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Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and Neurodevelopmental disorders

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Acta Pharmaceutica Sinica B 2023年第5期13卷 1866-1886页

作者： Rania Awad Avi Avital Alejandro Sosnik Laboratory of Pharmaceutical Nanomaterials Science Department of Materials Science and EngineeringTechnion-Israel Institute of TechnologyHaifa 3200003Israel Behavioral Neurobiology Laboratory Department of Occupational TherapyFaculty of Social Welfare and Health SciencesUniversity of HaifaHaifa 3498838Israel

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

关键词： Neurodegenerative diseases Neurodevelopmental disorders Central nervous system Blood—brain barrier Nano-drug delivery systems Nose-to-brain pathway Intranasal administration Polymeric nanoparticles Polymeric micelles Dendrimers

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The microbiota-gut-brain axis and Neurodevelopmental disorders

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Protein & Cell 2023年第10期14卷 762-775页

作者： Qinwen Wang Qianyue Yang Xingyin Liu State Key Laboratory of Reproductive Medicine and offspring Health School of Public HealthNanjing Medical UniversityNanjing 211166China Department of Pathogen Biology-Microbiology Division Key Laboratory of Pathogen of Jiangsu Province Key Laboratory of Human Functional Genomics of Jiangsu ProvinceNanjing Medical UniversityNanjing 211166China The Affiliated Suzhou Hospital of Nanjing Medical University Suzhou Municipal HospitalGusu SchoolNanjing Medical UniversityNanjing 211166China Department of Microbiota Medicine The Second Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China

The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis,regulating various physiological processes.In recent years,the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated.The gut microbiota is commonly considered to regulate neurodevelopment through three pathways,the immune pathway,the neuronal pathway,and the endocrine/systemic pathway,with overlaps and crosstalks in between.Accumulating studies have identified the role of the microbiota-gut-brain axis in Neurodevelopmental disorders including autism spectrum disorder,attention deficit hyperactivity disorder,and Rett Syndrome.Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in Neurodevelopmental disorders(NDDs).This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs.Furthermore,we analyzed both the current state of research progress and discuss future perspectives in this field.

关键词： Neurodevelopmental disorders gut microbiome microbiota gut brain axis

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Network biology:A promising approach for drug target identification against Neurodevelopmental disorders

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BIOCELL 2023年第8期47卷 1675-1687页

作者： WAYEZ NAQVI ANANYA SINGH PREKSHI GARG PRACHI SRIVASTAVA Amity Institute of Biotechnology Amity UniversityLucknow226028India

Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions.Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis,prognosis,and treatment.The network of biological entities can help us predict drug targets for several diseases.The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease.The novel strategical approach of system biologyassisted pharmacology coupled with computer-aided drug discovery(CADD)can help drugs fight multifactorial diseases efficiently.In the present review,we have summarized the role and application of network biology for not only unfolding the mechanism of complex Neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD,Autism,Epilepsy,and Intellectual Disability.Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of Neurodevelopmental disorders.

关键词： Network biology Neurodevelopmental disorders Drug target Pharmacology System biology assisted CADD

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Postnatal therapeutic approaches in genetic Neurodevelopmental disorders

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Neural Regeneration Research 2021年第3期16卷 414-422页

作者： Gilad Levy Boaz Barak The Sagol School of Neuroscience Tel Aviv UniversityTel AvivIsrael The School of Psychological Sciences Faculty of Social SciencesTel Aviv UniversityTel AvivIsrael

Genetic Neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of Neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for Neurodevelopmental disorders derived from preclinical studies in the laboratory.

关键词： adeno-associated virus CRISPR-Cas9 developmental window genetic therapy mouse models Neurodevelopmental disorders non-human primates preclinical studies

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Ultrasonic vocalizations in mice: relevance for ethologic and Neurodevelopmental disorders studies

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Neural Regeneration Research 2021年第6期16卷 1158-1167页

作者： Marika Premoli Maurizio Memo Sara Anna Bonini Department of Molecular and Translational Medicine University of BresciaViale Europa 11BresciaItaly

Mice use ultrasonic vocalizations(USVs)to communicate each other and to convey their emotional state.USVs have been greatly characterized in specific life phases and contexts,such as mother isolation-induced USVs for pups or female-induced USVs for male mice during courtship.USVs can be acquired by means of specific tools and later analyzed on the base of both quantitative and qualitative parameters.Indeed,different ultrasonic call categories exist and have already been defined.The understanding of different calls meaning is still missing,and it will represent an essential step forward in the field of USVs.They have long been studied in the ethological context,but recently they emerged as a precious instrument to study pathologies characterized by deficits in communication,in particular Neurodevelopmental disorders(NDDs),such as autism spectrum disorders.This review covers the topics of USVs characteristics in mice,contexts for USVs emission and factors that modulate their expression.A particular focus will be devoted to mouse USVs in the context of NDDs.Indeed,several NDDs murine models exist and an intense study of USVs is currently in progress,with the aim of both performing an early diagnosis and to find a pharmacological/behavioral intervention to improve patients’quality of life.

关键词： autism spectrum disorders behavioral phenotyping emotional state environmental modulation maternal immune activation mouse models Neurodevelopmental disorders social context ultrasonic communication vocalizations classification

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Targeted sequencing and integrative analysis of 3,195 Chinese patients with Neurodevelopmental disorders prioritized 26 novel candidate genes

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Journal of Genetics and Genomics 2021年第4期48卷 312-323页

作者： Tao Wang Yi Zhang Liqui Liu Yan Wang Huiqian Chen Tianda Fan Jinchen Li Kun Xia Zhongsheng Sun Center for Medical Genetics&Hunan Key Laboratory of Medical Genetics School of Life SciencesCentral South UniversityChangshaHunan 410083China Beijing Institutes of Life Science Chinese Academy of SciencesBeijing 100101China DIAGenes Precision Medicine Beijing 102600China National Clinical Research Centre for Geriatric disorders Department of GeriatricsXiangya HospitalCentral South UniversityChangshaHunan 410083China Shanghai Adeptus Biotechnology Shanghai 200126China Institute of Genomic Medicine Wenzhou Medical UniversityWenzhouZhejiang 325035China Department of Neurology Xiangya HospitalCentral South UniversityChangsha Hunan410083China CAS Center for Excellence in Brain Science and Intelligences Technology(CEBSIT) Shanghai 200031China School of Basic Medical Science Central South UniversityChangshaHunan410083China CAS Center for Excellence in Biotic Interactions University of Chinese Academy of SciencesBeijing 100049China State Key Laboratory of Integrated Management of Pest Insects and Rodents Chinese Academy of SciencesBeijing 100101China

Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.

关键词： De novo mutations X-linked variants Rare inherited variants Homozygous mutations Neurodevelopmental disorders Autism spectrum disorders Candidate genes

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A negative regulator of synaptic development:MDGA and its links to Neurodevelopmental disorders

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World Journal of Pediatrics 2019年第5期15卷 415-421页

作者： Rui Wang Jia-Xian Dong Lu Wang Xin-Yan Dong Eitan Anenberg Pei-Fang Jiang Ling-Hui Zeng Yi-Cheng Xie Children's Hospital Zhejiang University School of MedicineHangzhou 310052China Department of Clinical Medicine Zhejiang University City CollegeHangzhou 310015China

Background Formation of protein complexes across synapses is a critical process in neurodevelopment,having direct implications on brain function and animal behavior.Here,we present the understanding,importance,and potential impact of a newly found regulator of such a key interaction.Data sources A systematic search of the literature was conducted on PubMed(Medline),Embase,and Central-Cochrane Database.Results Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins(MDGAs)were recently discovered to regulate synaptic development and transmission via suppression of neurexins-neuroligins transsynaptic complex formation.MDGAs also regulate axonal migration and outgrowth.In the context of their physiological role,we begin to consider the potential links to the etiology of certain Neurodevelopmental disorders.We present the gene expression and protein structure of MDGAs and discuss recent progress in our understanding of the neurobiological role of MDGAs to explore its potential as a therapeutic target.Conclusion MDGAs play a key role in neuron migration,axon guidance and synapse development,as well as in regulating brain excitation and inhibition balance.

关键词： Adhesion molecule E/I balance Neurodevelopmental disorders Synapse

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Regulation and postsynaptic binding of neurexins - drug targets for neurodevelopmental and neuropsychiatric disorders

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Frontiers in Biology 2015年第3期10卷 239-251页

作者： Yicheng DingL Linda Howard Louise Gallagher Sanbing Shen Regenerative Medicine Institute School of Medicine National University of Ireland (NUI) Galway Galway Ireland Discipline of Psychiatry School of Medicine Trinity College Dublin Dublin Ireland

Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.

关键词： alternative splicing neurexins Neurodevelopmental disorders neuropsychiatric illness post-synaptic interactivepartners regulation synapse

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Management of sleep disorders among children and adolescents with Neurodevelopmental disorders: A practical guide for clinicians

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World Journal of Clinical Pediatrics 2022年第3期11卷 239-252页

作者： Michael O Ogundele Chinnaiah Yemula Department of Community Paediatrics Bridgewater Community Healthcare NHS Foundation TrustHalton DistrictRuncorn WA71TWUnited Kingdom Department of Community Paediatrics Bedfordshire Community Health ServicesCambridgeshire Community Services NHS TrustSt Ives PE274LGUnited Kingdom

There is a complex relationship between sleep disorders and childhood neurodevelopmental,emotional,behavioral and intellectual disorders(NDEBID).NDEBID include several conditions such as attention deficit/hyperactivity disorder,autism spectrum disorder,cerebral palsy,epilepsy and learning(intellectual)disorders.Up to 75%of children and young people(CYP)with NDEBID are known to experience different types of insomnia,compared to 3%to 36%in normally developing population.Sleep disorders affect 15%to 19%of adolescents with no disability,in comparison with 26%to 36%among CYP with moderate learning disability(LD)and 44%among those with severe LD.Chronic sleep deprivation is associated with significant risks of behavioural problems,impaired cognitive development and learning abilities,poor memory,mood disorders and school problems.It also increases the risk of other health outcomes,such as obesity and metabolic consequences,significantly impacting on the wellbeing of other family members.This narrative review of the extant literature provides a brief overview of sleep physiology,aetiology,classification and prevalence of sleep disorders among CYP with NDEBIDs.It outlines various strategies for the management,including parenting training/psychoeducation,use of cognitive-behavioral strategies and pharmacotherapy.Practical management including assessment,investigations,care plan formulation and follow-up are outlined in a flow chart.

关键词： Sleep Emotional Behavioural difficulties Neurodevelopmental disorders Pharmacotherapy Non-pharmacologic interventions Cognitive therapy Melatonin Adolescents Psychoeducation

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Neurodevelopmental disorders:An innovative perspective via the response to intervention model

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World Journal of Psychiatry 2021年第11期11卷 1017-1026页

作者： Celestino Rodríguez Debora Areces Trinidad García Marisol Cueli Paloma Gonzalez-Castro Department of Psychology University of OviedoOviedo 33003AsturiasSpain

Neurodevelopmental disorders are a group of conditions classified together by the most recent edition of the Diagnostic and Statistical Manual of Mental disorders which include intellectual disability,communication disorders,autism spectrum disorder,attention-deficit/hyperactivity disorder,specific learning disorder(SLD),and motor disorders.SLD is present in many students,who exhibit significant difficulties in the acquisition of reading,written expression,and mathematics,mostly due to problems with executive functions(EF).The present study is a review of the current situation of Neurodevelopmental disorders and SLD focusing on the benefits of the response to intervention model(RtI),which allows the combination of evaluation and intervention processes.It also addresses the key role of EF.The importance of adapting RtI to new possibilities such as the use of virtual reality is discussed and a theoretical framework for carrying that out is provided.

关键词： Neurodevelopmental disorders Specific learning disorder Response to intervention model Virtual reality

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