American journal of neurodegenerative disease最新文献

{"title":"Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice.","authors":"Yien-Ming Kuo,&nbsp;Ejike Innocent Nwankwo,&nbsp;Robert L Nussbaum,&nbsp;Jack Rogers,&nbsp;Maria L Maccecchini","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor symptoms, including gastrointestinal dysfunction. In humans, these precede the motor symptoms by decades. Previously developed and characterized transgenic mice expressing the mutant human α-synuclein gene (<i>SNCA</i>) (either A53T or A30P), but not the endogenous mouse <i>Snca</i>, serve as models for familial PD. These animals demonstrate both robust abnormalities in enteric nervous system (ENS) function as well as synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age, recapitulating early gastrointestinal abnormalities seen before the gait impairment characteristics of human and murine PD. Posiphen is a translational inhibitor of α-synuclein that targets the 5' untranslated region (UTR) of <i>SNCA</i> mRNA and could be a potential drug for the treatment of PD. However, its efficacy in ameliorating symptoms of PD has not yet been evaluated. Here, we used these transgenic mouse models to investigate the efficacy of Posiphen in reversing the gastrointestinal dysfunction. We show that Posiphen normalizes the colonic motility of both transgenic mouse models, although it did not affect the Whole Gut Transit Time (WGTT). Pharmacokinetics studies revealed that Posiphen is more abundant in the brain than in blood, in agreement with its lipophilicity, and the main metabolite is N⁸-NorPosiphen, a molecule with similar properties as Posiphen. The brain Posiphen levels necessary to effect optimal function were calculated and compared with efficacious brain levels from previous studies, showing that a 2-3 mM concentration of Posiphen and metabolites is sufficient for functional efficacy. Finally, 10 mg/kg Posiphen reduced α-synuclein levels in the gut of <i>hSNCA^A53T</i> mice treated for twenty-one weeks, while 50 and 65 mg/kg Posiphen reduced α-synuclein levels in the brain of <i>hSNCA^A53T</i> mice treated for twenty-one days. In conclusion, this is the first study showing the preclinical efficacy of Posiphen in normalizing the colonic motility in mouse models of gastrointestinal dysfunction in early PD. This result is in agreement with the ability of Posiphen to reach the nervous system, and its mechanism of action, the translational inhibition of α-synuclein expression. These significant findings support further development of Posiphen as a drug for the treatment of PD.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"8 1","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420700/pdf/ajnd0008-0001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37086836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of <i>ter94</i>, <i>Drosophila VCP</i>, improves motor neuron degeneration induced by knockdown of <i>TBPH</i>, <i>Drosophila TDP-43</i>.","authors":"Yukie Kushimura,&nbsp;Takahiko Tokuda,&nbsp;Yumiko Azuma,&nbsp;Itaru Yamamoto,&nbsp;Ikuko Mizuta,&nbsp;Toshiki Mizuno,&nbsp;Masanori Nakagawa,&nbsp;Morio Ueyama,&nbsp;Yoshitaka Nagai,&nbsp;Hideki Yoshida,&nbsp;Masamitsu Yamaguchi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration. <i>TBPH</i> is the <i>Drosophila</i> ortholog of human <i>TDP-43</i>. In the present study, we confirmed that <i>Drosophila</i> models harboring <i>TBPH</i> knockdown develop locomotive deficits and degeneration of motoneurons (MNs) due to loss of its nuclear functions, recapitulating the human ALS phenotypes. We previously suggested that <i>ter94</i>, the <i>Drosophila</i> ortholog of human <i>Valosin-containing protein</i> (<i>VCP</i>), is a modulator of degeneration in MNs induced by knockdown of <i>Caz</i>, the <i>Drosophila</i> ortholog of human <i>FUS</i>. In this study, to determine the effects of VCP on TDP-43-assosiated ALS pathogenic processes, we examined genetic interactions between <i>TBPH</i> and <i>ter94</i>. Overexpression of <i>ter94</i> suppressed the compound eye degeneration caused by <i>TBPH</i> knockdown and suppressed the morbid phenotypes caused by neuron-specific <i>TBPH</i> knockdown, such as locomotive dysfunction and degeneration of MN terminals. Further immunocytochemical analyses revealed that the suppression is caused by restoring the cytoplasmically mislocalized TBPH back to the nucleus. In consistent with these observations, a loss-of-function mutation of <i>ter94</i> enhanced the compound eye degeneration caused by <i>TBPH</i> knockdown, and partially enhanced the locomotive dysfunction caused by <i>TBPH</i> knockdown. Our data demonstrated that expression levels of <i>ter94</i> influenced the phenotypes caused by <i>TBPH</i> knockdown, and indicate that reagents that up-regulate the function of human VCP could modify MN degeneration in ALS caused by TDP-43 mislocalization.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"7 1","pages":"11-31"},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840287/pdf/ajnd0007-0011.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35907599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protective effects of crocin in the management of neurodegenerative diseases: a review.","authors":"Tahereh Farkhondeh,&nbsp;Saeed Samarghandian,&nbsp;Hanieh Shaterzadeh Yazdi,&nbsp;Fariborz Samini","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Flavonoids have been used in traditional medicine to promote human health. Crocin has been proposed to be effective in the management of the various diseases including the neurodegenerative diseases. Antiepileptic and anti-Alzheimer effects of crocin have also been indicated. The efficacy of crocis in the treatment of cerebral ischemia and traumatic brain injury was also confirmed by using animal models. Crocin treatment increased dopamine levels in the brain of experimental model of Parkinson's disease. In addition, crocin modulates the opioid system to decrease the withdrawal syndrome. Thus, the present study highlighted the effects of crocin on the nervous system and the underling mechanisms. This review also indicated that crocins can be considered as an effective candidate in the management of nervous system diseases due to their antioxidant and anti-inflammation effects.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"7 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840286/pdf/ajnd0007-0001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35907598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One case with dexmedetomidine-induced stuporous state in epileptic patient undergoing abdominal surgery.","authors":"Dong-Ji Han,&nbsp;Zhi-Gang He,&nbsp;Zhi-Qiang Zhou,&nbsp;Li Feng,&nbsp;Cheng Liu,&nbsp;Yan Xiang,&nbsp;Hong-Bing Xiang","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A 56-year-old epileptic patient underwent right hemicolectomy and cholecystectomy surgery under general endotracheal anesthesia. Anesthesia was maintained with sevoflurane, and sufentanil, rocuronium, and dexmedetomidine infusions. After the operation and confirmation of neuromuscular recovery, the patient woke from anesthesia within 15 min and successfully extubated. After the vital signs of patient were stable, the patient was transported to post anesthesia care unit (PACU). 6 h after the surgery, he fell into a stuporous state for lasting 14 h and EEG showed no epileptiform discharges. Stupor did re-occur in 2 days after operation. 36 hours after operation, all signs of the stuporous state resolved spontaneously. Apparent dexmedetomidine-induced stuporous state has not been reported in the human literature.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"6 3","pages":"26-31"},"PeriodicalIF":0.0,"publicationDate":"2017-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545215/pdf/ajnd0006-0026.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35320040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can levodopa prevent cognitive decline in patients with Parkinson's disease?","authors":"Masahiro Ikeda,&nbsp;Hiroshi Kataoka,&nbsp;Satoshi Ueno","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Cognitive impairment in Parkinson's disease (PD) will become more important since the number of elderly patients with PD is increasing. We prospectively studied non-demented patients with PD over the course of 3 years to identify factors associated with PD that contribute to a decline in cognitive function. From among 100 consecutive patients, we registered 79 patients with PD. A total of 55 patients completed the study during 3 years and were divided to two groups: patients with a decline in cognitive function and those without a decline in cognitive function after 3 years. Seventeen independent variables were evaluated with the use of logistic regression models. The increase in the daily levodopa dose was related to a decline in cognitive function on univariate logistic regression analysis (OR = 0.279, p = 0.024, 95% CI = 0.092-0.848). Other variables were not related to a decline in cognitive function. The increase in the daily dose of levodopa was greater in patients without a decline in cognitive function than those with a decline in cognitive function; on the other hand, the cognitive function unchanged. Our results suggest that the treatment with levodopa might prevent a decline in cognitive function in PD.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"6 2","pages":"9-14"},"PeriodicalIF":0.0,"publicationDate":"2017-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498848/pdf/ajnd0006-0009.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35157595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered mechanisms of protein synthesis in frontal cortex in Alzheimer disease and a mouse model.","authors":"Paula Garcia-Esparcia,&nbsp;Georgios Sideris-Lampretsas,&nbsp;Karina Hernandez-Ortega,&nbsp;Oriol Grau-Rivera,&nbsp;Theodoros Sklaviadis,&nbsp;Ellen Gelpi,&nbsp;Isidro Ferrer","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Expression of the nucleolar chaperones nucleolin (<i>NCL</i>) and nucleophosmin (<i>NPM1</i>), upstream binding transcription factor (<i>UBTF</i>), rRNA18S, rRNA28S, and several genes encoding ribosomal proteins (RPs) is decreased in frontal cortex area 8 at advanced stages of Alzheimer's disease (AD). This is accompanied by reduced protein levels of elongation factors eEF1A and eEF2. Changes are more marked in AD cases with rapid course (rpAD), as initiation factor eIF3η is significantly down-regulated and several RP genes up-regulated in rpAD when compared with typical AD. These changes contrast with those seen in APP/PS1 transgenic mice used as a model of AD-like β-amyloidopathy; <i>Ncl</i> mRNA, rRNA18S, rRNA28S and seven out of fifteen assessed RP genes are up-regulated in APP/PS1 mice aged 20 months; only eEF2 protein levels are reduced in transgenic mice. Our findings show marked altered expression of molecules linked to the protein synthesis machinery from the nucleolus to the ribosome in frontal cortex at terminal stages of AD which differs from that seen in APP/PS1 transgenic mice, thus further suggesting that molecular signals in mouse models do not apply to real human disease counterparts.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"6 2","pages":"15-25"},"PeriodicalIF":0.0,"publicationDate":"2017-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498849/pdf/ajnd0006-0015.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35157596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etiology and treatment of amyotrophic lateral sclerosis.","authors":"Hernando Rafael,&nbsp;Juan Oscar David,&nbsp;Antonio Santiago Vilca","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>To date all researchers conclude that the etiology of Amyotrophic lateral sclerosis (ALS) is not known. On the contrary, since August 2009, we believe that disease is of ischemic origin in the anterior surface of the medulla oblongata.</p><p><strong>Material and method: </strong>We present our surgical experience into 45 patients with ALS (bulbar form in 36 cases and spinal form in 9). Preoperative MRI scans revealed microinfarcts in the medulla oblongata and/or cervical cord. During surgery we found: 1) poor quality of omentum in most cases; 2) degenerative changes in the cervical spine; 3) anatomical anomalies at the V4 segments of the vertebral arteries; 4) moderate to severe atherosclerosis at both V4 segments; 5) unilateral absence or stenosis in the anterior-ventral spinal arteries (AVSAs). All patients received omentum on the anterior, lateral and posterior surface of the medulla oblongata, and in 9 cases, an additional segment at the C5-C6 level.</p><p><strong>Results: </strong>Neurological improvement was better during the first days or weeks after surgery than in the following months or years, in all patients. However, 13 patients suffered neurological impairment in about 4 months later, due to greater deterioration of the cervical spine, by contrast, 7 patients with mild ALS have experienced neurological improvement by 80 to 100% during a follow-up of 4 and 6 years.</p><p><strong>Conclusions: </strong>These results confirm that ALS is of ischemic origin in the intraparenchymal territory of the AVSAs and/or in anterior spinal artery caused by atherosclerosis and associated to anatomical variants in the V4 segments of the vertebral arteries. Because in contrast to this, its revascularization by means of omentum can cure (mild degree) or improve this disease.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"6 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2017-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435608/pdf/ajnd0006-0001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35018541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fundamental role of pan-inflammation and oxidative-nitrosative pathways in neuropathogenesis of Alzheimer's disease [Retraction].","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>[This retracts the article on p. 1 in vol. 5, PMID: 27073740.]. </p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"5 3","pages":"152"},"PeriodicalIF":0.0,"publicationDate":"2016-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965615/pdf/ajnd0005-0152.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34743491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omental transplantation in a patient with mild ALS.","authors":"Hernando Rafael","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>To demonstrate that amyotrophic lateral sclerosis (ALS) is not a neurodegenerative disease. The patient, a 33-year-old man began with symptoms of the bulbar form of ALS, characterized by burning pain in both feet during two months and then, he presented right crural monoparesis, fasciculations, slight dysarthria and he walked with help of orthopedic devices. A preoperative MRI scans showed atherosclerosis at the V4 segment of the left vertebral artery. On May 2012, he received an omental transplantation on the anterior, left lateral and posterior surface of the medulla oblongata. About 48 hours after surgery, the dysarthria disappeared and the voluntary movement of the right foot improved. Three days later, he walked without aid of orthopedic device. At present, four years after operation he present complete reversal of symptoms. In conclusión, this patient confirms that bulbar ALS is of ischemic origin and therefore, mild ALS can be cured. </p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"5 3","pages":"153-7"},"PeriodicalIF":0.0,"publicationDate":"2016-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965616/pdf/ajnd0005-0153.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34743492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fundamental role of pan-inflammation and oxidative-nitrosative pathways in neuropathogenesis of Alzheimer's disease in focal cerebral ischemic rats.","authors":"Mak Adam Daulatzai","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a chronic progressive neurodegenerative condition of the brain, and it is the most common cause of dementia. Several neurobiological etiologies of AD are described in the literature. These include vascular, infectious, toxic, nutritional, metabolic, and inflammatory. However, these heterogeneous etiologies have a common denominator - viz. Inflammation and oxidative stress. Lipopolysaccharide (LPS) elevates the synthesis of proinflammatory cytokines and chemokines; chronically, together they trigger various pathological responses in the periphery and the CNS including dysfunctional memory consolidation and memory decline. Aging - the main risk factor for AD is inherently associated with inflammation. There are several age-related comorbidities that are also associated with inflammation and oxidative stress. Such co-prevailing aggravating factors, therefore, persist against a background of underlying aging-related pathology. They may converge, and their synergistic propagation may modify the disease course. A critical balance exists between homeostasis/repair and inflammatory factors; chronic, unrelenting inflammatory milieu succeeds in promoting a neuroinflammatory and neurodegenerative outcome. Extensive evidence is available that CNS inflammation is associated with neurodegeneration. LPS, proinflammatory cytokines, several mediators secreted by microglia, and oxidative-nitrosative stress in concert play a pivotal role in triggering neuroinflammatory processes and neurodegeneration. The persistent uncontrolled activity of the above factors can potentiate cognitive decline in tandem enhancing vulnerability to AD. Despite significant progress during the past twenty years, the prevention and treatment of AD have been tantalizingly elusive. Current studies strongly suggest that amelioration/prevention of the deleterious effects of inflammation may prove beneficial in preventing AD onset and retarding cognitive dysfunction in aging and AD. A concerted multi-focal therapeutic effort around the inflammation-oxidative-nitrosative stress paradigm may be crucial in preventing and treating AD. This paper informs on such relevant polypharmacy approach. </p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":"5 2","pages":"102-30"},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913220/pdf/ajnd0005-0102.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34668336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}