American journal of neurodegenerative disease最新文献

{"title":"Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation, in a cuprizone neurotoxic demyelinating mouse model.","authors":"Maryam Mohammadi, Mahdad Abdi, Mehdi Alidadi, Wael Mohamed, Kazem Zibara, Iraj Ragerdi Kashani","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Clinical data reported a reduction of Multiple sclerosis (MS) symptoms during pregnancy when progesterone levels are high. Medroxyprogesterone acetate (MPA) is a synthetic progestin contraceptive with unknown neuroprotective effects. This study investigated the effect of a contraceptive dose of MPA on microglia polarization and neuroinflammation in the neurotoxic cuprizone (CPZ)-induced demyelinating mouse model of MS. Mice received 1 mg of MPA weekly, achieving similar serum concentrations in human contraceptive users. Results revealed that MPA therapy significantly reduced the demyelination in the corpus callosum. In addition, MPA treatment induced a significant reduction in microglia M1-markers (iNOS, IL-1β and TNF-α) while M2-markers (Arg-1, IL-10 and TGF-β) were significantly increased. Moreover, MPA resulted in a significant decrease in the number of iNOS positive cells (M1), whereas TREM-2 positive cells (M2) significantly increased. Furthermore, MPA decreased the protein expression levels of NF-κB and NLRP3 inflammasome as well as mRNA expression levels of the downstream product IL-18. In summary, MPA reduces the level of demyelination and has an anti-inflammatory role in CNS demyelination by inducing M2 microglia polarization and suppressing the M1 phenotype through the inhibition of NF-κB and NLRP3 inflammasome. Our results suggest that MPA should be a suitable contraceptive pharmacological agent in demyelinating diseases.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610806/pdf/ajnd0010-0057.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39772568","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":"Evaluation of the effectiveness of methylphenidate and modafinil in the treatment of daily drowsiness in patients with refractory epilepsy and their comparison with the control group.","authors":"Neda Sheikhina,&nbsp;Mohammad-Reza Najafi,&nbsp;Ahmad Chitsaz,&nbsp;Keyvan Ghadimi","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Various articles show the high prevalence of sleep disorders and especially excessive daytime sleepiness (EDS) in patients with refractory epilepsy and the importance of personal and social burden of this complication on individuals. Considering the insufficient evidence to draw efficacy and safety of modafinil and methylphenidate to treat EDS in the patient with intractable seizures, we decided to compare the effect of methylphenidate and modafinil with the control group. It is hoped that this study will pave the way for further studies.</p><p><strong>Methods: </strong>This study is a clinical trial (IRCT20171030037093N22) (URL: https://www.irct.ir/trial/42485). The study population was patients with refractory epilepsy referred to the neurology clinic of Al-Zahra Hospital, Isfahan, Iran, from 2019 to 2020. The patients were randomly divided into three groups. The first group was treated with methylphenidate, the second group was treated with modafinil, and the third group was not received any medication such as modafinil and methylphenidate. Methylphenidate dosage was 10-20 mg/day. The patients were treated with modafinil at a dose of 200-600 mg/day. EPWORTH sleepiness scale (ESS) and Total Sleep Time (TST) were calculated before and 8 weeks after the intervention for the patients.</p><p><strong>Results: </strong>47 patients were included and divided into 3 groups, methylphenidate (10 males and 9 females), modafinil (7 males and 13 females), and control (4 males and 4 females). There was no significant difference among the groups based on ESS before and after intervention and TST after the intervention (P>0.05), but the mean of TST was significantly lower in the control group than in methylphenidate and modafinil groups before the intervention (P=0.003). The change of ESS and TST before compared to after intervention in the methylphenidate and modafinil group were significant (P<0.001), but the changes of ESS and TST in the control group were not significant (P>0.05). The frequency of complications (P=0.74) and outcomes (P=0.07) were similar in both groups.</p><p><strong>Conclusion: </strong>Modafinil and methylphenidate are two effective and safe drugs to increase the quality of sleep in the patients. Additionally, ESS and TST scores are better in the patients who used modafinil and methylphenidate.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610805/pdf/ajnd0010-0069.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39772569","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":"Gabapentin versus Pregabalin for management of chronic inflammatory demyelinating polyradiculoneuropathy.","authors":"Moulood Rayani,&nbsp;Behnaz Ansari,&nbsp;Sajad Asadi Boroujeni,&nbsp;Hossein Abdollahi Veshnavei,&nbsp;Keivan Basiri","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic autoimmune demyelinating peripheral neuropathy that leads to symmetrical muscular weakness, sensory deficit, hyporeflexia, chronic fatigue, and impaired quality of life (QoL). The current study aims to investigate the effects of gabapentin versus pregabalin on pain, sleep disturbances, and QoL in CIDP patients.</p><p><strong>Methods: </strong>This clinical trial was conducted on 40 patients diagnosed with CIDP randomly allocated to treatment with 100-500 mg gabapentin (n=20) or 50-300 mg pregabalin (n=20) both co-medicated with 37.5 mg venlafaxine. The dose of gabapentin/pregabalin was adjusted based on the patient's tolerability/response to the treatment. Visual analogue scale (VAS), Pittsburg Sleep Quality Questionnaire and Short Form Health Survey (SF-36) were filled at baseline, within three, six, nine and 12 months after the interventions to assess pain severity, sleep quality and QoL, respectively. The Iranian Registry of Clinical Trials (IRCT) code: IRCT20200217046523N16, https://fa.irct.ir/search/result?query=IRCT20200217046523N16.</p><p><strong>Results: </strong>Gabapentin revealed a dose-dependent efficacy in pain severity (<i>P</i>-value =0.004, r=0.287), sleep quality (<i>P</i>-value <0.001, r=0.387) and QoL (<i>P</i>-value =0.001, r=-0.378), but pregabalin (<i>P</i>-value >0.05). Co-medication of gabapentin plus venlafaxine could significantly improve sleep quality (<i>P</i>-value =0.009) and QoL (<i>P</i>-value =0.004), but pain severity (<i>P</i>-value =0.796). Pregabalin plus venlafaxine showed statistically significant improvement in pain (<i>P</i>-value =0.046), sleep quality (<i>P</i>-value <0.001) and QoL (<i>P</i>-value <0.001). The comparison of the two medications revealed the superiority of pregabalin in pain relief (<i>P</i>-value >0.001) and QoL (<i>P</i>-value =0.03) to pregabalin.</p><p><strong>Conclusion: </strong>Based on this study, the co-medication of pregabalin and venlafaxine led to remarkable superior outcomes compared to venlafaxine plus gabapentin in the management of pain, sleep quality, and QoL due to CIDP.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546632/pdf/ajnd0010-0050.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39572597","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":"Parsonage-Turner syndrome: a firsthand experience of an uncommon malady.","authors":"Vinod P Jerath,&nbsp;Vikram K Mahajan","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Parsonage Turner Syndrome (syn. idiopathic brachial plexopathy, neurologic amyotrophy) is a rare syndrome of poorly understood etiology with a reported incidence of 1.64 in 1 lakh persons per year. It affects men more often than women with a highest incidence in the third and seventh decades of life. Its pathophysiology is obscure and the syndrome has been reported in the postoperative, post infectious and recent viral illness, and post-vaccination settings. Trauma from manipulation of tissues and various positioning techniques used to facilitate surgical techniques, or immune-mediated inflammation remains the most common associated risk factor. It mostly remains under diagnosed for lack of clinical suspicion and specific diagnostic tools. Herein, we share a personal experience of this uncommon disorder by the first author, a healthy 67-year-old man, having no significant medical or surgical disorder and presenting with several weeks of weakness of right shoulder. The diagnosis was made after its aggravation following stretch injury sustained from a fall with upper limbs in full abduction. Treatment with high dose dexamthasone (100 mg in 200 ml 5% dextrose given once by slow i.v. infusion), NSAIDs (as needed) and physiotherapy given over 12 months was remittive.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546633/pdf/ajnd0010-0034.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39572654","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":"Link of neurocognitive deficit to impaired cardiovagal modulation in prehypertensives is comparable to newly diagnosed hypertensives in young Indian population.","authors":"Gopal Krushna Pal,&nbsp;Thiruchengodu Ammaiyappan Subathra,&nbsp;Yerrabelli Dhanalakshmi,&nbsp;Pravati Pal,&nbsp;Manoharan Renugasundari,&nbsp;Nivedita Nanda","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Hypertension has been reported to cause impaired cardiovagal modulation and a wide variety of cognitive loss. However, the link cardiovagal modulation to neurocognitive impairment has not been studied yet. The present study has compared the link cardiovagal modulation to neurocognitive impairment between prehypertension and newly diagnosed hypertension in young adults.</p><p><strong>Methods: </strong>One hundred forty-seven subjects (42 normotensives, 54 prehypertensives and 51 newly diagnosed hypertensives) aged between 18-44 years were included in this case-control study. The demographic, anthropometric, basal parameters, heart rate variability (HRV), cardiovascular autonomic function tests (CAFTs), event-related potential P300 and biochemical parameters were recorded in all the groups. Association of various parameters with neurocognitive deficit was studied by Pearson correlation analysis and independent contribution of various factors to cognitive deficit was assessed by multiple regression analysis in the study groups.</p><p><strong>Results: </strong>Total power (TP) of HRV, the marker of cardiovagal modulation was reduced in both prehypertensives and hypertensives compared to controls. Among CAFTs, the ΔDBP_IHG was increased, and 30:15 ratio and E:I ratio were decreased in both study groups. The latency of P300 (the marker of neurocognition) was significantly prolonged in prehypertensives and hypertensives and P300 latency was significantly associated with reduction in TP in both the groups. HOMA-IR was increased, and total oxidant capacity was decreased in prehypertensives and hypertensives, and both these parameters had independent contribution to P300.</p><p><strong>Conclusion: </strong>Prehypertensives had considerable autonomic imbalance, reduced cardiovagal modulation and neurocognitive deficit that were comparable to newly diagnosed hypertensives. Though the causal relationship between cardiovagal modulation and neurocognitive impairment can't be established from the findings of the present study, it appears that neurocognitive deficit might have some possible link to the decreased cardiovagal modulation and metabolic derangements in young prehypertensives and hypertensives.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546634/pdf/ajnd0010-0038.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39572655","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":"MicroRNA expression changes in Parkinson's disease (PD) patients' leukocytes prior to and following deep brain stimulation (DBS).","authors":"Soreq Lilach,&nbsp;Bergman Hagai,&nbsp;Israel Zvi,&nbsp;Soreq Hermona,&nbsp;Mohamed Wael","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The second most prevalent neurodegenerative disorder worldwide in the elderly is Parkinson's disease (PD). It is a major risk factor for aging. <i>Objectives:</i> Currently the involvement of miRNAs in the disease is mainly unclear. Additionally, the disease aetiology is complex and there are no available disease-modifying medications. Therefore, more evidence is required concerning its pathogenesis and developing new treatment modalities. <i>Methods:</i> Here, we studied the expression profiles of about 900 miRNAs in PD patients prior to and following deep brain stimulation (DBS) both on and following 1 hour off electrical stimulation and as compared with age and gender matched healthy control (HC) donor samples, using Affymetrix miRNA microarrays. We analysed statistically the data using Affymetrix expression console software. <i>Results:</i> We detected significantly altered miRNAs pre and post DBS treatment. <i>Conclusions:</i> Our findings indicate the involvement of miRNAs in PD. Future studies can enlarge the number of samples and use RNA sequencing platform to quantify further miRNAs in PD samples. We may also use the expression levels of miRNAs as biomarkers for PD in the blood.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310831/pdf/ajnd0010-0028.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39258403","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":"Therapeutic potential of <i>Allium Sativum</i> against the Aβ_(1-40)-induced oxidative stress and mitochondrial dysfunction in the <i>Wistar</i> rats.","authors":"Neetu Saini, Monika Kadian, Alka Khera, Aanchal Aggarwal, Anil Kumar","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>From the early stages of any neurodegenerative-disease mitochondrial functionality has been mortally extricated, though the exact timeline of these events is still unclear, it is likely to represent a progressive neurons-decline and cognitive-functions. Hence strategies suggested by herbal extract to restore mitochondrial functions may be a remedial approach to chronic neurodegenerative disorder like Alzheimer's disease (AD). This research was designed to evaluate if Aβ_1-40 induced oxidative stress and mitochondrial dysfunction could be inhibited by <i>Allium Sativum</i> (AS) supplementation. AD was induced by a single intra-hippocampal injection of Aβ_1-40 (5 μg/4 μl), while herbal supplementation was given orally (100, 250, 500 mg/kg body weight, daily) for 3 weeks. Morris water maze was used to assess cognitive function shows deficits in Aβ_1-40 treated animals, there is no significant alteration in locomotor function as examined by actophotometer. This was accompanied by enhancement in oxidative stress indicating by accentuated ROS and protein carbonyl levels. Concomitantly, decrease in activity of antioxidant enzymes was observed in diseased animals; as expressed by reduced superoxide-dismutase and catalase activity, as well as reduction in GSH levels and impaired mitochondrial functions. Medium dose of AS has been found effective in restoring the memory impairment along with antioxidant levels but high dose is more efficient as observed in the Aβ_1-40 treated rats. High dose of AS, on the other hand significantly ameliorates the mitochondrial-dysfunction in comparison to medium dose. Taken together, the findings reveal that AS reverses Aβ_1-40 induced brain alteration, it could be an efficient clinical mitigation action against AD growth.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166581/pdf/ajnd0010-0013.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38991277","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":"Neurodegeneration and axonal mRNA transportation.","authors":"Mohammad Mofatteh","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to tackle the global issue of neurodegeneration in the future. A better understanding of the potential molecular mechanism causing neurodegeneration can shed light on dysfunctional processes in diseased neurons, which can pave the way to design and synthesize novel targets for early diagnosis during the asymptomatic phase of the disease. Abnormal protein aggregation is a hallmark of neurodegenerative diseases which can hamper transportation of cargoes into axons. Recent evidence suggests that disruption of local protein synthesis has been observed in neurodegenerative diseases. Because of their highly asymmetric structure, highly polarized neurons require trafficking of cargoes from the cell body to different subcellular regions to meet the extensive demands of cellular physiology. Localization of mRNAs and subsequent local translation to corresponding proteins in axons is a mechanism which allows neurons to rapidly respond to external stimuli as well as establishing neuronal networks by synthesizing proteins on demand. Axonal protein synthesis is required for axon guidance, synapse formation and plasticity, axon maintenance and regeneration in response to injury. Different types of excitatory and inhibitory neurons in the central and peripheral nervous systems have been shown to localize mRNA. Rising evidence suggests that the repertoire of localizing mRNA in axons can change during aging, indicating a connection between axonal mRNA trafficking and aging diseases such as neurodegeneration. Here, I briefly review the latest findings on the importance of mRNA localization and local translation in neurons and the consequences of their disruption in neurodegenerative diseases. In addition, I discuss recent evidence that dysregulation of mRNA localization and local protein translation can contribute to the formation of neurodegenerative diseases such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. In addition, I discuss recent findings on mRNAs localizing to mitochondria in neurodegeneration.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012751/pdf/ajnd0010-0001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25560912","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":"Outcome of patients with lumbar spinal canal stenosis due to discogenic under percutaneous laser disc decompression.","authors":"Ahmad Shekarchizadeh,&nbsp;Ali Mohammadi-Moghadam,&nbsp;Majid Rezvani,&nbsp;Peyman Rahmani,&nbsp;Nourallah Eshraghi,&nbsp;Keyvan Ghadimi","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>The Percutaneous laser disc decompression (PLDD) method was first described by Daniel Choy in Australia in 1987. Therefore, in this study, we examined the clinical signs and symptoms of patients with spinal canal stenosis due to disc protrusion after PLDD surgery.</p><p><strong>Methods: </strong>In this clinical trial study, 43 patients with spinal canal stenosis due to lumbar disks who referred to Kashani and Zahra Marzieh educational hospitals from 2006 to 2016 were entered the study. The patients were divided into two groups as discogenic canal stenosis (3 females and 9 males) and complex degenerative disorder (canal stenosis due to discogenic and ligamentos) (16 females and 15 males). Patients underwent PLDD surgery and the clinical manifestations such as back and radicular pain, claudication, and complications of the surgery (hematoma, reoperation, and neurological symptoms) in patients were evaluated until one year after the operation.</p><p><strong>Results: </strong>After one year of surgery, the mean of back and radicular pains significantly decreased in both groups (P<0.05). All patients with claudication in the discogenic group improved and 35.5% of patients with complex degenerative disorder were not claudication after one year of surgery. The outcomes of treatment in patients with discogenic canal stenosis were 91.7% excellent, and 8.3% fair and in the complex degenerative disorder group were 64.5% excellent, 19.4% good and 16.1% fair (P=0.16). None of the patients had new neurological symptoms, and 12.9% of the complex degenerative disorder group patients needed reoperation.</p><p><strong>Conclusion: </strong>The PLDD method is a better procedure for discogenic canal stenosis than complex degenerative disorder. Therefore, more studies are required in this field for long time.</p>","PeriodicalId":72170,"journal":{"name":"American journal of neurodegenerative disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811930/pdf/ajnd0009-0001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38789038","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":"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":null,"pages":null},"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}