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Marta Vicente‐Rodríguez Carmen Pérez‐García Marcel Ferrer‐Alcón María Uribarri María G. Sánchez‐Alonso María P. Ramos Gonzalo Herradón 《Journal of neurochemistry》2014,131(5):688-695
Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up‐regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN?/?) mice and in mice with cortex‐ and hippocampus‐specific transgenic PTN over‐expression (PTN‐Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN?/? compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN‐Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN‐Tg mice, suggesting that up‐regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.
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S‐allyl cysteine activates the Nrf2‐dependent antioxidant response and protects neurons against ischemic injury in vitro and in vivo 下载免费PDF全文
Huanying Shi Xu Jing Xinbing Wei Ruth G. Perez Manru Ren Xiumei Zhang Haiyan Lou 《Journal of neurochemistry》2015,133(2):298-308
Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. S‐allyl cysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has been reported to possess neuroprotective effects against stroke. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study tests the hypothesis that SAC attenuates ischemic neuronal injury by activating the nuclear factor erythroid‐2‐related factor 2 (Nrf2)‐dependent antioxidant response in both in vitro and in vivo models. Our findings demonstrate that SAC treatment resulted in an increase in Nrf2 protein levels and subsequent activation of antioxidant response element pathway genes in primary cultured neurons and mice. Exposure of primary neurons to SAC provided protection against oxygen and glucose deprivation‐induced oxidative insults. In wild‐type (Nrf2+/+) mice, systemic administration of SAC attenuated middle cerebral artery occlusion‐induced ischemic damage, a protective effect not observed in Nrf2 knockout (Nrf2?/?) mice. Taken together, these findings provide the first evidence that activation of the Nrf2 antioxidant response by SAC is strongly associated with its neuroprotective effects against experimental stroke and suggest that targeting the Nrf2 pathway may provide therapeutic benefit for the treatment of stroke.
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Xiaojuan He Masato Ishizeki Naoki Mita Seitaro Wada Yoshifumi Araki Hiroo Ogura Manabu Abe Maya Yamazaki Kenji Sakimura Katsuhiko Mikoshiba Takafumi Inoue Toshio Ohshima 《Journal of neurochemistry》2014,131(1):53-64
Previous studies have implicated the role of Purkinje cells in motor learning and the underlying mechanisms have also been identified in great detail during the last decades. Here we report that cyclin‐dependent kinase 5 (Cdk5)/p35 in Purkinje cell also contributes to synaptic plasticity. We previously showed that p35?/? (p35 KO) mice exhibited a subtle abnormality in brain structure and impaired spatial learning and memory. Further behavioral analysis showed that p35 KO mice had a motor coordination defect, suggesting that p35, one of the activators of Cdk5, together with Cdk5 may play an important role in cerebellar motor learning. Therefore, we created Purkinje cell‐specific conditional Cdk5/p35 knockout (L7‐p35 cKO) mice, analyzed the cerebellar histology and Purkinje cell morphology of these mice, evaluated their performance with balance beam and rota‐rod test, and performed electrophysiological recordings to assess long‐term synaptic plasticity. Our analyses showed that Purkinje cell‐specific deletion of Cdk5/p35 resulted in no changes in Purkinje cell morphology but severely impaired motor coordination. Furthermore, disrupted cerebellar long‐term synaptic plasticity was observed at the parallel fiber‐Purkinje cell synapse in L7‐p35 cKO mice. These results indicate that Cdk5/p35 is required for motor learning and involved in long‐term synaptic plasticity.
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Hannah Scheiblich Anna Schlütter Douglas T. Golenbock Eicke Latz Pilar Martinez‐Martinez Michael T. Heneka 《Journal of neurochemistry》2017,143(5):534-550
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Reduced blood‐brain barrier expression of fatty acid‐binding protein 5 is associated with increased vulnerability of APP/PS1 mice to cognitive deficits from low omega‐3 fatty acid diets 下载免费PDF全文
Yijun Pan Kwok H. C. Choy Philip J. Marriott Siew Y. Chai Martin J. Scanlon Christopher J. H. Porter Jennifer L. Short Joseph A. Nicolazzo 《Journal of neurochemistry》2018,144(1):81-92
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Natalia Dominguez Jan R. T. van Weering Ricardo Borges Ruud F. G. Toonen Matthijs Verhage 《Journal of neurochemistry》2018,144(3):241-254
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Deletion of Atf6α impairs astroglial activation and enhances neuronal death following brain ischemia in mice 下载免费PDF全文
Akifumi Yoshikawa Tomoya Kamide Koji Hashida Hieu Minh Ta Yuki Inahata Mika Takarada‐Iemata Tsuyoshi Hattori Kazutoshi Mori Ryosuke Takahashi Tomohiro Matsuyama Yutaka Hayashi Yasuko Kitao Osamu Hori 《Journal of neurochemistry》2015,132(3):342-353
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Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis 下载免费PDF全文
Zhen Yuan Lifeng Yang Baian Chen Ting Zhu Mohammad Farooque Hassan Xiaomin Yin Xiangmei Zhou Deming Zhao 《Journal of neurochemistry》2015,133(5):722-729
The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into β‐state oligomers. Herein, we demonstrate that β‐state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full‐length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP‐induced neurotoxicity. We have characterized protein misfolding cyclic amplification‐induced monomer‐to‐oligomer conversion of PrP from three species using western blotting, circular dichroism, size‐exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting β‐oligomers are toxic to primary mouse cortical neurons independent of the presence of PrPC in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer‐induced apoptosis via regulation of Bcl‐2, Bax, and caspase‐3 in both wild‐type and PrP?/? cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain.
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The non‐peptidic δ‐opioid receptor agonist Tan‐67 mediates neuroprotection post‐ischemically and is associated with altered amyloid precursor protein expression,maturation and processing in mice 下载免费PDF全文
Jia‐Wei Min Yanying Liu David Wang Fangfang Qiao Hongmin Wang 《Journal of neurochemistry》2018,144(3):336-347
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Takefumi Kofuji Tomonori Fujiwara Masumi Sanada Tatsuya Mishima Kimio Akagawa 《Journal of neurochemistry》2014,130(4):514-525
Two types of syntaxin 1 isoforms, HPC‐1/syntaxin 1A (STX1A) and syntaxin 1B (STX1B), are thought to have similar functions in exocytosis of synaptic vesicles. STX1A?/? mice which we generated previously develop normally, possibly because of compensation by STX1B. We produced STX1B?/? mice using targeted gene disruption and investigated their phenotypes. STX1B?/? mice were born alive, but died before postnatal day 14, unlike STX1A?/? mice. Morphologically, brain development in STX1B?/? mice was impaired. In hippocampal neuronal culture, the cell viability of STX1B?/? neurons was lower than that of WT or STX1A?/? neurons after 9 days. Interestingly, STX1B?/? neurons survived on WT or STX1A?/? glial feeder layers as well as WT neurons. However, STX1B?/? glial feeder layers were less effective at promoting survival of STX1B?/? neurons. Conditioned medium from WT or STX1A?/? glial cells had a similar effect on survival, but that from STX1B?/? did not promote survival. Furthermore, brain‐derived neurotrophic factor (BDNF) or neurotrophin‐3 supported survival of STX1B?/? neurons. BDNF localization in STX1B?/? glial cells was disrupted, and BDNF secretion from STX1B?/? glial cells was impaired. These results suggest that STX1A and STX1B may play distinct roles in supporting neuronal survival by glia.
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Clenbuterol reduces GABAergic transmission in prefrontal cortex layer 5/6 pyramidal neurons of juvenile rat via reducing action potentials firing frequency of GABAergic interneurons 下载免费PDF全文
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Fisetin provides antidepressant effects by activating the tropomyosin receptor kinase B signal pathway in mice 下载免费PDF全文
Yamin Wang Bin Wang Jiaqi Lu Haixia Shi Siyi Gong Yufan Wang Ronald C. Hamdy Balvin H. L. Chua Lingli Yang Xingshun Xu 《Journal of neurochemistry》2017,143(5):561-568
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Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male, and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4 to 20 months (20–60%). Fat, muscle, and free fluid levels were all significantly higher in adult (7–9 months) as well as old (18–20 months) female KO mice compared to age‐matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age‐matched WT mice, but no significant change in body weight. Respiratory quotient (?19%) and metabolic rates (?14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18–20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age‐ and sex‐matched WT mice. We conclude that absence of the Hcrt peptide has gender‐specific effects. In contrast, Hcrt‐ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.
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Frances Corrigan Emma Thornton Laila C. Roisman Anna V. Leonard Robert Vink Peter C. Blumbergs Roberto Cappai 《Journal of neurochemistry》2014,128(1):196-204
We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPα (the secreted ectodomain of APP generated by α‐secretase cleavage). Two neuroprotective regions were identified in sAPPα, the N and C‐terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96‐110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96‐110 rescued motor and cognitive deficits in APP?/? mice following focal TBI. APP96‐110 also provided neuroprotection in Sprague–Dawley rats following diffuse TBI. Treatment with APP96‐110 significantly improved functional outcome as well as preserve histological cellular morphology in APP?/? mice following focal controlled cortical impact injury. Furthermore, following administration of APP96‐110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPα, represented by the sequence APP96‐110, as the neuroprotective site to confer neuroprotection following TBI.
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Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors 下载免费PDF全文
Siddhartha Dalvi Hieu H. Nguyen Ngoc On Ryan W. Mitchell Harold M. Aukema Donald W. Miller Grant M. Hatch 《Journal of neurochemistry》2015,135(5):867-879
The blood–brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14‐cis‐eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n ? 6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell® inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2), an eicosanoid known to facilitate opening of the blood–brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein‐labeled dextran from apical to basolateral medium. ARA‐mediated permeability was attenuated by specific cyclooxygenase‐2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA‐mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA.