start-ver=1.4 cd-journal=joma no-vol=1502 cd-vols= no-issue= article-no= start-page=55 end-page=70 dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=20130328 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fe fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease. en-copyright= kn-copyright= en-aut-name=TayraJudith Thomas en-aut-sei=Tayra en-aut-mei=Judith Thomas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamedaMasahiro en-aut-sei=Kameda en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YasuharaTakao en-aut-sei=Yasuhara en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AgariTakashi en-aut-sei=Agari en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KadotaTomohito en-aut-sei=Kadota en-aut-mei=Tomohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WangFeifei en-aut-sei=Wang en-aut-mei=Feifei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KikuchiYoichiro en-aut-sei=Kikuchi en-aut-mei=Yoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=LiangHanbai en-aut-sei=Liang en-aut-mei=Hanbai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ShinkoAiko en-aut-sei=Shinko en-aut-mei=Aiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=WakamoriTakaaki en-aut-sei=Wakamori en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=VcelarBrigitta en-aut-sei=Vcelar en-aut-mei=Brigitta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WeikRobert en-aut-sei=Weik en-aut-mei=Robert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=DateIsao en-aut-sei=Date en-aut-mei=Isao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=2 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=6 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=7 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=8 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=9 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=10 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg affil-num=11 en-affil= kn-affil=Polymun Sci GmbH affil-num=12 en-affil= kn-affil=Polymun Sci GmbH affil-num=13 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg en-keyword=Carbamylated erythropoietin kn-keyword=Carbamylated erythropoietin en-keyword=Dopamine kn-keyword=Dopamine en-keyword=Neuroprotection kn-keyword=Neuroprotection en-keyword=Neurorescue kn-keyword=Neurorescue en-keyword=Parkinson's disease kn-keyword=Parkinson's disease END start-ver=1.4 cd-journal=joma no-vol=1397 cd-vols= no-issue= article-no= start-page=66 end-page=75 dt-received= dt-revised= dt-accepted= dt-pub-year=2011 dt-pub=20110623 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=In vivo optical imaging for evaluating the efficacy of edaravone after transient cerebral ischemia in mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Detection and protection of apoptosis, autophagy and neurovascular unit (NVU) are essentially important in understanding and treatment for ischemic stroke patients. In this study, we have conducted an in vivo optical imaging for detecting apoptosis and activation of matrix metalloproteinases (MMPs), then evaluated the protective effect of 2 package types of free radical scavenger edaravone (A and B) on apoptosis, autophagy and NVU in mice after transient middle cerebral artery occlusion (tMCAO). As compared to vehicle treatment, edaravones A and B showed a significant improvement of clinical scores and infarct size at 48 h after 90 min of tMCAO with great reductions of in vivo fluorescent signal for MMPs and early apoptotic annexin V activations. Ex vivo imaging of MMPSense 680 or annexin V-Cy5.5 showed a fluorescent signal, while which was remarkably different between vehicle and edaravone groups, and colocalized with antibody for MMP-9 or annexin V. Edaravone A and B ameliorated the apoptotic neuronal cell death in immunohistochemistry, and activations of MMP-9 and aquaporin 4 with reducing autophagic activations of microtubule-associated protein 1 light chain 3 (LC3) in Western blot. In this study, edaravone in both packages showed a similar strong neuroprotection after cerebral ischemia, which was confirmed with in vivo and ex vivo optical imagings for MMPs and annexin V as well as reducing cerebral infarct, inhibiting apoptotic/autophagic mechanisms, and protecting a part of neurovascular unit. en-copyright= kn-copyright= en-aut-name=LiuNing en-aut-sei=Liu en-aut-mei=Ning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShangJingwei en-aut-sei=Shang en-aut-mei=Jingwei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TianFengfeng en-aut-sei=Tian en-aut-mei=Fengfeng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishiHiroyoshi en-aut-sei=Nishi en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AbeKoji en-aut-sei=Abe en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Dept Neurol, Grad Sch Med Dent & Pharmaceut Sci affil-num=2 en-affil= kn-affil=Okayama Univ, Dept Neurol, Grad Sch Med Dent & Pharmaceut Sci affil-num=3 en-affil= kn-affil=Okayama Univ, Dept Neurol, Grad Sch Med Dent & Pharmaceut Sci affil-num=4 en-affil= kn-affil=Yokohama Coll Pharm, Dept Clin Pharmacol affil-num=5 en-affil= kn-affil=Okayama Univ, Dept Neurol, Grad Sch Med Dent & Pharmaceut Sci en-keyword=Apoptosis kn-keyword=Apoptosis en-keyword=Autophagy kn-keyword=Autophagy en-keyword=Cerebral ischemia kn-keyword=Cerebral ischemia en-keyword=Edaravone kn-keyword=Edaravone en-keyword=In vivo imaging kn-keyword=In vivo imaging END start-ver=1.4 cd-journal=joma no-vol=1473 cd-vols= no-issue= article-no= start-page=55 end-page=62 dt-received= dt-revised= dt-accepted= dt-pub-year=2012 dt-pub=20120914 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Impaired response of hypoxic sensor protein HIF-1 alpha and its downstream proteins in the spinal motor neurons of ALS model mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=We have recently reported spinal blood flow-metabolism uncoupling in an amyotrophic lateral sclerosis (ALS) animal model using Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mice, suggesting a relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway has not been well studied in ALS. Here, we examined temporal and spatial changes of the hypoxic stress sensor proteins HIF-1 alpha and its downstream proteins (VEGF, HO-1, and EPO) during the normcodccourse of motor neuron (MN) degeneration in the spinal cord of these ALS model mice. We found that HIP-1 alpha protein expression progressively increased both in the anterior large MNs and the surrounding glial cells in Tg mice from early symptomatic 14 week (W) and end stage 18W. Double immunofluorescence analysis revealed that HIP-1 alpha, plus GFAP and Iba-1 double-positive surrounding glial cells, progressively increased from 14 W to 18 W, although the immunohistochemistiy in large MNs did not change. Expression levels of VEGF and HO-1 also showed a progressive increase but were significant only in the surrounding glial cells at 18W. In contrast, EPO protein expression was decreased in the surrounding glial cells of Tg mice at 18W. Because HIF1-alpha serves as an important mediator of the hypoxic response, these findings indicate that MNs lack the neuroprotective response to hypoxic stress through the HIF-1 alpha system, which could be an important mechanism of neurodegeneration in ALS. en-copyright= kn-copyright= en-aut-name=SatoKota en-aut-sei=Sato en-aut-mei=Kota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MorimotoNobutoshi en-aut-sei=Morimoto en-aut-mei=Nobutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KurataTomoko en-aut-sei=Kurata en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MimotoTakafumi en-aut-sei=Mimoto en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiyazakiKazunori en-aut-sei=Miyazaki en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IkedaYoshio en-aut-sei=Ikeda en-aut-mei=Yoshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AbeKoji en-aut-sei=Abe en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=2 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=6 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol affil-num=7 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol en-keyword=ALS kn-keyword=ALS en-keyword=HIF-1 alpha kn-keyword=HIF-1 alpha en-keyword=VEGF kn-keyword=VEGF en-keyword=HO-1 kn-keyword=HO-1 en-keyword=EPO kn-keyword=EPO END