CNS Neuroscience and Therapeutics
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Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice Summary Aims Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI ) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI ) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB ) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS ) accumulation with malondialdehyde (MDA ) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI . We used cresyl violet (CV ) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GP x) activity, and the accumulation of lipid‐reactive oxygen species (ROS ). Three days (d) after TBI , transmission electron microscopy (TEM ) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function.Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.
CNS Neuroscience and Therapeutics - Tập 25 Số 4 - Trang 465-475 - 2019
Expression Profile of Long Noncoding <scp>RNA</scp>s in Peripheral Blood Mononuclear Cells from Multiple Sclerosis Patients Summary Aims Long noncoding RNA s (lncRNA s) play a key role in regulating immunological functions. Their impact on the chronic inflammatory disease multiple sclerosis (MS ), however, remains unknown. We investigated the expression of lncRNA s in peripheral blood mononuclear cells (PBMC s) of patients with MS and attempt to explain their possible role in the process of MS . Methods For this study, we recruited 26 patients with MS according to the revised McDonald criteria. Then, we randomly chose 6 patients for microarray analysis. Microarray assays identified outstanding differences in lncRNA expression, which were verified through real‐time PCR . LncRNA functions were annotated for target genes using Gene Ontology (GO ) and Kyoto Encyclopedia of Genes and Genomes (KEGG ) analyses, and regulatory relationships between lncRNA s and target genes were analyzed using the “cis” and “trans” model. Results There were 2353 upregulated lncRNA s, 389 downregulated lncRNA s, 1037 upregulated mRNA s, and 279 downregulated mRNA s in patients with MS compared to healthy control subjects (fold change >2.0). Real‐time PCR results of six aberrant lncRNA s were consistent with the microarray data. The coexpression network comprised 864 lncRNA s and 628 mRNA s. Among differentially expressed lncRNA s, 10 lncRNA s were predicted to have 10 cis‐regulated target genes, and 33 lncRNA s might regulate their trans target genes. Conclusions We identified a subset of dysregulated lncRNA s and mRNA s. The differentially expressed lncRNA s may be important in the process of MS . However, the specific molecular mechanisms and biological functions of these lncRNA s in the pathogenesis of MS need further study.
CNS Neuroscience and Therapeutics - Tập 22 Số 4 - Trang 298-305 - 2016
Quercetin Improves Behavioral Deficiencies, Restores Astrocytes and Microglia, and Reduces Serotonin Metabolism in 3‐Nitropropionic Acid‐Induced Rat Model of Huntington's Disease Summary Aim Huntington's disease (HD ) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3‐nitropropionic acid (3‐NP )‐induced HD in rats where both drugs were administered simultaneously. Methods Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3‐NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion. Results Quercetin significantly attenuated 3‐NP ‐induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper‐metabolism was unaffected, quercetin provided a significant reduction of 3‐NP mediated increase in serotonin metabolism. Quercetin failed to affect 3‐NP ‐induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core. Conclusion These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD , but also for addressing inflammatory damages.
CNS Neuroscience and Therapeutics - Tập 20 Số 1 - Trang 10-19 - 2014
Oligodendrocyte Pathophysiology and Treatment Strategies in Cerebral Ischemia Summary Oligodendrocytes (OL s), the myelin‐forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia–ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult‐onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OL s, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OL s in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.
CNS Neuroscience and Therapeutics - Tập 20 Số 7 - Trang 603-612 - 2014
Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway Abstract Aims Microglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro‐inflammatory phenotype to anti‐inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown. Methods In vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro‐inflammatory state with conditioned media (CM) collected from oxygen‐glucose deprivation (OGD) challenged neuronal cell line Neuro‐2a (N2a). Real‐time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron‐microglia co‐culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro‐inflammatory microglia to post‐OGD neurons. Results Melatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro‐inflammatory markers and increased expression of anti‐inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro‐inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro‐inflammatory phenotype exacerbated post‐OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced the effect of melatonin on microglial phenotype shift. Conclusion: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro‐inflammatory to anti‐inflammatory polarity in a STAT3‐dependent manner.
CNS Neuroscience and Therapeutics - Tập 25 Số 12 - Trang 1353-1362 - 2019
Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease‐modifying therapies Summary Aims To evaluate the immunogenicity and safety of a seasonal influenza vaccine in a cohort of multiple sclerosis (MS) patients receiving different immunomodulating/immunosuppressive therapies and assess predictors of immune response. Methods A prospective, multicenter, non‐randomized observational study including 108 patients receiving a trivalent seasonal influenza vaccination was conducted. Influenza‐specific antibody titers (H1N1, H3N2, and influenza B) were measured to evaluate rates of seroprotection and seroconversion/significant titer increase. Univariable and multivariable analyses were performed to identify prognostic factors of vaccination outcomes. Results Regarding the whole cohort, seroprotection rates >70% were achieved for each influenza strain. Interferon‐treated patients reached high seroprotection rates (>84%). Good seroprotection rates were seen in patients treated with glatiramer acetate. In particular for H3N2, response rates were low in natalizumab‐treated patients and in the small subgroup of fingolimod‐treated patients. Patients with a previous disease‐modifying therapy and a longer disease duration were less likely to respond sufficiently. No severe adverse events were reported. MS disease activity was not increased after a one‐year follow‐up period. Conclusion Vaccination led to good immunogenicity, especially in MS patients treated with interferons and glatiramer acetate. At least for the H1N1 strain, rates of seroprotection and seroconversion/significant titer increase were high (>70% and >60%, respectively) for all therapeutic subgroups. Patients with a longer duration of the disease are exposed to an increased risk of insufficient immune response to vaccination.
CNS Neuroscience and Therapeutics - Tập 25 Số 2 - Trang 245-254 - 2019
Therapeutic Time Window and Dose Dependence of Xenon Delivered via Echogenic Liposomes for Neuroprotection in Stroke Summary Aims Neurologic impairment following ischemic injury complicates the quality of life for stroke survivors. Xenon (Xe) has favorable neuroprotective properties to modify stroke. Xe delivery is hampered by a lack of suitable administration strategies. We have developed Xe‐containing echogenic liposomes (Xe‐ELIP ) for systemic Xe delivery. We investigated the time window for Xe‐ELIP therapeutic effect and the most efficacious dose for neuroprotection. Molecular mechanisms for Xe neuroprotection were investigated. Methods Xenon‐containing echogenic liposomes were created by a previously developed pressurization‐freezing method. Following right middle cerebral artery occlusion (2 h), animals were treated with Xe‐ELIP at 2, 3, or 5 h to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3 h after stroke onset. Expression of brain‐derived neurotrophic factor (BDNF ), protein kinase B (Akt), and mitogen‐activated protein kinases (MAPK ) was determined. Results Xenon‐containing echogenic liposomes administration for up to 5 h after stroke onset reduced infract size. Treatment groups given 7 and 14 mg/kg of Xe‐ELIP reduced infarct size. Behavioral outcomes corresponded to changes in infarct volume. Xe‐ELIP treatment reduced ischemic neuronal cell death via activation of both MAPK and Akt. Elevated BDNF expression was shown following Xe‐ELIP delivery. Conclusion This study demonstrates the therapeutic efficacy of Xe‐ELIP administered within 5 h after stroke onset with an optimal dosage range of 7–14 mg/kg for maximal neuroprotection.
CNS Neuroscience and Therapeutics - Tập 19 Số 10 - Trang 773-784 - 2013
Use of PEGylated Immunoliposomes to Deliver Dopamine Across the Blood–Brain Barrier in a Rat Model of Parkinson's Disease Summary Aim To treat neurodegenerative disorders such as Parkinson's disease (PD ), drugs must be able to cross the blood–brain barrier (BBB ). Patients with PD are deficient in dopamine (DA ), a neurotransmitter that cannot pass through the BBB . Liposomes modified by adding polyethylene glycol (PEG ylated liposomes (PL s)) can be conjugated with antibody to form DA –PEG ylated immunoliposomes (DA ‐PIL s), and we tested their use as carriers of DA for treating PD . Methods PEG ylated liposomes (PL s) were prepared by evaporation method, and [3 H]dopamine was encapsulated within the dried lipid film using a freeze/thaw cycle to form DA ‐PL . Thiolated OX 26 MA b, an antitransferrin receptor monoclonal antibody, was then conjugated to 46‐nm PEG ylated liposomes. Particle size, zeta potential, and stability were assessed, and in vivo effects were determined after the intravenous injection of DA , DA ‐PL , and DA ‐PIL by examining brain tissue in normal rats and rats that underwent transection of the medial forebrain bundle to induce PD .Results The uptake of DA ‐PIL in the brains of this PD rat model increased about 8‐fold compared with that of DA alone and about 3‐fold compared with that of encapsulated DA –PEG ylated liposomes (DA ‐PL ). The volume of distribution of DA ‐PIL in the brain by the perfusion method was 4‐fold higher than that of DA ‐PL , indicating that conjugation of OX 26 MA b to the transferrin receptor of brain capillary endothelium mediated the effective delivery of DA to brain tissue. Conclusions Dopamine can be effectively delivered to the brain by means of a PIL ‐based drug delivery system in PD rats.
CNS Neuroscience and Therapeutics - Tập 22 Số 10 - Trang 817-823 - 2016
Pharmacotherapy for Alcohol Dependence: The 2015 Recommendations of the French Alcohol Society, Issued in Partnership with the European Federation of Addiction Societies Summary Background The latest French good practice recommendations (GPR s) for the screening, prevention, and treatment of alcohol misuse were recently published in partnership with the European Federation of Addiction Societies (EUFAS ). This article aims to synthesize the GPR s focused on the pharmacotherapy of alcohol dependence. Methods A four‐member European steering committee defined the questions that were addressed to an 18‐member multiprofessional working group (WG ). The WG developed the GPR s based on a systematic, hierarchical, and structured literature search and submitted the document to two review processes involving 37 French members from multiple disciplines and 5 non‐French EUFAS members. The final GPR s were graded A, B, or C, or expert consensus (EC ) using a reference recommendation grading system. Results The treatment of alcohol dependence consists of either alcohol detoxification or abstinence maintenance programs or drinking reduction programs. The therapeutic objective is the result of a decision made jointly by the physician and the patient. For alcohol detoxification, benzodiazepines (BZD s) are recommended in first‐line (grade A). BZD dosing should be guided by regular clinical monitoring (grade B). Residential detoxification is more appropriate for patients with a history of seizures, delirium tremens, unstable psychiatric comorbidity, or another associated substance use disorder (grade B). BZD s are only justified beyond a 1‐week period in the case of persistent withdrawal symptoms, withdrawal events or associated BZD dependence (grade B). BZD s should not be continued for more than 4 weeks (grade C). The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC ). For relapse prevention, acamprosate and naltrexone are recommended as first‐line medications (grade A). Disulfiram can be proposed as second‐line option in patients with sufficient information and supervision (EC ). For reducing alcohol consumption, nalmefene is indicated in first line (grade A). The second‐line prescription of baclofen, up to 300 mg/day, to prevent relapse or reduce drinking should be carried out according to the “temporary recommendation for use” measure issued by the French Health Agency (EC ). During pregnancy, abstinence is recommended (EC ). If alcohol detoxification is conducted during pregnancy, BZD use is recommended (grade B). No medication other than those for alcohol detoxification should be initiated in pregnant or breastfeeding women (EC ). In a stabilized pregnant patient taking medication to support abstinence, the continuation of the drug should be considered on a case‐by‐case basis, weighing the benefit/risk ratio. Only disulfiram should be always stopped, given the unknown risks of the antabuse effect on the fetus (EC ). First‐line treatments to help maintain abstinence or reduce drinking are off‐label for people under 18 years of age and should thus be considered on a case‐by‐case basis after the repeated failure of psychosocial measures alone (EC ). Short half‐life BZD s should be preferred for the detoxification of elderly patients (grade B). The initial doses of BZD s should be reduced by 30 to 50% in elderly patients (EC ). In patients with chronic alcohol‐related physical disorders, abstinence is recommended (EC ). Any antidepressant or anxiolytic medication should be introduced after a psychiatric reassessment after 2–4 weeks of alcohol abstinence or low‐risk use (grade B). A smoking cessation program should be offered to any smokers involved in an alcohol treatment program (grade B).
CNS Neuroscience and Therapeutics - Tập 22 Số 1 - Trang 25-37 - 2016
Symptom Dimensions in Chinese Patients with Obsessive‐Compulsive Disorder To study the symptom dimensions of Chinese patients with obsessive‐compulsive disorder (OCD), the symptom checklist of the Dimensional Yale–Brown Obsessive‐Compulsive Scale (DY‐BOCS) was used to assess the symptom dimensions of 139 OCD patients at a mental health center in Shanghai. The most common symptom dimensions were symmetry (67.6%), contamination (43.2%), and aggression (31.7%). The frequency of patients with the miscellaneous, sexual/religious, and hoarding symptom dimensions was 25.9%, 10.8%, and 8.6%, respectively. The frequency of male patients with symmetry concerns was higher than that of the female patients, and the frequency of female patients with contamination concerns was higher than that of male patients. OCD symptom dimensions can be identified in the Chinese context but there is a low frequency of endorsement of certain dimensions: sexual/religious, aggression, and hoarding concerns. Future studies need to further investigate the sociocultural and gender factors that may result in these findings: low numbers of people in China with a religious affiliation and the Chinese emphasis on Confucian harmony philosophy, thrift, and saving.
CNS Neuroscience and Therapeutics - Tập 15 Số 3 - Trang 276-282 - 2009
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