N, Nitta A, Nabeshima T, Yoneda Y and Yamada K: Neonatal polyI:C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neurosci. Res., 64, 297-305, 2009.
15. Ibi D, Nagai T, Koike H, Kitahara Y, Mizoguchi H, Niwa M, Jaaro-Peled H, Nitta A, Yoneda Y, Nabeshima T, Sawa A, and Yamada K: Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behav. Brain Res., 206, 32-37, 2010.
16. Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T and Yamada K: Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: a possible involvement of a brain specific transcription factor Npas4. J. Neurochem, 114:1840-1851, 2010.
17. Mizoguchi H, Ibi D, Takase F, Nagai T, Kamei H, Toth E, Sato J, Takuma K and Yamada K: Nicotine ameliorates impairment of working memory in methamphetamine-treated rats. Behav. Brain Res. 220:159-163, 2011.
18. Kuroda K, Yamada S, Tanaka, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K and Kaibuchi K: Behavioral alterations associated with targeted disruption of exons 2 and 3 of the DISC1 gene in the mouse. Hum. Mol. Genet., 20, 4666-4683, 2011.
19. Furukawa-Hibi Y, Yun J, Nagai T and Yamada K.: Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter. J. Neurochem, 123:866-875, 2012.
20. Miyazaki M, Noda Y, Mouri A, Kobayashi K, Mishina M, Nabeshima N, Yamada K: Role of convergent activation of glutamatergic and dopaminergic systems in the nucleus accumbens in the development of methamphetamine psychosis and dependence. Int. J. Neuropsychopharmacol., 16(6):1341-50, 2013.
21. 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 and Yamada K: Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. Glia 61: 679-693, 2013.
22. Alkam,T, Kim HC, Hiramatsu M, Mamiya T, Aoyama Y, Nitta A, Yamada K and Nabeshima T: Evaluation of emotional behaviors in young offspring of C57BL/6J mice after gestational and/or perinatal exposure to nicotine in six different time-windows. Behav. Brain Res., 239:80-89, 2013.
23. Yan Y, Miyamoto Y, Nitta A, Muramatsu S, Ozawa K, Yamada K and Nabeshima T: Intrastriatal gene delivery of GDNF persistently attenuates methamphetamine self-administration and relapse in mice. Int. J. Neuropsychopharmacol., 16:1559-1567, 2013.
24. Yamada S, Nagai T, Nakai T, Ibi D, Nakajima A, and Yamada K: Matrix metalloproteinase-3 is a possible mediator of neurodevelopmental impairment due to polyI:C-induced innate immune activation of astrocytes. Brain Behav Immun., 38:272-282, 2014.
25. Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, Yamada K: Alterations of GABAergic and dopaminergic system in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. Neurochem. Int., 74:74-83, 2014.

Alzheimer’s disease and other neurodegenerative disorders
1. Iida R, Saito K, Yamada K, Basile AS, Sekikawa K, Takemura M, Fujii H, Wada H, Seishima M and Nabeshima T: Suppression of neurocognitive damage in LP-BM5 infected mice with a targeted deletion of the TNF-? gene. FASEB J. 14, 1023-1031, 2000.
2. Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH and Nabeshima T: Amyloid ?-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB. J. 15, 1407-1409, 2001.
3. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y and Nabeshima T: Cognition impairment in the genetic model of aging, klotho gene mutant mice: a role of oxidative stress. FASEB J. 17, 50-52, 2003.
4. Tran MH, Yamada K, Nakajima A, Mizuno M, He J, Kamei H and Nabeshima T: Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid ?-peptide-induced cholinergic dysfunction. Mol. Psychiatry 8, 407-412, 2003.
5. Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, Arai S, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M and Yamada K: 17?-Estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience 146, 60-68, 2007.
6. Alkam T, Nitta A, Mizoguchi H, Itoh A, Murai R, Nagai T, Yamada K and Nabeshima T: The extensive nitration of neurofilament light chain in the hippocampus is associated with the cognitive impairment induced by amyloid ? in mice. J. Pharmacol. Exp. Ther. 327, 137-147, 2008.
7. Mizoguchi H, Takuma K, Fukuzaki E, Ibi D, Someya E, Akazawa K, Alkam T, Tsunekawa H, Mouri A, Noda Y, Nabeshima T and Yamada K: Matrix metalloprotease-9 inhibition improves amyloid ?-mediated cognitive impairment and neurotoxicity in mice. J. Pharmacol. Exp. Ther., 331, 14-22, 2009.
8. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K and Yan SD: RAGE-mdiated signaling contributes to intraneuronal transport of amyloid-? and neuronal dysfunction. Proc Natl Acad Sci USA, 106, 20021-20026, 2009.
9. Furukawa-Hibi Y, Alkam T, Nitta A, Matsuyama A, Mizoguchi H, Suzuki K, Moussaoui S, Yu Q-S, Greig NH, Nagai T and Yamada K: Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-s peptide in mice. Behav Brain Res., 225:222-229, 2011.
10. Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J and Yamada K: Matrix metalloproteinase-9 contributes to kindlined seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci., 31:12963-12971, 2011.
11. 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: Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice. Neuroscience, 207:261-273, 2012.
12. Nakajima A, Aoyama Y, Nguyen TTL, Shin EJ, Kim HC, Yamada S, Nakai T, Nagai T, Yokosuka A, Mimaki Y, Ohizumi Y and Yamada K: Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav. Rain Res., 250:351-360, 2013.

Basic mechanisms of learning/memory and other brain functions
1. Mizuno M, Yamada K, Olariu A, Nawa H and Nabeshima T: Involvement of BDNF in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci. 20, 7116-7121, 2000.
2. He J, Yamada K and Nabeshima T: A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 26, 259-268, 2002.
3. Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H and Nabeshima T: Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol. Psychiat. 8, 217-224, 2003.
4. Mizuno M, Yamada K, He J, Nakajima A and Nabeshima T: Involvement of BDNF receptor TrkB in spatial memory formation. Learn. Mem. 10, 108-115, 2003.
5. Ito M, Nagai T, Kamei H, Nakamichi N, Nabeshima T, Takuma K and Yamada K: Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice. Mol. Pharmacol. 70, 1720-1725, 2006.
6. Takahashi K, Nagai T, Kamei H, Maeda K, Matsuya T, Arai S, Mizoguchi H, Yoneda Y, Nabeshima T, Takuma K and Yamada K: Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice. Biol. Psychiatry 62, 148-157, 2007.
7. Nagai T, Takuma K, Kamei H, Ito Y, Nakamichi N, Ibi D, Nakanishi Y, Murai M, Mizoguchi H, Nabeshima T and Yamada K: Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex. Learn Mem. 14, 117-125, 2007.
8. Yun J, Nagai T, Furukawa-Hibi Y, Kuroda K, Kaibuchi K and Yamada K: Neuronal Per Arnt Sim (PAS) domain protein 4 (Npas4) regulates neurite outgrowth and phosphorylation of synapsin I. J. Biol. Chem., 288: 2655-2664, 2013.
9. Yoshihara S, Takahashi H, Nishimura N, Kinoshita M, Asahina R, Kitsuki M, Tatsumi K, Hibi Y, Hirai H, Nagai T, Yamada K and Tsuboi A: Npas4 regulates the expression of Mdm2 that ubiquitinates Dcx to remodel dendritic spines in olfactory bulb interneurons after sensory experience. Cell Reports, 8:1-15, 2014.
10. Nakai T, Nagai T, Tanaka M, Itoh N, Asai N, Enomoto A, Asai M, Yamada S, Saifullah MAB, Sokabe M, Takahashi M, and Yamada K: Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor. J. Neurosci., 34:14995-15008, 2014.

Review
1. Yamada K and Nabeshima T: Animal models of Alzheimer’s disease and evaluation of anti-dementia drugs. Pharmacol. Therapeut. 88, 93-113, 2000.
2. Yamada K, Mizuno M and Nabeshima T: Role for brain-derived neurotrophic factor in learning and memory. Life Sci. 70, 735-744, 2002.
3. Tran MH, Yamada K and Nabeshima T: Amyloid ?-peptide induces cholinergic dysfunction and cognitive deficits. Peptides 23, 1271-1283 2002.
4. Yamada K Kamei Y and Nabeshima T: Therapeutic approaches for the treatment of Alzheimer’s disease. Drugs Today 38, 631-637, 2002.
5. Yamada K and Nabeshima T: BDNF/TrkB signaling in memory processes. J. Pharmacol. Sci. 91, 267-270, 2003.
6. Yamada K and Nabeshima T: Pro- and anti-addictive neurotrophic factors and cytokines in psychostimulant addiction. Ann. N.Y. Acad. Sci. 1025, 198-204, 2004.
7. Yamada K, Mizuno M and Nabeshima T: Interaction of BDNF/TrkB signaling and NMDA receptors in learning and memory. Drug News Perspect. 17, 1-4, 2004.
8. Olariu A, Yamada K and Nabeshima T: Amyloid pathology and protein kinase C (PKC): possible therapeutics effects of PKC activators. J. Pharmacol. Sci. 97, 1-5, 2005.
9. Yamada K, Nagai T and Nabeshima T: Drug dependence, synaptic plasticity, and tissue plasminogen activator. J. Pharmacol. Sci. 97, 157-161, 2005.
10. Takuma K, Yan SS, Stern DM and Yamada K: Mitochondrial dysfunction, endoplasmic reticulum stress and apoptosis in Alzheimer's disease. J. Pharmacol. Sci. 97, 312-316, 2005.
11. Mizoguchi H, Yamada K and Nabeshima T: Neuropsychotoxicity of Abused Drugs: Involvement of matrix metalloproteinase-2 and -9, and tissue inhibitor of matrix metalloproteinase-2 in methamphetamine-induced behavioral sensitization and reward in rodents. J. Pharmacol. Sci. 106, 9-14, 2008.
12. Yamada K: Role for anti-addictive and pro-addictive factor in drug dependence. Nagoya J. Med. Sci. 70, 67-72, 2008.
13. Yamada K: Endogenous modulators for drug dependence. Biol. Pharm. Bull. 31, 1635-1638, 2008.
14. Nagai T, Nabeshima T and Yamada K: Basic and translational research on proteinase-activated receptors: Regulation of nicotine reward by the tissue plasminogen activator (tPA)-plasmin system via proteinase-activated receptor 1. J. Pharmacol. Sci. 108, 408-414, 2008.
15. Mizoguchi H. and Yamada K: Pharmacologic treatment with GABAB receptor agonist on methamphetamine-induced cognitive impairment in mice. Curr. Neuropharmacol., 9, 109-112, 2011.
16. Yamada K: Translational research in neurodevelopmental disorders: Development of etiology-based animal models (Foreword). Biol. Pharm. Bull. 34, 1357, 2011.
17. Nagai T, Ibi D and Yamada K: Animal model for schizophrenia that reflects gene-environment interactions. Biol. Pharm. Bull. 34, 1364-1368, 2011.
18. Mouri A, Nagai T, Ibi D and Yamada K: Animal models of schizophrenia for molecular and pharmacological intervention and potential candidate molecules. Neurobiol. Dis., 53:61-74, 2013.
19. Mizoguchi H and Yamada K: Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures. Clin. Psychopharmacol. Neurosci., 11:45-52, 2013
20. Nakajima N, Ohizumi Y, Yamada K: Anti-dementia activity of nobiletin, a citrus flavonoid. Clin. Psychopharmacol. Neurosci., 12:75-82, 2014.

Department of Hospital Pharmacy
1. Maruyama T, Sugiura S, Kojima J, Arimasa Y, Satoh Y, Kanaji K, Matsumura T, Ohsumi K, Yamada K and Nabeshima T: Improvement in drug compliance by medical consultation at a pharmacist outpatients’ clinic (Part 1). J. Appl. Therapeut. Res. 4, 18-24, 2003.
2. Kuzuya, T., Kobayashi, T., Moriyama, N., Nagasaka, T., Yokoyama, I., Uchida, K., Nakao, A. and Nabeshima, T.: Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation 76, 865-868, 2003.
3. Ishikawa, K., Kajita, Y., Hasegawa, Y., Noda, Y., Yoshida, J. and Nabeshima, T.: Irinotecan therapy in a 12-year-old girl with recurrent brain stem glioma and without functional polymorphisms in UGT1A1 activity: case report. J. Neurooncol. 74, 283-286, 2005.
4. Hasegawa, M., Takagi, K., Shimosaka, K., Byrd, H.J. and Nabeshima, T.: Evaluation of “Bronchial Asthma Pharmaceutical Care Clinic for Outpatients” run by pharmacists at Nagoya University Hospital. Jpn. J. Pharm. Health Care Sci. 32, 1038-1043, 2006.
5. Yoshida M, Morita R, Lefor AT and Nabeshima T: Implementation and evaluation of a once daily amikacin dosing protocol in a long-term care facility. Int. J. Antimicrob. Agents 29, 113-116, 2007.
6. Amioka K, Kuzuya T, Kushihara H, Ejiri M, Nitta A and Nabeshima T: Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport. J. Pharm. Pharmacol. 59, 1383-1387, 2007.
7. Umegaki H, Itoh A, Suzuki Y and Nabeshima T: Discontinuation of donepezil for the treatment of Alzheimer's disease in geriatric practice. Int. Psychogeriatr. 20, 800-806, 2008.
8. Yano K, Yamamura K, Osada T, Fukase F, Kiriyama N, Torimoto M, Yamada K, Kishi DT and Nabeshima T: Documenting the value of a pharmacist-managed anticoagulation classroom. J. Appl. Ther. Res. 6, 41-48, 2008.
9. Yamamoto, Kuzuya, Yamada K and Nabeshima T: Population pharmacokinetic analysis of vancomycin in patients with gram-positive infections and the influence of infectious disease type. J. Clin. Pharm. Ther., 34, 473-483, 2009.
10. Tanimura M, Mori K, Nagata H, Tadokoro K, Miyake T, Hamaguchi Y, Sessink PJM, Sugiura S, Yamada K and Nabeshima T. An environmental and biological study of occupational exposure to cyclophosphamide in the pharmacy of a Japanese community hospital designated for the treatment of cancer. J. Health Sci., 55, 750-756, 2009.
11. Kato K, Sugiura S, Yano K, Fukuoka T, Itoh A, Nagino M, Nabeshima T and Yamada K: The latent risk of acidosis in commercially available total parenteral nutrition (TPN) products: a randomized clinical trial in postoperative patients. J. Clin. Biochem. Nutr., 45, 68-73, 2009.
12. Miyagawa Y, Ejiri M, Kuzuya T, Osada T, Ishiguro N and Yamada K: Methylprednisolone reduces postoperative nausea in total knee and hi arthroplasty. J. Clin. Pharm.Ther. 35:679-683, 2010.
13. Yoshimi A, Aleksic B, Kawamura Y, Takahashi N, Yamada S, Usui H, Saito S, Ito Y, Iwata N, Inada T, Noda Y, Yamada K and Ozaki N.: Gene-wide association study between methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population with an updated meta-analysis on currently available data. Schizophr. Res. 124: 216-222, 2010.
14. Mizuno T, Mizuno M, Morgan BP, Noda Y, Yamada K, Okada N, Yuzawa Y, Matsuo S, Ito Y: Specific collaboration between rat membrane complement regulators Crry and CD59 protects peritoneum from damage by autologous complement activation. Nephrol. Dial. Transplant. 26: 1821-1830, 2011.
15. Ishizuka M, Fujimoto Y, Itoh Y, Sano M, Miyagawa Y, Ando A, Hiramatsu M, Hirasawa N, Ishihara S, Nabeshima T, Yamada K: Relationship between hematotoxicity and serum albumin level in the Treatment of head and neck cancers with concurrent chemoradiotherapy using cisplatin. Jpn. J. Clin. Oncol. 41: 973-979 2011.
16. Mizuno T, Ito K, Miyagawa Y, Kimura K, Suzuki Y, Mizuno M, Ito Y, Funahasi Y, Hattori R, Gotoh M, Noda Y and Yamada K: Renal impairment after laparoscopic radical nephrectomy affects hypoglycaemic therapy. J Clinic. Pharm. Therapeu., 37:49-52, 2012.
17. Kamei H, Isaji A, Noda Y, Ishikawa K, Senzaki K, Yamada K, Sugiura K, Tomita Y, Nabeshima T: Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-response: a randomized double-blind, placebo-controlled study in healthy volunteers. Arh. Dermatol. Res., 304: 263-272, 2012.
18. Mizuno T, Sato W, Ishikawa K, Shinjo H, Miyagawa Y, Noda Y Imai E and Yamada K: KDIGO criteria could be useful outcome predictor of cisplatin-induced acute kidney injury. Oncology, 82:354-359, 2012.
19. Mizuno T, Ito K, Miyagawa Y, Ishikawa K, Suzuki Y, Mizuno M, Ito Y, Funahashi Y, Hattori R, Gotoh M, Yamada K and Noda Y.: Short-term administration of diclofenac sodium affects renal function after laparoscopic radical nephrectomy in elderly patients. Jpn J Clin Oncol., 42:1073-1078, 2012.
20. Watanabe N, Yamamura K, Suzuki Y, Umegaki H, Shigeno K, Sai Y, Miyamoto K and Yamada K: Pharmacist-based donepezil outpatient consultation service to improve medication persistence. Patient Preference Adherence, 6:1-7. 2012.
21. Tokura T, Kimura H, Yoshimi A, Ohashi M, Masuda M, Senzaki K, Yoshida K, Aleksic B, Noda Y, Yamada K, Ozaki N: Reliability and validity of the Japanese version of BEMIB modified for patients with bipolar disorder: a self-rating evaluation scale for medication adherence. Clinc. Neuropsychopharmacol. Ther., 3: 26-32, 2012.
22. Kato H, Mizuno T, Mizuno M, Sawai A, Suzuki Y, Kinashi H, Nagura F, Maruyama S, Noda Y, Yamada K, Matsuo S, and Ito Y: Atrial natriuretic peptide ameliorates peritoneal fibrosis in rat peritonitis model. Nephrol. Dial. Transplant. 27:526-536, 2012.
23. Y, Yoshida N, Matsumoto K, Kato K, Kudo K, Furukawa-Hibi Y, Yamada K, Kojima S: Correlation of CYP2C19 phenotype with voriconazole plasma concentration in children. J. Pediatr. Hematol. Oncol., 35:219-223, 2013.
24. Mizuno T, Ishikawa K, Sato W, Koike T, Kushida M, Miyagawa Y, Yamada K, Hirata S, Imai E and Noda Y: The risk factors of severe acute kidney injury induced by cisplatin. Oncology, 85: 364-369, 2013.
25. Maeda O, Ando T, Ohmiya N, Ishiguro K, Watanabe O, Miyahara R, Hibi Y, Nagai T, Yamada K, Goto H: Alteration of gene expression and DNA methylation in drug-resistant gastric cancer. Oncol Rep., 31:1883-1890, 2014.
26. Kurata Y, Kuzuya T, Miwa Y, Iwasaki K, Haneda M, Amioka K, Yamada K, Watari Y, Katayama A, Uchida K, Kobayashi T: Clinical relevance of post-transplant pharmacodynamics analysis of cyclosporine in renal transplantation. Int. Immunophamacol., 31:1883-1890, 2014.
27. Yoshimi A, Noda Y, Aleksic B, Senzaki K, Ohashi M, Yamada S, Yamada K and Ozaki N: The survey of antipsychotic polypharmacy in outpatients at Nagoya University Hospital. Clin. Neuropsychopharmacol. Ther.,in press.
28. Umemura M, Itoh A, Ando Y, Yamada K, Wakiya Y, Nabeshima T: Effects of outside air temperature on the preparation of antineoplastic drug solutions in biological safety cabinets. J. Oncol. Pharm. Pract., in press.

Review
1. Yamada K, Nabeshima T: Pharmacist-managed clinics for patient education and counseling in Japan: current status and future perspectives. J. Pharm. Health Care Sci., in press.

Department of Neuropsychopharmacology & Hospital Pharmacy
Nagoya University Graduate School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan
Tel : +81-52-744-2674, Fax : +81-52-744-2979
E-mail : pharmacy@med.nagoya-u.ac.jp