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Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Neural Regeneration Research 2024年第1期19卷 16-21页

作者： Marika Alborghetti Edoardo Bianchini Lanfranco De Carolis Silvia Galli Francesco E.Pontieri Domiziana Rinaldi neurology unit NESMOS DepartmentFaculty of Medicine&PsychologySapienza-University of RomeSant’Andrea University HospitalRomeItaly Department of Clinical and Behavioral neurology IRCCS-Fondazione Santa LuciaRomeItaly

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

关键词： glial cell line-derived neurotrophic factor(GDNF) glutamate neurological disorders neuroprotection Parkinson's disease preclinical studies rasagiline safinamide selegiline type-B monoamine oxidase(MAO_(B))inhibitors

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Heterogeneity of mature oligodendrocytes in the central nervous system

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Neural Regeneration Research 2025年第5期20卷 1336-1349页

作者： Chao Weng Adam M.R.Groh Moein Yaqubi Qiao-Ling Cui Jo Anne Stratton G.R.Wayne Moore Jack P.Antel Neuroimmunology unit Montreal Neurological Institute-HospitalDepartment of Neurology and NeurosurgeryMcGill UniversityMontrealQCCanada Department of neurology Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic

关键词： aging central nervous system diseases electron microscopy heterogeneity immunohistochemistry myelin sheath natural history neuroglia oligodendroglia single-cell gene expression analysis

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Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

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Neural Regeneration Research 2024年第8期19卷 1768-1771页

作者： Federica Azzolini Ettore Dolcetti Antonio Bruno Valentina Rovella Diego Centonze Fabio Buttari unit of neurology IRCCS NeuromedPozzilliItaly Department of System Medicine University of Tor VergataRomeItaly Synaptic Immunopathology Lab Department of Systems MedicineTor Vergata UniversityRomeItaly

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

关键词： disease-modifying behaviour endocannabinoid system long-term potentiation multiple sclerosis neuroplasticity neuroprotection physical exercise synaptopathy

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Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

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Neural Regeneration Research 2024年第4期19卷 881-886页

作者： Fan Bu Jia-Wei Min Md Abdur Razzaque Ahmad El Hamamy Anthony Patrizz Li Qi Akihiko Urayama Jun Li Department of neurology University of Texas Health Science Center Department of neurology&Psychology The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain unclear.It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke.Mounting evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced age.Previous studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model.Here,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic stroke.We found that as mice aged,Rac1 expression declined in the brain.Delayed overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–28.This was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by immunostaining.In a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells.Furthermore,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke.Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

关键词： aging angiogenesis brain-derived neurotrophic factor(BDNF) cerebral ischemia cognitive recovery neurite Pak1 Rac1 sensorimotor recovery

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Statistical evaluation of cluster formation of relapse in neuromyelitis optica spectrum disorder

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Neural Regeneration Research 2024年第9期19卷 1888-1889页

作者： Tetsuya Akaishi Ichiro Nakashima Department of neurology Tohoku UniversitySendaiJapan Department of neurology Tohoku Medical and Pharmaceutical UniversitySendaiJapan

Evaluating the cluster formation of clinical attacks in chronic relapsing diseases is an important statistical issue because the presence of attack clusters may influence therapeutic strategies for relapse prevention.We recently reported the occurrence of unevenly clustered attacks in patients with anti-aquaporin-4(AQP4)antibody-positive neuromyelitis optica spectrum disorder(NMOSD)(Akaishi et al.,2020a).

关键词： AQP4 relapse

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Acute symptomatic seizures in newborns:a narrative review

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Acta Epileptologica 2024年第1期7卷 1-13页

作者： Carlotta Spagnoli Francesco Pisani Child neurology unit Pediatric DepartmentAzienda USL-IRCCS Di Reggio EmiliaReggio Emilia42123Italy Child neurology and Psychiatry unit Department of Human NeurosciencesSapienza University of RomeRome00185Italy Azienda Ospedaliero Universitaria Policlinico Umberto I Rome00185Italy

Acute symptomatic seizures are the main sign of neurological dysfunction in newborns.This is linked to the unique characteristics of the neonatal brain,making it hyperexcitable compared to older ages,and to the common occurrence of some forms of acquired brain injury,namely hypoxic-ischemic encephalopathy.In this narrative review we will provide an overview of neonatal seizures definition,their main underlying etiologies,diagnostic work-up and differential diagnoses,and will discuss about therapeutic options and prognostic outlook.The latest publications from the ILAE Task Force on Neonatal Seizures will be presented and discussed.Of note,they highlight the current lack of robust evidence in this field of clinical neurology.We will also report on specificities pertaining to low-and-middle income countries in terms of incidence,main etiologies and diagnosis.The possibilities offered by telemedicine and automated seizures detection will also be summarized in order to provide a framework for future directions in seizures diagnosis and management with a global perspective.Many challenges and opportunities for improving identification,monitoring and treatment of acute symptomatic seizures in newborns exist.All current caveats potentially represent different lines of research with the aim to provide better care and reach a deeper understanding of this important topic of neonatal neurology.

关键词： Acute symptomatic Neonatal seizures EEG Newborn Outcome Diagnosis Etiologies

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Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open- label, controlled trial

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Stroke & Vascular neurology 2024年第1期9卷 82-89页

作者： Yunyun Xiong Bruce C V Campbell Marc Fisher Lee H Schwamm Mark Parsons Hao Li Yuesong Pan Xia Meng Xingquan Zhao Yongjun Wang neurology Beijing Tiantan HospitalBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina Department of Medicine and neurology The University of MelbourneMelbourneVictoriaAustralia neurology Beth Israel Deaconess Medical CenterBostonMassachusettsUSA Department of neurology and Comprehensive Stroke Center Massachusetts General HospitalBostonMassachusettsUSA Department of neurology University of New South Wales South Western Sydney Clinical SchoolLiverpoolNew South WalesAustralia

Background and purpose Recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)was not inferior to alteplase for ischaemic stroke within 4.5hours.Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion(LVO)of anterior circulation beyond 4.5hours.Methods and design Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III(TRACE III)is a multicentre,prospective,randomised,open-label,blind endpoint,controlled clinical trial.Patients who had an ischaemic stroke due to anterior circulation LVO(internal carotid artery,middle cerebral artery M1 and M2 segments)within 4.5–24hours from last known well(including wake-up stroke and no witness stroke)and with salvageable tissue(ischaemic core volume6s at 24 hours and NIHSS score change from baseline at 7days.Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.Discussion TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5hours.Trial registration number NCT05141305.

关键词： Therapy random Rational

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Non-linear dynamic state-space network modeling for decoding neurodegeneration

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Neural Regeneration Research 2024年第9期19卷 1879-1880页

作者： Venkata C.Chirumamilla Chi Wang Ip Martin Reich Robert Peach Jens Volkmann Bahman Nasseroleslami Muthuraman Muthuraman Prenatal Pediatrics Institute Children’s National HospitalWashingtonDCUSA Neural Engineering with Signal Analytics and Artificial Intelligence Department of NeurologyUniversity of WürzburgWürzburgGermany Academic unit of neurology Trinity Biomedical Sciences InstituteTrinity College DublinUniversity of DublinDublinIreland

Neurodegenerative disorders represent a pervasive global health challenge,yet therapeutic options remain conspicuously limited.These disorders are inherently dynamic processes within the central nervous system,unfolding across distinct sub-stages:initial structural neuronal alterations(sub-stage 1),functional impairment(sub-stage 2),and culminating in neuronal death(sub-stage 3).

关键词： alterations impairment dynamic

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Blood biomarkers of Alzheimer’s disease:important considerations for use in clinical practice

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Neural Regeneration Research 2025年第1期20卷 205-206页

作者： Sarah Fullam Sean O’Dowd Antoinette O’Connor Department of neurology Tallaght University HospitalDublinIreland Academic unit of neurology Trinity College DublinIreland

Introduction:Fluid and positron emission tomography(PET)biomarkers that enable the detection of the hallmark proteins of Alzheimer’s disease(AD)(amyloid and tau)have revolutionized our approach to the diagnosis of AD.The evolution of AD diagnostic criteria to include biological characterization(Alzheimer’s Association Working Group,2023)provides an appropriate framework to reduce levels of clinico-pathologic mismatch and improve in-vivo diagnostic accuracy.As the therapeutic landscape for neurodegenerative disease evolves,it is increasingly incumbent on clinicians to provide timely,and pathologically precise diagnoses for patients.However,the expensive and invasive nature of these tests limits their scalability.

关键词： Blood Alzheimer diagnosis

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Use of MLC901 in cerebral venous sinus thrombosis:Three case reports

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World Journal of Clinical Cases 2024年第2期12卷 346-353页

作者： Anita Ante Arsovska Narayanaswamy Venketasubramanian Department of Urgent neurology University Clinic of NeurologyUniversity Ss.Cyril and Methodius-Faculty of MedicineSkopje 1000North Macedonia Department of neurology Raffles HospitalSingapore 188770Singapore

BACKGROUND Cerebral venous sinus thrombosis(CVT)is rare cause of cerebrovascular disease.The incidence is 0.5%of all stroke.The majority of affected patients are young adults(mean age:35-40 years)with mild to moderate disabilities.Poor outcome with severe disability is seen in 13%of cases.Early diagnosis and treatment are important for good outcomes and preventing complications.Treatment options are limited and mostly based on consensus.NeuroAiD II™(MLC901;Moleac Pte,Ltd,Singapore)has a potential beneficial role in post-stroke recovery,by aiding the natural brain recovery process.CASE SUMMARY MLC901 consists of nine natural herbal ingredients.Studies have shown its safety profile and aid in post stroke recovery.The aim of this case series was to demonstrate the potential role of MLC901 in stroke recovery of patients with cerebral venous sinus thrombosis(CVST)who received MLC901 in addition to standard of care.The prescribed dose of MLC901 is 400 mg/cap two capsules,three times a day.Data from these patients were prospectively collected at baseline and at monthly visits,for a duration of 3 mo.Outcome measures included adherence to therapy,side effects,National Institutes of Health Stroke Scale,Glasgow Coma Scale,modified Rankin Scale,and the Short Orientation-Memory-Concentration Test.MLC901 was well tolerated and no side effects were reported.All patients were stable with improved condition.CONCLUSION This case series highlights the potential therapeutic effects of MLC901 on CVST and provides support for further studies.

关键词： MLC901 Cerebral venous sinus thrombosis Anticoagulation therapy Safety Case report

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