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Signalling pathways in autism spectrum disorder:mechanisms and therapeutic implications

Signal Transduction and Targeted Therapy 2022年第8期7卷 2863-2898页

作者： Chen-Chen Jiang Li-Shan Lin Sen Long Xiao-Yan Ke kohji fukunaga Ying-Mei Lu Feng Han International Joint Laboratory for Drug Target of Critical Illnesses Key Laboratory of Cardiovascular&Cerebrovascular MedicineSchool of PharmacyNanjing Medical UniversityNanjing 211166China Department of Physiology School of Basic Medical SciencesNanjing Medical UniversityNanjing 211166China Department of Pharmacy Hangzhou Seventh People’s HospitalMental Health Center Zhejiang University School of MedicineHangzhou 310013China Child Mental Health Research Center Nanjing Brain HospitalNanjing Medical UniversityNanjing 210029China Department of CNS Drug Innovation Graduate School of Pharmaceutical SciencesTohoku UniversitySendai 980-8578Japan Institute of Brain Science The Affiliated Brain Hospital of Nanjing Medical UniversityNanjing 210029China Gusu School Nanjing Medical UniversitySuzhou Municipal HospitalThe Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou 215002China

Autism spectrum disorder(ASD)is a prevalent and complex neurodevelopmental disorder which has strong genetic *** the rapidly rising incidence of autism,little is known about its aetiology,risk factors,and disease *** are currently neither validated biomarkers for diagnostic screening nor specific medication for *** the last two decades,there have been remarkable advances in genetics,with hundreds of genes identified and validated as being associated with a high risk for *** convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of *** have been devoted to exploring the behavioural functions,key pathological mechanisms and potential treatments of ***,as we highlight in this review,emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription,translation,synaptic transmission,epigenetics and immunoinflammatory *** involvement has important implications for the discovery of precise molecular targets for ***,we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular,cellular,neural circuit,and neurobehavioural ***,the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.

关键词： mechanisms spectrum behaviour

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Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice

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Advances in Alzheimer's Disease 2013年第4期2卷 161-170页

作者： Yui Yamamoto kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical Science Tohoku University Sendai Japan

Olfactory bulbectomy (OBX) causes cognitive dysfunction by degeneration of cholinergic neurons in the medial septum. Here, we define an involvement of nicotinic acetylcholine receptor (nAChR) in neuroprotective effect of donepezil in the septum neurons of OBX mice. Neuroprotective effects on the medial septal cholinergic neurons were assessed after chronic donepezil administration in OBX mice. We also measured Akt and ERK phosphorylation to define the neuroprotective mechanism of donepezil. We found that treatment with donepezil (1 - 3 mg/kg) for 15 consecutive days completely rescued cholinergic neurons in the OBX mice with concomitant improved memory. Reduction of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were restored by chronic donepezil administration (1 - 3 mg/kg) in OBX mouse medial septum. Both phosphorylated Akt and ERK immunoreactivities were localized in cell bodies of choline acetyltransferase (ChAT)-positive cholinergic cells in the medial septum. Enhancement of Akt and ERK phosphorylation seen following donepezil administration was totally blocked by pre-administration of mecamylamine (10 μM), a nicotinic acetylcholine receptor antagonist. Donepezil increases phosphorylation of Akt and ERK via nAChR stimulation in the medial septum cholinergic neurons. The Akt and ERK stimulation by donepezil is associated with its ability of neuroprotection in the medial septum and memory improvement.

关键词： Donepezil Neuroprotection Medial Septum Nicotinic Acetylcholine Receptors

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Microsphere embolism-induced protein tyrosine nitration mediates the disruption of blood-brain barrier in the rat brain

Microsphere embolism-induced protein tyrosine nitration medi...

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第十五届国际药理学大会

作者： Yasufumi Shirasaki kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan New Product Research Laboratories Ⅱ Daiichi Pharmac eutical Co.Ltd.TokyoJapan Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan New Product Research Laboratories Ⅱ Daiichi Pharmac eutical Co.Ltd.TokyoJapan

＜正＞ Brain ischemic injury elicits cerebral microvascular injury and results in blood -brain barrier (BBB disruption,which exacerbates the postischemic edema. The precise molecular mechanisms underlying ischemia - induced BBB disruption remain unclear. We here determine whether peroxynitrite formation in the vascular endothe lial cells （ECs） mediates BBB disruption after microsphere embolism （ME） ischemia in rat. The present study indicated that eNOS expression was significantly up - regulated in the brain microvessels 2-48 hours after ME. preceding disruption of BBB. In the vascular ECs. ME- induced eNOS expression was closely associated with protein tyrosine nitration. Leakage of rabbit IgG was also evident around nitrotyrosine - immunoreactive microvessels. To support the idea of undesirable roles of eNOS overexpression. a novel calmodulin - dependent NOS inhibitor. DY - 9760e. significantly inhibits protein tyrosine nitration after ME. Taken together. ME - induced eNOS expression and subsequently peroxynitrite formation in the vascular ECs likely accounts for the ischemia - induced BBB disruption.

关键词： DY-9760e peroxynitrite ischemia blood - brain barrier

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Rivastigmine Restores 5-HT<sub>1A</sub>Receptor Levels in the Hippocampus of Olfactory Bulbectomized Mice

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Advances in Alzheimer's Disease 2014年第3期3卷 128-136页

作者： Muhammad Rashedul Islam Shigeki Moriguchi Hideaki Tagashira kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical Sciences Tohoku University Sendai Japan

Rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, is used for symptomatic treatment of patients with mild to moderately severe dementia in Alzheimer’s disease (AD) patients. In the present study, we found that 5-HT1A receptor (5-HT1AR) is downregulated, whereas 5-HT2A receptor (5-HT2AR) is upregulated in the hippocampal dentate gyrus (DG) and CA1 region by olfactory bulbectomy (OBX) in mice. Furthermore, chronic treatment with rivastigmine (1.0 mg/kg) for 2 weeks starting 2 weeks after OBX operation restored the decreased 5-HT1AR and the increased 5-HT2AR levels. To determine whether cholinergic receptor stimulation by rivastigmine is involved in the rivastigmine-induced regulation of 5-HTR levels, we treated the mice with mecamylamine (2.5 mg/kg), or atropine (5.0 mg/kg) with rivastigmine (1.0 mg/kg) once a day for 2 weeks. Notably, the rivastigmine-induced 5-HT1AR upregulation was eliminated by mecamylamine but not by atropine treatments. On the other hand, the restored 5-HT2AR level by rivastigmine was not affected by either mecamylamine or atropine. Treatment with 8-OH-DPAT, a selective 5-HT1AR agonist improved the decreased 5-HT1AR and the increased 5-HT2AR levels in OBX mice. On the other hand, treatment with TCB-2, a potent 5-HT2AR agonist had no effects on the 5-HT1AR and 5-HT2AR dysregulation in OBX mice. Taken together, nicotinic acetylcholine receptor (nAChR) stimulation mediates rivastigmine-induced upregulation of 5-HT1AR. Therefore, we speculate that the increased ACh levels by rivastigmine can stimulate nAChR located on serotonergic nerve terminals and stimulate 5-HT1AR by the enhanced 5-HT release in the hippocampus. The 5-HT1AR stimulation likely mediates the improvement of 5-HT1AR levels as auto-receptor in OBX hippocampus.

关键词： Rivastigmine 5-HT1A Receptor 5-HT2A Receptor Nicotinic Acetylcholine Receptor Olfactory Bulbectomized Mice

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Ovariectomy aggravates pressure overload-induced cardiac hypertrophy by impairing nitric oxide synthase signaling pathways in female rats

Ovariectomy aggravates pressure overload-induced cardiac hyp...

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2008北京国际生理科学学术大会

作者： BHUIYAN Md.Shenuarin SHIODA Norifumi fukunaga kohji Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan Tohoku University 21st Century COE Program“CRESCENDO” SendaiJapan

Objective:Epidemiological studies show that the incidence of cardiovascular disease is higher in men than in premenopausal women but increases in postmenopausal *** elucidate molecular mechanism of ovarian hormone mediated protection against left ventricular(LV)hypertrophy and remodeling,we analyzed cardiac functions as well as hypertrophy-related protein expression in ovariectomized and aortic banded ***: Female Wistar rats(7 weeks old)weighing 150-200 g were subjected to bilateral ovariectomy(OVX)and sham *** weeks after ovariectomy,pressure overload(PO)cardiac hypertrophy was initiated in both groups by abdominal aortic banding using 25-gauge needle(outside diameter,0.5 mm).Four weeks after aortic banding LV morphology and functions were assessed using echocardiography and expression of proteins were determined by Western blot analysis.A subgroup of rats was further treated with isoproterenol(5 mg/kg)intraperitoneally once a day for four weeks and Kaplan-Meier survival analysis were ***:The LV weight/body weight ratio significantly increased in the OVX-PO group compared to OVX group and in the PO group compared to *** most significant increases in left ventricular end diastolic pressure,left ventricular developed pressure and left ventricular contractility(±dp/dt)were observed in the OVX-PO group compared to OVX group,reflecting compensatory phenotypes against *** eNOS expression and its activity were markedly reduced and Akt activity was largely attenuated in the OVX-PO ***,significant increased expressions on the eNOS regulatory proteins including HSP 90 and Caveolin 3 were observed in the hearts of the OVX *** further reduced their expression on the OVX-PO ***,significant increased mortality was observed in the OVX-PO group following chronic isoproterenol ***:Our results demonstrate that rats subject to ovariectomy are unable to compensate for hypertrophy and dete

关键词： pressure overload-induced hypertrophy ovariectomy eNOS Akt

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Intranasal Administration of Conditioned Medium from Cultured Mesenchymal Stem Cells Improves Cognitive Impairment in Olfactory Bulbectomized Mice

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Advances in Alzheimer's Disease 2020年第3期9卷 47-56页

作者： Kazuhiro Kojima Ichiro Kawahata Hisanao Izumi Sei-ichi Yoshihara Katsuyuki Oki kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical Sciences Tohoku University Sendai Japan BioMimetics Sympathies Inc. Tokyo Japan

Alzheimer’s disease (AD) is the common cause of dementia which shows the neuro-pathologies like an accumulation of amyloid-β (Aβ) and degeneration of cholinergic neuron. Olfactory bulbectomized (OBX) mice show some of AD features, so they have been used to research as AD model. Mesenchymal stem cells (MSCs) can differentiate into many kinds of cells, including neuronal cells. In this study, we intranasally administrated the conditioned medium derived from cultured umbilical cord (UC) MSCs. The intranasal administration of the MSCs medium restored the cognitive impairment observed in OBX mice. In addition, the decreased number of choline acetyltransferase-positive cells in the medial septum was restored by the conditioned medium administration. In conclusion, MSCs-derived conditioned medium may have protective effects of cholinergic neurons in the medial septum, thereby rescuing the cognitive impairment of OBX.

关键词： Alzheimer’s Disease Cholinergic Neuron Olfactory Bulbectomy Mesenchymal Stem Cells (MSCs) MSCs-Derived Conditioned Medium

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Microsphere embolism:a window to investigate brain microvascualr damage

Microsphere embolism:a window to investigate brain microvasc...

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浙江省毒理学会第二届学术年会

作者： Mahmood Qaisar Hong-yu Yang kohji fukunaga Feng Han Institute of Pharmacology Toxicology and Biochemical PharmaceuticsZhejiang University Department of Pharmacy The First Affiliated HospitalCollege of MedicineZhejiang University Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku University

Despite the growing knowledge on the causes of multiple brain infarcts,undefined mechanisms and lacking therapeutic drugs remain a major clinical challenge Appropriate animal models are needed to study the pathophysio... 详细信息

关键词： microsphere embolism cerebral ischemia blood-brain barrier multiple cerebral infarcts animal model

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Memory Improvement by Yokukansankachimpihange and Atractylenolide III in the Olfactory Bulbectomized Mice

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Advances in Alzheimer's Disease 2016年第2期5卷 35-45页

作者： Hisanao Izumi Yuzuru Sasaki Yasushi Yabuki Yasuharu Shinoda Nina Fujita Satoshi Yomoda kohji fukunaga Department of Pharmacology Tohoku University Graduate School of Pharmaceutical Sciences Sendai Japan Department of Pharmacology Kampo Research Laboratories Kracie Pharma Ltd. Toyama Japan

Alzheimer’s Disease (AD) shows cognitive dysfunction as core symptoms and Behavioral and Psychological Symptoms of Dementia (BPSD). Since acetylcholine nerve system derived from septum is collapsed in the AD patients, we have used Olfactory Bulbectomized (OBX) mice whose cholinergic system is largely impaired in the septum. Recently, Yokukansankachimpihange (YKH), a traditional Japanese Kampo medicine has used for BPSD in addition to improve cognitive dysfunction in AD patients. However the essential components for cognition and BPSD improvement and their mechanism are largely unknown. In present study, we found that Atractylenolide III (Aen-III), one of the components of YKH, improved cognitive deficits and depression in the OBX mice. OBX mice were orally administered with Aen-III (1.0 and 3.0 mg/kg) and YKH extracts daily for 18 days. Like YKH extracts, the Aen-III treatments ameliorated cognitive deficits and depression-like behavior observed in OBX mice. Importantly, Aen-III administration significantly restored the decreases in Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and cyclic AMP response element binding protein (CREB). The restoration of CaMKII and CaMKIV signaling is closely related to the increased BDNF levels. Furthermore, ATP reduction in OBX mice was rescued by Aen-III (3.0 mg/kg) and YKH (1000 mg/kg) treatment. In summary, Aen-III as a component of YKH ameliorates cognitive dysfunctions and depression via restoring CaMKII and CaMKIV signaling.

关键词： Yokukansankachimpihange Atractylenolide III Olfactory Bulbectomized Mice CaMKII BDNF

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BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2490-2503页

作者： Xiu-Xiu Liu Xing-Hui Chen Zhi-Wei Zheng Qin Jiang Chen Li Lin Yang Xiang Chen Xing-Feng Mao Hao-Yang Yuan Li-Li Feng Quan Jiang Wei-Xing Shi Takuya Sasaki kohji fukunaga Zhong Chen Feng Han Ying-Mei Lu Key Laboratory of Cardiovascular&Cerebrovascular Medicine Drug Target and Drug Discovery CenterSchool of PharmacyNanjing Medical University211166 NanjingChina Department of Physiology School of Basic Medical SciencesNanjing Medical University211166 NanjingChina Institute of Pharmacology and Toxicology College of Pharmaceutical SciencesZhejiang University310058 HangzhouChina Department of Pharmaceutical and Administrative Sciences Loma Linda University School of PharmacyLoma LindaCA 92350USA Department of Basic Sciences Loma Linda University School of MedicineLoma LindaCA 92350USA Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendai 980-8578Japan Institute of Brain Science the Affiliated Brain Hospital of Nanjing Medical University210029 NanjingChina Gusu School Nanjing Medical UniversitySuzhou Municipal HospitalThe Affiliated Suzhou Hospital of Nanjing Medical University215002 SuzhouChina

Cerebellar ataxias are characterized by a progressive decline in motor coordination,but the specific output circuits and underlying pathological mechanism remain poorly *** cell-type-specific manipulations,we discovered a novel GABAergic Purkinje cell(PC)circuit in the cerebellar IV/V lobe that projected to CaMKIIα+neurons in the fastigial nucleus(FN),which regulated sensorimotor ***,transcriptomics profiling analysis revealed various cerebellar neuronal identities,and we validated that biorientation defective 1(BOD1)played an important role in the circuit of IV/V lobe to ***1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs,accompany with ataxia ***,BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+neurons in the FN and ameliorated ataxia behaviors in L7-Cre;BOD1f/f ***,these findings further suggest that specific regulation of the cerebellar IV/V lobePCs→FNCaMKIIα+circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.

关键词： fastigial reversed Together

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Simultaneous Imaging and Amelioration of Endothelial Injury with Chemical Probes

Simultaneous Imaging and Amelioration of Endothelial Injury ...

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第十一届海峡两岸心血管科学研讨会、2017年全国心脑血管药理学术会议、中国卒中学会第一次新药研讨会

作者： Wang Chengkun Cheng Juan Liang Xing-Guang Tan Chao Jiang Quan Hu Yong-Zhou Lu Ying-Mei fukunaga kohji Han Feng Li Xin Zhejiang University Zhejiang University City College Tohoku University

Oxidative stress caused by the overproduction of H O is the hallmark of vascular diseases. To track native H O in the endothelium and simultaneously fulfill the task of therapy,we have provided a"click-to-release-two" strategy and devised a series of chemical probes by conjugating a vascular beneficial agent with a pro-fluorophore via a H O-sensitive linkage. The probes have been shown

关键词： Simultaneous Imaging and Amelioration of Endothelial Injury with Chemical Probes

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