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Darwish M, El Hajj R, Khayat L, Alaaeddine N. Stem Cell Secretions as a Potential Therapeutic Agent for Autism Spectrum Disorder: A Narrative Review. Stem Cell Rev Rep 2024; 20:1252-1272. [PMID: 38630359 DOI: 10.1007/s12015-024-10724-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2024] [Indexed: 07/04/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental illness characterized by impaired social interaction and restricted repetitive behaviors or interests. The rising prevalence of ASD diagnosis has triggered a surge in research into investigating the underlying neuropathological processes and finding new therapeutic approaches. ASD is characterized by neuroinflammation and dysregulation of neuro-immune cross-talk, which suggests that stem cell treatment might be a potential therapeutic approach. The beneficial and restorative effects of stem cells are mainly due to their paracrine activity, in which stem cells generate and release extracellular vesicles such as exosomes and distinct secreted non-vesicle soluble proteins, including, growth factors, chemokines, cytokines, and immunomodulatory molecules referred to as the Secretome. In this paper, we reviewed the existing research exploring the therapeutic potential of stem cell secretome focusing on their role in addressing ASD pathology. Furthermore, we proposed a comprehensive mechanism of action for stem cell secretions, encompassing the broader secretome as well as the specific contribution of exosomes, in alleviating ASD neuropathology. Across the reviewed studies, exosomes and secreted soluble factors of the transplanted stem cell demonstrate a potential efficacy in ameliorating autistic-like behaviors. The proposed mechanism of action involves the modulation of signaling pathways implicated in neuroinflammation, angiogenesis, cellular apoptosis, and immunomodulation.
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Affiliation(s)
- Mariam Darwish
- Faculty of Medical Sciences, Neuroscience Research Center, Lebanese University, Beirut, Lebanon
| | | | | | - Nada Alaaeddine
- Dean of Health Sciences, Modern University for Business & Science, Beirut, Lebanon.
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Pedrazzi JFC, Hassib L, Ferreira FR, Hallak JC, Del-Bel E, Crippa JA. Therapeutic potential of CBD in Autism Spectrum Disorder. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 177:149-203. [PMID: 39029984 DOI: 10.1016/bs.irn.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/21/2024]
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive research, effective pharmacological interventions for ASD remain limited. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has potential therapeutic effects on several neurological and psychiatric disorders. CBD interacts with the endocannabinoid system, a complex cell-signaling system that plays a crucial role in regulating various physiological processes, maintaining homeostasis, participating in social and behavioral processing, and neuronal development and maturation with great relevance to ASD. Furthermore, preliminary findings from clinical trials indicate that CBD may have a modulatory effect on specific ASD symptoms and comorbidities in humans. Interestingly, emerging evidence suggests that CBD may influence the gut microbiota, with implications for the bidirectional communication between the gut and the central nervous system. CBD is a safe drug with low induction of side effects. As it has a multi-target pharmacological profile, it becomes a candidate compound for treating the central symptoms and comorbidities of ASD.
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Affiliation(s)
- João F C Pedrazzi
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - Lucas Hassib
- Department of Mental Health, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | | | - Jaime C Hallak
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Elaine Del-Bel
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; National Institute for Science and Technology, Translational Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cannabinoid Research, Mental Health Building, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - José A Crippa
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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Maric DM, Vojvodic D, Maric DL, Velikic G, Radomir M, Sokolovac I, Stefik D, Ivkovic N, Susnjevic S, Puletic M, Dulic O, Abazovic D. Cytokine Dynamics in Autism: Analysis of BMAC Therapy Outcomes. Int J Mol Sci 2023; 24:15080. [PMID: 37894761 PMCID: PMC10606637 DOI: 10.3390/ijms242015080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/29/2023] [Accepted: 09/30/2023] [Indexed: 10/29/2023] Open
Abstract
Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural manifestations in autism. In this study, we employed a comprehensive statistical approach, fusing both overarching and granular methods to examine the concentration of 16 cytokines in the cerebrospinal fluid (CSF) across each autologous bone marrow aspirate concentrate (BMAC) intrathecal administration in 63 male and 17 female autism patients. Following a six-month period post the third administration, patients were stratified into three categories based on clinical improvement: Group 1- no/mild (28 subjects), Group 2-moderate (16 subjects), and Group 3-major improvement (15 subjects). Our integrated analysis revealed pronounced disparities in CSF cytokine patterns and clinical outcomes in autism subjects pre- and post-BMAC transplantation. Crucially, our results suggest that these cytokine profiles hold promise as predictive markers, pinpointing ASD individuals who might not exhibit notable clinical amelioration post-BMAC therapy.
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Affiliation(s)
- Dusan M. Maric
- Department for Research and Development, Clinic Orto MD-Parks Dr Dragi Hospital, 21000 Novi Sad, Serbia; (D.M.M.); (M.R.)
- Faculty of Stomatology Pancevo, University Business Academy, 26101 Pancevo, Serbia;
| | - Danilo Vojvodic
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (D.V.); (D.S.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Dusica L. Maric
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
| | - Gordana Velikic
- Department for Research and Development, Clinic Orto MD-Parks Dr Dragi Hospital, 21000 Novi Sad, Serbia; (D.M.M.); (M.R.)
- Hajim School of Engineering, University of Rochester, Rochester, NY 14627, USA
| | - Mihajlo Radomir
- Department for Research and Development, Clinic Orto MD-Parks Dr Dragi Hospital, 21000 Novi Sad, Serbia; (D.M.M.); (M.R.)
| | | | - Debora Stefik
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (D.V.); (D.S.)
| | - Nemanja Ivkovic
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
| | - Sonja Susnjevic
- Department of Social Medicine and Health Statistics with Informatics, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
| | - Miljan Puletic
- Faculty of Stomatology Pancevo, University Business Academy, 26101 Pancevo, Serbia;
| | - Oliver Dulic
- Department of Surgery, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
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Shamim S, Khan N, Greene DL, Habiba UE, Umer A. The promise of autologous and allogeneic cellular therapies in the clinical trials of autism spectrum disorder. Regen Med 2023; 18:347-361. [PMID: 36935631 DOI: 10.2217/rme-2022-0176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/02/2023] [Indexed: 03/21/2023] Open
Abstract
Autism spectrum disorder (ASD) is a consortium of developmental conditions. As scientists have not yet identified the exact underlying cause for these disorders, it is not easy to narrow down a singular therapy to propose a reliable cure. The preponderance of research suggests that stem-cell therapy improves aspects of outcome measure scales in patients with ASD; therefore, future studies should give us more confidence in the results. This overview considers the data that have emerged from the small set of published trials conducted using different approaches in stem-cell therapy for ASD, evaluates their results and proposes additional steps that could be taken if this field of endeavor is to be pursued further.
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Affiliation(s)
- Sabiha Shamim
- Bello Bio Labs & Therapeutics (SMC) Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13 Islamabad, 44000, Pakistan
| | - Nasar Khan
- Bello Bio Labs & Therapeutics (SMC) Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13 Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ 85262, United States of America
| | - David L Greene
- Bello Bio Labs & Therapeutics (SMC) Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13 Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ 85262, United States of America
| | - Umm E Habiba
- Bello Bio Labs & Therapeutics (SMC) Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13 Islamabad, 44000, Pakistan
| | - Amna Umer
- Bello Bio Labs & Therapeutics (SMC) Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13 Islamabad, 44000, Pakistan
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Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022. Genes (Basel) 2022; 13:genes13091646. [PMID: 36140813 PMCID: PMC9498399 DOI: 10.3390/genes13091646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022] Open
Abstract
Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed.
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Pedrazzi JFC, Ferreira FR, Silva-Amaral D, Lima DA, Hallak JEC, Zuardi AW, Del-Bel EA, Guimarães FS, Costa KCM, Campos AC, Crippa ACS, Crippa JAS. Cannabidiol for the treatment of autism spectrum disorder: hope or hype? Psychopharmacology (Berl) 2022; 239:2713-2734. [PMID: 35904579 DOI: 10.1007/s00213-022-06196-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 07/18/2022] [Indexed: 11/30/2022]
Abstract
RATIONALE Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system. OBJECTIVES Review the preclinical and clinical data supporting CBD's potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.
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Affiliation(s)
- João F C Pedrazzi
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - Frederico R Ferreira
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-900, Brazil
| | - Danyelle Silva-Amaral
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Daniel A Lima
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Jaime E C Hallak
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Antônio W Zuardi
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Elaine A Del-Bel
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
- Department of Morphology, Physiology, and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Francisco S Guimarães
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Karla C M Costa
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Alline C Campos
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Ana C S Crippa
- Graduate Program in Child and Adolescent Health, Neuropediatric Center of the Hospital of Clinics (CENEP), Federal University of Paraná, Curitiba, Paraná, Brazil
| | - José A S Crippa
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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Tian J, Gao X, Yang L. Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics. Front Neurosci 2022; 16:780407. [PMID: 35310097 PMCID: PMC8924045 DOI: 10.3389/fnins.2022.780407] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/09/2022] [Indexed: 01/28/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.
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Affiliation(s)
| | | | - Li Yang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Beijing, China
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Tsagkaris C, Moysidis DV, Papazoglou AS, Khan A, Papadakos S, Louka AM, Scordilis DM, Shkodina A, Varmpompiti K, Batiha GES, Alexiou A. Current Trends of Stem Cells in Neurodegenerative Diseases. NUTRITIONAL NEUROSCIENCES 2022:311-339. [DOI: 10.1007/978-981-15-9781-7_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2024]
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Paprocka J, Kaminiów K, Kozak S, Sztuba K, Emich-Widera E. Stem Cell Therapies for Cerebral Palsy and Autism Spectrum Disorder-A Systematic Review. Brain Sci 2021; 11:1606. [PMID: 34942908 PMCID: PMC8699362 DOI: 10.3390/brainsci11121606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/27/2021] [Accepted: 12/01/2021] [Indexed: 12/05/2022] Open
Abstract
Autism spectrum disorder (ASD) and cerebral palsy (CP) are some of the most common neurodevelopmental diseases. They have multifactorial origin, which means that each case may manifest differently from the others. In patients with ASD, symptoms associated with deficits in social communication and characteristic, repetitive types of behaviors or interests are predominant, while in patients with CP, motor disability is diagnosed with accompanying cognitive impairment of various degrees. In order to minimize their adverse effects, it is necessary to promptly diagnose and incorporate appropriate management, which can significantly improve patient quality of life. One of the therapeutic possibilities is stem cell therapy, already known from other branches of medicine, with high hopes for safe and effective treatment of these diseases. Undoubtedly, in the future we will have to face the challenges that will arise due to the still existing gaps in knowledge and the heterogeneity of this group of patients. The purpose of this systematic review is to summarize briefly the latest achievements and advances in stem cell therapy for ASD and CP.
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Affiliation(s)
- Justyna Paprocka
- Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Konrad Kaminiów
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Sylwia Kozak
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Karolina Sztuba
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Ewa Emich-Widera
- Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
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Ebrahimi A, Ahmadi H, Ghasrodashti ZP, Tanideh N, Shahriarirad R, Erfani A, Ranjbar K, Ashkani-Esfahani S. Therapeutic effects of stem cells in different body systems, a novel method that is yet to gain trust: A comprehensive review. Bosn J Basic Med Sci 2021; 21:672-701. [PMID: 34255619 PMCID: PMC8554700 DOI: 10.17305/bjbms.2021.5508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/25/2021] [Indexed: 11/30/2022] Open
Abstract
Stem cell therapy has been used to treat several types of diseases, and it is expected that its therapeutic uses shall increase as novel lines of evidence begin to appear. Furthermore, stem cells have the potential to make new tissues and organs. Thus, some scientists propose that organ transplantation will significantly rely on stem cell technology and organogenesis in the future. Stem cells and its robust potential to differentiate into specific types of cells and regenerate tissues and body organs, have been investigated by numerous clinician scientists and researchers for their therapeutic effects. Degenerative diseases in different organs have been the main target of stem cell therapy. Neurodegenerative diseases such as Alzheimer's, musculoskeletal diseases such as osteoarthritis, congenital cardiovascular diseases, and blood cell diseases such as leukemia are among the health conditions that have benefited from stem cell therapy advancements. One of the most challenging parts of the process of incorporating stem cells into clinical practice is controlling their division and differentiation potentials. Sometimes, their potential for uncontrolled growth will make these cells tumorigenic. Another caveat in this process is the ability to control the differentiation process. While stem cells can easily differentiate into a wide variety of cells, a paracrine effect controlled activity, being in an appropriate medium will cause abnormal differentiation leading to treatment failure. In this review, we aim to provide an overview of the therapeutic effects of stem cells in diseases of various organ systems. In order to advance this new treatment to its full potential, researchers should focus on establishing methods to control the differentiation process, while policymakers should take an active role in providing adequate facilities and equipment for these projects. Large population clinical trials are a necessary tool that will help build trust in this method. Moreover, improving social awareness about the advantages and adverse effects of stem cell therapy is required to develop a rational demand in the society, and consequently, healthcare systems should consider established stem cell-based therapeutic methods in their treatment algorithms.
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Affiliation(s)
- Alireza Ebrahimi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hanie Ahmadi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Pourfraidon Ghasrodashti
- Molecular Pathology and Cytogenetics Laboratory, Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Tanideh
- Stem Cells Technology Research Center, Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Shahriarirad
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Thoracic and Vascular Surgery Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Erfani
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Keivan Ranjbar
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheil Ashkani-Esfahani
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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A Brief Review on Erythropoietin and Mesenchymal Stem Cell Therapies for Paediatric Neurological Disorders. CURRENT STEM CELL REPORTS 2021. [DOI: 10.1007/s40778-021-00189-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Saposnik FE, Huber JF. Trends in Web Searches About the Causes and Treatments of Autism Over the Past 15 Years: Exploratory Infodemiology Study. JMIR Pediatr Parent 2020; 3:e20913. [PMID: 33284128 PMCID: PMC7752533 DOI: 10.2196/20913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/29/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ninety percent of adults in the United States use the internet, and the majority of internet users report looking on the web for health information using search engines. The rising prevalence of autism spectrum disorder (ASD), uncertainty surrounding its etiology, and variety of intervention approaches contribute to questions about its causes and treatments. It is not known which terms people search most frequently about ASD and whether web search queries have changed over time. Infodemiology is an area of health informatics research using big data analytics to understand web search behavior. OBJECTIVE The objectives were to (1) use infodemiological data to analyze trends in web-based searches about the causes and treatments of ASD over time and (2) inform clinicians and ASD organizations about web queries regarding ASD. METHODS Google Trends was used to analyze web searches about the causes and treatments of ASD in the United States from 2004 to 2019. The search terms analyzed for queries about causes of ASD included vaccines, genetics, environmental factors, and microbiome and those for therapies included applied behavior analysis (ABA), gluten-free diet, chelation therapy, marijuana, probiotics, and stem cell therapy. RESULTS Google Trends results are normalized on a scale ranging from 0 to 100 to represent the frequency and relative interest of search topics. For searches about ASD causes, vaccines had the greatest frequency compared to other terms, with an initial search peak observed in 2008 (scaled score of 81), reaching the highest frequency in 2015 (scaled score of 100), and a current upward trend. In comparison, searches about genetics, environmental factors, and microbiome occurred less frequently. For web searches about ASD therapies, ABA consistently had a high frequency of search interest since 2004, reaching a maximum scaled score of 100 in 2019. The analyses of chelation therapy and gluten-free diet showed trending interest in 2005 (scaled score of 68) and 2007 (scaled score of 100), respectively, followed by a steady decline since (scaled scores of only 10 and 16, respectively, in 2019). Searches related to ASD and marijuana showed a rise in 2009 (scaled score of 35), and they continue to trend upward. Searches about probiotics and stem cell therapy have been relatively low (scaled scores of 22 and 18, respectively), but are gradually gaining interest. Web search volumes for stem cell therapy in 2019 surpassed both gluten-free diet and chelation therapy as web-searched interventions for ASD. CONCLUSIONS Google Trends is an effective infodemiology tool to analyze large-scale web search trends about ASD. The results showed informative variation in search trends over 15 years. These data are useful to inform clinicians and organizations about web queries on topics related to ASD, identify knowledge gaps, and target web-based education and knowledge translation strategies.
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Affiliation(s)
| | - Joelene F Huber
- Paediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Division of Developmental Paediatrics, Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Surrey Place, Toronto, ON, Canada
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Morè L, Lauterborn JC, Papaleo F, Brambilla R. Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders. Neurosci Biobehav Rev 2020; 110:28-45. [PMID: 30981451 DOI: 10.1016/j.neubiorev.2019.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 02/04/2019] [Accepted: 02/05/2019] [Indexed: 12/29/2022]
Abstract
In this review we discuss the role of environmental and pharmacological treatments to enhance cognition with special regards to neurodevelopmental related disorders and aging. How the environment influences brain structure and function, and the interactions between rearing conditions and gene expression, are fundamental questions that are still poorly understood. We propose a model that can explain some of the discrepancies in findings for effects of environmental enrichment on outcome measures. Evidence of a direct causal correlation of nootropics and treatments that enhanced cognition also will be presented, and possible molecular mechanisms that include neurotrophin signaling and downstream pathways underlying these processes are discussed. Finally we review recent findings achieved with a wide set of behavioral and cognitive tasks that have translational validity to humans, and should be useful for future work on devising appropriate therapies. As will be discussed, the collective findings suggest that a combinational therapeutic approach of environmental enrichment and nootropics could be particularly successful for improving learning and memory in both developmental disorders and normal aging.
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Affiliation(s)
- Lorenzo Morè
- School of Pharmacy and Biomedical Sciences, University of Central Lancashire, PR1 2XT, Preston, UK.
| | - Julie C Lauterborn
- Department of Anatomy & Neurobiology, School of Medicine, University of California, Irvine, CA, 92617, USA.
| | - Francesco Papaleo
- Genetics of Cognition Laboratory, Istituto Italiano di Tecnologia, Via Morego, 30, 16163, Genova, Italy.
| | - Riccardo Brambilla
- Neuroscience and Mental Health Research Institute (NMHRI), Division of Neuroscience, School of Biosciences, Cardiff University, CF24 4HQ, Cardiff, UK.
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Hong J, Bang M. Anti-inflammatory Strategies for Schizophrenia: A Review of Evidence for Therapeutic Applications and Drug Repurposing. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2020; 18:10-24. [PMID: 31958901 PMCID: PMC7006977 DOI: 10.9758/cpn.2020.18.1.10] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 09/12/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
Schizophrenia is a debilitating psychiatric disorder with a substantial socioeconomic and humanistic burden. Currently available treatment strategies mostly rely on antipsychotic drugs, which block dopaminergic effects in the mesolimbic pathway of the brain. Although antipsychotic drugs help relieve psychotic symptoms, a definitive cure for schizophrenia has yet to be achieved. Recent advances in neuroinflammation research suggest that proinflammatory processes in the brain could cause alterations in neurobehavioral development and increase vulnerability to schizophrenia. With a growing need for novel strategies in the treatment of schizophrenia, it would be meaningful to review the current evidence supporting the therapeutic potential of anti-inflammatory strategies. This review details the key findings of clinical trials that investigate the efficacy of anti-inflammatory agents as adjuvants to antipsychotic treatment. We further discuss the possibilities of repurposing anti-inflammatory agents and developing novel strategies for the treatment of schizophrenia.
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Affiliation(s)
- Jonghee Hong
- CHA University School of Medicine, Seongnam, Korea
| | - Minji Bang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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15
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Alessio N, Brigida AL, Peluso G, Antonucci N, Galderisi U, Siniscalco D. Stem Cell-Derived Exosomes in Autism Spectrum Disorder. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:944. [PMID: 32033002 PMCID: PMC7037429 DOI: 10.3390/ijerph17030944] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 02/06/2023]
Abstract
Neurodevelopmental lifelong pathologies defined by problems with social interaction, communication capacity and presence of repetitive/stereotyped clusters of behavior and interests are grouped under the definition of autism spectrum disorder (ASD). ASD prevalence is still increasing, indicating the need to identify specific biomarkers and novel pharmacotherapies. Neuroinflammation and neuro-immune cross-talk dysregulation are specific hallmarks of ASD, offering the possibility of treating these disorders by stem cell therapy. Indeed, cellular strategies have been postulated, proposed and applied to ASD. However, less is known about the molecular action mechanisms of stem cells. As a possibility, the positive and restorative effects mediated by stem cells could be due to their paracrine activity, by which stem cells produce and release several ameliorative and anti-inflammatory molecules. Among the secreted complex tools, exosomes are sub-organelles, enriched by RNA and proteins, that provide cell-to-cell communication. Exosomes could be the mediators of many stem cell-associated therapeutic activities. This review article describes the potential role of exosomes in alleviating ASD symptoms.
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Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | | | - Gianfranco Peluso
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy, (CNR), via P. Castellino 111, 80131 Naples, Italy;
| | - Nicola Antonucci
- Biomedical Centre for Autism Research and Therapy, 70126 Bari, Italy;
| | - Umberto Galderisi
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | - Dario Siniscalco
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
- Centre for Autism—La Forza del Silenzio, 81036 Caserta, Italy
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Pharmacological, non-pharmacological and stem cell therapies for the management of autism spectrum disorders: A focus on human studies. Pharmacol Res 2019; 152:104579. [PMID: 31790820 DOI: 10.1016/j.phrs.2019.104579] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/13/2019] [Accepted: 11/27/2019] [Indexed: 01/03/2023]
Abstract
In the last decade, the prevalence of autism spectrum disorders (ASD) has dramatically escalated worldwide. Currently available drugs mainly target some co-occurring symptoms of ASD, but are not effective on the core symptoms, namely impairments in communication and social interaction, and the presence of restricted and repetitive behaviors. On the other hand, transplantation of hematopoietic and mesenchymal stem cells in ASD children has been shown promising to stimulate the recruitment, proliferation, and differentiation of tissue-residing native stem cells, reducing inflammation, and improving some ASD symptoms. Moreover, several comorbidities have also been associated with ASD, such as immune dysregulation, gastrointestinal issues and gut microbiota dysbiosis. Non-pharmacological approaches, such as dietary supplementations with certain vitamins, omega-3 polyunsaturated fatty acids, probiotics, some phytochemicals (e.g., luteolin and sulforaphane), or overall diet interventions (e.g., gluten free and casein free diets) have been considered for the reduction of such comorbidities and the management of ASD. Here, interventional studies describing pharmacological and non-pharmacological treatments in ASD children and adolescents, along with stem cell-based therapies, are reviewed.
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Siniscalco D, Kannan S, Semprún-Hernández N, Eshraghi AA, Brigida AL, Antonucci N. Stem cell therapy in autism: recent insights. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2018; 11:55-67. [PMID: 30425534 PMCID: PMC6204871 DOI: 10.2147/sccaa.s155410] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autism spectrum disorders (ASDs) are characterized by core domains: persistent deficits in social communication and interaction; restricted, repetitive patterns of behavior, interests, or activities. ASDs comprise heterogeneous and complex neurodevelopmental pathologies with well-defined inflammatory conditions and immune system dysfunction. Due to neurobiologic changes underlying ASD development, cell-based therapies have been proposed and applied to ASDs. Indeed, stem cells show specific immunologic properties, which make them promising candidates in ASD treatment. This comprehensive up-to-date review focuses on ASD cellular/molecular abnormalities, potentially useful stem cell types, animal models, and current clinical trials on the use of stem cells in treating autism. Limitations are also discussed.
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Affiliation(s)
- Dario Siniscalco
- Department of Experimental Medicine, University of Campania, Napoli, Italy,
| | - Suresh Kannan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Neomar Semprún-Hernández
- Research Division, Autism Immunology Unit of Maracaibo, Catedra libre de Autismo, Universidad del Zulia, Maracaibo, Venezuela
| | - Adrien A Eshraghi
- Department of Otolaryngology, Hearing Research and Cochlear Implant Laboratory, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Nicola Antonucci
- Biomedical Centre for Autism Research and Treatment, Bari, Italy
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Human adipose-derived stem cells ameliorate repetitive behavior, social deficit and anxiety in a VPA-induced autism mouse model. Behav Brain Res 2016; 317:479-484. [PMID: 27717813 DOI: 10.1016/j.bbr.2016.10.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 09/30/2016] [Accepted: 10/03/2016] [Indexed: 12/15/2022]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication, and patients often display co-occurring repetitive behaviors. Although the global prevalence of ASD has increased over time, the etiology and treatments for ASD are poorly understood. Recently, some researchers have suggested that stem cells have therapeutic potential for ASD. Thus, in the present study, we investigated the therapeutic effects of human adipose-derived stem cells (hASCs), a kind of autologous mesenchymal stem cells (MSCs) isolated from adipose tissue, on valproic acid (VPA)-induced autism model mice. Human ASCs were injected into the neonatal pups (P2 or P3) intraventricularly and then we evaluated major behavior symptoms of ASD. VPA-treated mice showed increased repetitive behaviors, decreased social interactions and increased anxiety but these autistic behaviors were ameliorated through transplantation of hASCs. In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice. The decreased level of vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10) by VPA were rescued in the brains of the hASC-injected VPA mice. With these results, we experimentally found hASCs' therapeutic effects on autistic phenotypes in a ASD model mice for the first time. This animal model system can be used to elucidate further mechanisms of therapeutic effects of hASCs in ASD.
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Simberlund J, Ferretti CJ, Hollander E. Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. World J Biol Psychiatry 2015; 16:368-375. [PMID: 26230216 DOI: 10.3109/15622975.2015.1067372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES In this conceptual review, the authors discuss the promises and pitfalls in the use of mesenchymal stem cells as a potential experimental therapeutic for autism spectrum and other neurodevelopmental disorders. METHODS The relevant literature in autism spectrum disorders and other neurodevelopmental disorders regarding immune dysregulation and neuroinflammation and relevant therapeutics with mesenchymal stem cell infusion is reviewed. The relevant literature pertaining to mesenchymal stem cells and their clinical applications is also reviewed. RESULTS It is proposed that immune dysregulation and neuroinflammation play a role in the aetiology of autism spectrum disorders. Mesenchymal stem cells have been shown to have immune-modulating capabilities and are neuroprotective. There are three international studies that have utilized mesenchymal stem cell infusions as a treatment for children with autism spectrum disorders, all of which demonstrated improvement in autism rating scale scores, although each study has limitations which are described. CONCLUSIONS Mesenchymal stem cell transplantation for the treatment of autism spectrum disorders is a novel approach that deserves further investigation, however substantial methodological and theoretical challenges and pitfalls remain before this can be considered a viable therapeutic option.
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Affiliation(s)
- Jessica Simberlund
- a Department of Psychiatry , New York Presbyterian-Weill Cornell Medical College , New York , NY , USA
| | - Casara Jean Ferretti
- b Autism and Obsessive-Compulsive Spectrum Program, Department of Psychiatry , Albert Einstein College of Medicine and Montefiore Medical Center , New York , NY , USA
| | - Eric Hollander
- b Autism and Obsessive-Compulsive Spectrum Program, Department of Psychiatry , Albert Einstein College of Medicine and Montefiore Medical Center , New York , NY , USA
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Ardhanareeswaran K, Coppola G, Vaccarino F. The use of stem cells to study autism spectrum disorder. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2015; 88:5-16. [PMID: 25745370 PMCID: PMC4345539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Autism spectrum disorder (ASD) affects as many as 1 in 68 children and is said to be the fastest-growing serious developmental disability in the United States. There is currently no medical cure or diagnostic test for ASD. Furthermore, the U.S. Food and Drug Administration has yet to approve a single drug for the treatment of autism's core symptoms. Despite numerous genome studies and the identification of hundreds of genes that may cause or predispose children to ASD, the pathways underlying the pathogenesis of idiopathic ASD still remain elusive. Post-mortem brain samples, apart from being difficult to obtain, offer little insight into a disorder that arises through the course of development. Furthermore, ASD is a disorder of highly complex, human-specific behaviors, making it difficult to model in animals. Stem cell models of ASD can be generated by performing skin biopsies of ASD patients and then dedifferentiating these fibroblasts into human-induced pluripotent stem cells (hiPSCs). iPSCs closely resemble embryonic stem cells and retain the unique genetic signature of the ASD patient from whom they were originally derived. Differentiation of these iPSCs into neurons essentially recapitulates the ASD patient's neuronal development in a dish, allowing for a patient-specific model of ASD. Here we review our current understanding of the underlying neurobiology of ASD and how the use of stem cells can advance this understanding, possibly leading to new therapeutic avenues.
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Affiliation(s)
- Karthikeyan Ardhanareeswaran
- Child Study Center, Yale School of Medicine, New Haven, Connecticut,Program in Neurodevelopment and Regeneration, Yale School of Medicine, New Haven, Connecticut,Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut
| | - Gianfilippo Coppola
- Child Study Center, Yale School of Medicine, New Haven, Connecticut,Program in Neurodevelopment and Regeneration, Yale School of Medicine, New Haven, Connecticut
| | - Flora Vaccarino
- Child Study Center, Yale School of Medicine, New Haven, Connecticut,Program in Neurodevelopment and Regeneration, Yale School of Medicine, New Haven, Connecticut,Yale Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut,Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut,To whom all correspondence should be addressed: Flora Vaccarino MD, Yale Child Study Center, 230 South Frontage Rd, New Haven, CT 06520; Tele: 203-737-4147; Fax: 203-737-3524;
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Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, Siniscalco D. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant 2014; 23 Suppl 1:S105-12. [PMID: 25302490 DOI: 10.3727/096368914x684916] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well-characterized genetic, immunological, and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particular, the known autoimmune disorders associated with autism are appealing targets for potential stem cell therapeutics. Of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable "biopharmacies" capable of delivering trophic signals to the host, which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations, which consisted of two doses of intravenously and subcutaneously administered FSCs. The Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p < 0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores when compared to pretreatment values. We recognize that the use of FSCs remains controversial for the present. The results of this study, however, warrant additional investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as "biopharmacies" capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
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22
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Siniscalco D, Bradstreet JJ, Sych N, Antonucci N. Mesenchymal stem cells in treating autism: Novel insights. World J Stem Cells 2014; 6:173-178. [PMID: 24772244 PMCID: PMC3999775 DOI: 10.4252/wjsc.v6.i2.173] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 12/19/2013] [Accepted: 03/18/2014] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, abnormal to absent verbal communication, restricted interests, and repetitive stereotypic verbal and non-verbal behaviors, influencing the ability to relate to and communicate. The core symptoms of ASDs concern the cognitive, emotional, and neurobehavioural domains. The prevalence of autism appears to be increasing at an alarming rate, yet there is a lack of effective and definitive pharmacological options. This has created an increased sense of urgency, and the need to identify novel therapies. Given the growing awareness of immune dysregulation in a significant portion of the autistic population, cell therapies have been proposed and applied to ASDs. In particular, mesenchymal stem cells (MSCs) possess the immunological properties which make them promising candidates in regenerative medicine. MSC therapy may be applicable to several diseases associated with inflammation and tissue damage, where subsequent regeneration and repair is necessary. MSCs could exert a positive effect in ASDs through the following mechanisms: stimulation of repair in the damaged tissue, e.g., inflammatory bowel disease; synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors; integrating into existing neural and synaptic network, and restoring plasticity. The paracrine mechanisms of MSCs show interesting potential in ASD treatment. Promising and impressive results have been reported from the few clinical studies published to date, although the exact mechanisms of action of MSCs in ASDs to restore functions are still largely unknown. The potential role of MSCs in mediating ASD recovery is discussed in light of the newest findings from recent clinical studies.
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Siniscalco D, Bradstreet JJ, Cirillo A, Antonucci N. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J Neuroinflammation 2014; 11:78. [PMID: 24739187 PMCID: PMC3996516 DOI: 10.1186/1742-2094-11-78] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 04/02/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. METHODS To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. RESULTS GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. CONCLUSIONS This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.
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Affiliation(s)
- Dario Siniscalco
- Department of Experimental Medicine, Second University of Naples, via S, Maria di Costantinopoli, 16 - 80138 Naples, Italy.
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Abstract
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.
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Perspectives on the use of stem cells for autism treatment. Stem Cells Int 2013; 2013:262438. [PMID: 24222772 PMCID: PMC3810518 DOI: 10.1155/2013/262438] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 08/22/2013] [Accepted: 09/06/2013] [Indexed: 12/13/2022] Open
Abstract
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.
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26
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Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N. Epigenetic findings in autism: new perspectives for therapy. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2013; 10:4261-73. [PMID: 24030655 PMCID: PMC3799534 DOI: 10.3390/ijerph10094261] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/14/2013] [Accepted: 09/06/2013] [Indexed: 12/22/2022]
Abstract
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.
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Affiliation(s)
- Dario Siniscalco
- Department of Experimental Medicine, Second University of Naples; via S. Maria di Costantinopoli, Napoli 16-80138, Italy
- Centre for Autism—La Forza del Silenzio, Caserta 81036, Italy
- Cancellautismo—Non-Profit Association for Autism Care, Florence 50132, Italy
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-0-81-566-5880; Fax: +39-0-81-566-7503
| | - Alessandra Cirillo
- Institute of Protein Biochemistry, National Research Council of Italy; Naples 80128, Italy; E-Mail:
| | | | - Nicola Antonucci
- Biomedical Centre for Autism Research and Treatment, Bari 70126, Italy; E-Mail:
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27
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Lv YT, Zhang Y, Liu M, Qiuwaxi JNT, Ashwood P, Cho SC, Huan Y, Ge RC, Chen XW, Wang ZJ, Kim BJ, Hu X. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med 2013; 11:196. [PMID: 23978163 PMCID: PMC3765833 DOI: 10.1186/1479-5876-11-196] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 08/23/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Autism is a pervasive neurodevelopmental disorder. At present there are no defined mechanisms of pathogenesis and therapy is mostly limited to behavioral interventions. Stem cell transplantation may offer a unique treatment strategy for autism due to immune and neural dysregulation observed in this disease. This non-randomized, open-label, single center phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism. METHODS 37 subjects diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects. The Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the therapeutic efficacy at baseline (pre-treatment) and following treatment. RESULTS There were no significant safety issues related to the treatment and no observed severe adverse effects. Statistically significant differences were shown on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05). CONCLUSIONS Transplantation of CBMNCs demonstrated efficacy compared to the control group; however, the combination of CBMNCs and UCMSCs showed larger therapeutic effects than the CBMNC transplantation alone. There were no safety issues noted during infusion and the whole monitoring period. TRIAL REGISTRATION ClinicalTrials.gov: NCT01343511, Title "Safety and Efficacy of Stem Cell Therapy in Patients with Autism".
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Affiliation(s)
- Yong-Tao Lv
- Shandong Jiaotong Hospital, Jinan, Shandong, China
| | - Yun Zhang
- Shenzhen Beike Cell Engineering Research Institute, 2/F, Yuanxing Technology Building, #1 Songpingshan Street, Nanshan District, Shenzhen, Guangdong 518057, China
| | - Min Liu
- Shandong Jiaotong Hospital, Jinan, Shandong, China
| | - Jia-na-ti Qiuwaxi
- Shenzhen Beike Cell Engineering Research Institute, 2/F, Yuanxing Technology Building, #1 Songpingshan Street, Nanshan District, Shenzhen, Guangdong 518057, China
| | - Paul Ashwood
- Department of Medical Microbiology & Immunology, University of California Davis, Davis, CA, USA
| | - Sungho Charles Cho
- Department of Neurology and Neurosurgery, Stanford University, Stanford, CA, USA
| | - Ying Huan
- Shandong Jiaotong Hospital, Jinan, Shandong, China
| | - Ru-Cun Ge
- Shandong Jiaotong Hospital, Jinan, Shandong, China
| | | | - Zhao-Jing Wang
- Shenzhen Beike Cell Engineering Research Institute, 2/F, Yuanxing Technology Building, #1 Songpingshan Street, Nanshan District, Shenzhen, Guangdong 518057, China
| | - Byung-Jo Kim
- Department of Neurology, Korea University Anam Medical Center, Seoul, Korea
| | - Xiang Hu
- Shenzhen Beike Cell Engineering Research Institute, 2/F, Yuanxing Technology Building, #1 Songpingshan Street, Nanshan District, Shenzhen, Guangdong 518057, China
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Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. Stem Cells Int 2013; 2013:623875. [PMID: 24062774 PMCID: PMC3767048 DOI: 10.1155/2013/623875] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2013] [Revised: 06/24/2013] [Accepted: 07/07/2013] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.
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Siniscalco D, Bradstreet JJ, Antonucci N. Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation. Front Immunol 2013; 4:140. [PMID: 23772227 PMCID: PMC3677147 DOI: 10.3389/fimmu.2013.00140] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 05/26/2013] [Indexed: 12/24/2022] Open
Abstract
Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive – stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders.
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Affiliation(s)
- Dario Siniscalco
- Department of Experimental Medicine, Second University of Naples , Naples , Italy ; Centre for Autism - La Forza del Silenzio , Caserta , Italy ; Cancellautismo , Florence , Italy
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Possible use of Trichuris suis ova in autism spectrum disorders therapy. Med Hypotheses 2013; 81:1-4. [PMID: 23597946 DOI: 10.1016/j.mehy.2013.03.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 03/01/2013] [Accepted: 03/17/2013] [Indexed: 12/24/2022]
Abstract
Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neurodevelopmental pathologies. The main core symptoms are: dysfunctions in social interactions and communication skills, restricted interests, repetitive and stereotypic verbal and non-verbal behaviors. Several biochemical processes are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation. Current available treatments for ASDs can be divided into behavioral, nutritional and medical approaches, although no defined standard approach exists. Current drugs fail to benefit the ASD core symptoms and can have marked adverse effects, are mainly palliative and only sometimes efficacy in attenuating specific autistic behaviors. Helminthic therapy shows potential for application as anti-inflammatory agent. Several human diseases can be treated by helminths (i.e. inflammatory bowel disease, asthma, multiple sclerosis and autoimmune diabetes). Trichuris suis ova (TSO) show strong immunomodulatory properties. Authors hypothesize that TSO could be useful in addressing ASD immune dysregulations. TSO could be a novel therapeutic option for ASD management.
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Abstract
Two major environmental developments have occurred in mammalian evolution which have impacted on the genetic and epigenetic regulation of brain development. The first of these was viviparity and development of the placenta which placed a considerable burden of time and energy investment on the matriline, and which resulted in essential hypothalamic modifications. Maternal feeding, maternal care, parturition, milk letdown and the suspension of fertility and sexual behaviour are all determined by the maternal hypothalamus and have evolved to meet foetal needs under the influence of placental hormones. Viviparity itself provided a new environmental variable for selection pressures to operate via the co-existence over three generations of matrilineal genomes (mother, developing offspring and developing oocytes) in one individual. Also of importance for the matriline has been the evolution of epigenetic marks (imprint control regions) which are heritable and undergo reprogramming primarily in the oocyte to regulate imprinted gene expression according to parent of origin. Imprinting of autosomal genes has played a significant role in mammalian evolutionary development, particularly that of the hypothalamus and placenta. Indeed, many imprinted genes that are co-expressed in the placenta and hypothalamus play an important role in the co-adapted functioning of these organs. Thus the action and interaction of two genomes (maternal and foetal) have provided a template for transgenerational selection pressures to operate in shaping the mothering capabilities of each subsequent generation. The advanced aspects of neocortical brain evolution in primates have emancipated much of behaviour from the determining effects of hormonal action. Thus in large brain primates, most of the sexual behaviour is not reproductive hormone dependent and maternal care can and does occur outside the context of pregnancy and parturition. The neocortex has evolved to be adaptable and while the adapted changes are not inherited, the epigenetic predisposing processes can be. This provides each generation with the same ability to generate new adaptations while retaining a "cultural" predisposition to retain others. A significant evolutionary contribution to this epigenetic dimension has again been the matriline. The extensive neocortical development which takes place post-natally does so in an environment which is predominantly that of the caring guidance of the mother. Evidence for the epigenetic regulation of neocortical development is best illustrated by the GABA-ergic neurons and their long tangential migratory pathway from the ganglionic eminence, in contrast to the radial migration of principle neurons. GABA-ergic neurons play an integral role both in the developmental formation of canonical localised circuits and in synchronising widespread functional activity by the regulation of network oscillations. Such synchronisation enables distributed regions of the neocortex to coordinate firing. GABA-ergic dysfunction contributes to a broad spectrum of neurological and psychiatric disorders which can differ even across identical monozygotic twins. Moreover, major treatments for schizophrenia over the past 40 years have included the drugs lithium and valproate, both of which we now know are histone deacetylases. It is rarely the heritable dysfunctioning of these epigenetic mechanisms that is at fault, but the timing, duration and place where they are deployed. The timing and complexity in the development of the neocortex makes this region of the brain more vulnerable to perturbations.
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Affiliation(s)
- E B Keverne
- Sub-Department of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB23 8AA, UK.
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