Biological role of mitochondrial TLR4-mediated NF-κB signaling pathway in central nervous system injury.

Previous studies suggested that central nervous system injury is often accompanied by the activation of Toll-like receptor 4/NF-κB pathway, which leads to the upregulation of proapoptotic gene expression, causes mitochondrial oxidative stress, and further aggravates the inflammatory response to induce cell apoptosis. Subsequent studies have shown that NF-κB and IκBα can directly act on mitochondria. Therefore, elucidation of the specific mechanisms of NF-κB and IκBα in mitochondria may help to discover new therapeutic targets for central nervous system injury. Recent studies have suggested that NF-κB (especially RelA) in mitochondria can inhibit mitochondrial respiration or DNA expression, leading to mitochondrial dysfunction. IκBα silencing will cause reactive oxygen species storm and initiate the mitochondrial apoptosis pathway. Other research results suggest that RelA can regulate mitochondrial respiration and energy metabolism balance by interacting with p53 and STAT3, thus initiating the mitochondrial protection mechanism. IκBα can also inhibit apoptosis in mitochondria by interacting with VDAC1 and other molecules. Regulating the biological role of NF-κB signaling pathway in mitochondria by targeting key proteins such as p53, STAT3, and VDAC1 may help maintain the balance of mitochondrial respiration and energy metabolism, thereby protecting nerve cells and reducing inflammatory storms and death caused by ischemia and hypoxia.

Adhesive and self-healing materials for central nervous system repair.

The central nervous system (CNS) has a limited ability to regenerate after a traumatic injury or a disease due to the low capacity of the neurons to re-grow and the inhibitory environment formed in situ. Current therapies include the use of drugs and rehabilitation, which do not fully restore the CNS functions and only delay the pathology progression. Tissue engineering offers a simple and versatile solution for this problem through the use of bioconstructs that promote nerve tissue repair by bridging cavity spaces. In this approach, the choice of biomaterial is crucial. Herein, we present recent advances in the design and development of adhesive and self-healing materials that support CNS healing. The adhesive materials have the advantage of promoting recovery without the use of needles or sewing, while the self-healing materials have the capacity to restore the tissue integrity without the need for external intervention. These materials can be used alone or in combination with cells and/or bioactive agents to control the inflammation, formation of free radicals, and proteases activity. We discuss the advantages and drawbacks of different systems. The remaining challenges that can bring these materials to clinical reality are also briefly presented.

Emerging roles for CNS fibroblasts in health, injury and disease.

Recent transcriptomic, histological and functional studies have begun to shine light on the fibroblasts present in the meninges, choroid plexus and perivascular spaces of the brain and spinal cord. Although the origins and functions of CNS fibroblasts are still being described, it is clear that they represent a distinct cell population, or populations, that have likely been confused with other cell types on the basis of the expression of overlapping cellular markers. Recent work has revealed that fibroblasts play crucial roles in fibrotic scar formation in the CNS after injury and inflammation, which have also been attributed to other perivascular cell types such as pericytes and vascular smooth muscle cells. In this Review, we describe the current knowledge of the location and identity of CNS perivascular cell types, with a particular focus on CNS fibroblasts, including their origin, subtypes, roles in health and disease, and future areas for study.

Indivíduos com lesão medular: assistência de enfermagem baseada na avaliação funcional e no sistema de linguagens padronizadas / Individuals with spinal cord injury: nursing care based on functional assessment and the standard language system

A avaliação funcional permite acompanhar a evolução de indivíduos com Lesão Medular Espinhal (LME), em programa de reabilitação, com adaptação às diferentes fases e condições de vida. A Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF) é um sistema de classificação universal, com aspectos biopsicossociais. Dentre os sistemas de classificações na prática de enfermagem, destaca-se a Classificação Internacional para a Prática de Enfermagem (CIPE®), uma terminologia com diagnósticos, resultados e intervenções de enfermagem. O estudo objetivou avaliar a funcionalidade dos indivíduos com LME, a partir de instrumento baseado no Core Set da CIF; analisar a correspondência terminológica dos sistemas de classificação CIF ao modelo da CIPE®; identificar os diagnósticos mais frequentes, descrever os resultados esperados e intervenções de enfermagem segundo a CIPE® e CIF. Estudo observacional, transversal e metodológico, realizado no Centro de Reabilitação do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, de junho de 2019 a março de 2021, em duas etapas: 1) Aplicação do instrumento baseado no Core Set da CIF para a avaliação do perfil funcional dos indivíduos com Lesão Medular Aguda (LMA); 2) Análise da correspondência terminológica do Sistema de CIF ao modelo da CIPE® para a Sistematização da Assistência de Enfermagem. Houve predomínio de jovens do sexo masculino, de 18 a 39 anos. Acerca da funcionalidade e extensão da deficiência segundo a CIF, as categorias mais acometidas foram: b620 Funções urinarias; b640 Funções sexuais e b810 Funções protetora da pele. Nos componentes Estruturas do corpo e Atividades e participação, houve maior gravidade na categoria s120 Medula espinhal e estruturas relacionadas e nas categorias referentes à mobilidade e atividades de vida diária d410 Mudar a posição básica do corpo; d420 Transferir a própria posição; d450 Andar; d510 Lavar-se; d5300 Regulação da micção; d5301 Regulação da defecação; d540 Vestir-se. No instrumento avaliado pelos indivíduos sobre a percepção quanto ao papel facilitador ou a barreira dos fatores ambientais, houve prevalência como facilitadoras as categorias e310 família imediata; e340 Cuidadores e assistentes pessoais e e355 Profissionais da saúde. Foi identificada como barreira a categoria e120, que avalia os produtos e as tecnologias para mobilidade e transporte pessoal em ambientes internos e externos. Ao correlacionar o tempo de reabilitação e o perfil de funcionalidade, o domínio atividades e participação apresentou correlação significativa (p<0,05), com melhor desempenho nas atividades de vida diária à medida que o tempo de reabilitação aumentava. No mapeamento cruzado identificaram-se 1.446 conceitos entre os componentes da CIF, com predomínio das categorias no componente Funções do corpo. Selecionaram-se 929 conceitos primitivos na CIPE® distribuídos por eixo, bem como 517 conceitos pré-coordenados, divididos entre diagnósticos, intervenções e resultados. A partir da aplicação do instrumento e do mapeamento cruzado entre a CIPE® e a CIF, constituiu-se um banco de dados de termos de linguagem especializada, que poderá ser utilizado na construção de um subconjunto terminológico da CIPE®, com vistas ao cuidado sistematizado ao indivíduo com LME

Functional assessment allows monitoring the evolution of individuals with Spinal Cord Injury (SCI) in a rehabilitation program, adapting to different stages and life conditions. The International Classification of Functioning, Disability and Health (ICF) is a universal classification system, with biopsychosocial aspects. Among the classification systems in nursing practice, the International Classification for Nursing Practice (ICNP®), a terminology with diagnoses, results and nursing interventions, stands out. The study aimed to evaluate the functioning of individuals with ICS, using an instrument based on the ICF Core Set; analyze the terminological correspondence of the ICF classification systems to the ICNP® model; identify the most frequent diagnoses, describe the expected results and nursing interventions according to the ICNP® and ICF. Observational, cross-sectional and methodological study, carried out at the Rehabilitation Center of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo, from June 2019 to March 2021, in two stages: 1) Application of the instrument based on the ICF Core Set for the assessment of the functional profile of individuals with Acute Spinal Cord Injury (ASCI); 2) Analysis of the terminological correspondence of the ICF System to the ICNP model for the Systematization of Nursing Care. There was a predominance of young males, aged between 18 and 39 years. Regarding the functioning and extent of the disability according to the ICF, the most affected categories were: b620 Urination functions; b640 Sexual functions and b810 Protective functions of the skin. In the Body Structures and Activities and Participation components, there was greater severity in the category s120 Spinal cord and related structures and in the categories referring to mobility and activities of daily living d410 Changing basic body position; d420 Transferring oneself; d450 Walking; d510 Washing oneself; d5300 Regulating urination; d5301 Regulating defecation; d540 Dressing. In the instrument evaluated by the individuals on the perception of the facilitating role or the barrier of environmental factors, the categories e310 immediate family prevailed as facilitators; e340 Personal care providers and personal assistants and e355 Health professionals. Category e120 was identified as a barrier, which evaluates Products and technology for personal indoor and outdoor mobility and transportation. When correlating the rehabilitation time and the functionality profile, the activities and participation domain showed a significant correlation (p<0.05), with better performance in activities of daily living as the rehabilitation time increased. In the cross-mapping, 1,446 concepts were identified among the components of the ICF, with a predominance of categories in the Body Functions component. 929 primitive concepts were selected in ICNP® distributed by axis, as well as 517 pre-coordinated concepts, divided between diagnoses, interventions and results. From the application of the instrument and the cross-mapping between the ICNP® and the ICF, a database of specialized language terms was created, which can be used in the construction of a terminological subset of the ICNP®, with a view to systematized care in the individual with SCI

[Function of NOD-like receptor protein 1 inflammasome in traumatic central nervous system injury].

NOD-like receptor protein 1 (NLRP1) inflammasome plays an important role in the innate immune response of human body. It can promote the activation of cysteinyl aspartate specific proteinases(Caspases), further activate interleukin-18 and interleukin-1 ß, and mediate pyroptosis. NlRP1 inflammasome plays a role in traumatic central nervous system injury. In this study, the structure of NLRP1 inflammasome, the activation of NLRP1 inflammasome in traumatic central nervous system injury and the treatment with NLRP1 inflammasome as a target are reviewed.

N6-methyladenosine RNA modification: A promising regulator in central nervous system injury.

In addition to DNA methylation, reversible epigenetic modification occurring in RNA has been discovered recently. The most abundant type of RNA methylation is N6-methyladenosine (m6A) modification, which is dynamically regulated by methylases ("writers"), demethylases ("erasers") and m6A-binding proteins ("readers"). As an essential posttranscriptional regulator, m6A can control mRNA splicing, processing, stability, export and translation. Recent studies have revealed that m6A modification has the strongest tissue specificity for brain tissue and plays crucial roles in central nervous system (CNS) injures by affecting its downstream target genes or non-coding RNAs. This review focuses on the expression and function of m6A regulatory proteins in CNS trauma in vitro and in vivo. We also highlight the latest insights into the molecular mechanisms of pathological damage in the CNS. Understanding m6A dynamics, functions, and machinery will yield an opportunity for designing and developing novel therapeutic agents for CNS injuries.

Identification of clinical and radiographic predictors of central nervous system injury in genetic skeletal disorders.

Some studies report neurological lesions in patients with genetic skeletal disorders (GSDs). However, none of them describe the frequency of neurological lesions in a large sample of patients or investigate the associations between clinical and/or radiological central nervous system (CNS) injury and clinical, anthropometric and imaging parameters. The project was approved by the institution's ethics committee (CAAE 49433215.5.0000.0022). In this cross-sectional observational analysis study, 272 patients aged four or more years with clinically and radiologically confirmed GSDs were prospectively included. Genetic testing confirmed the diagnosis in the FGFR3 chondrodysplasias group. All patients underwent blinded and independent clinical, anthropometric and neuroaxis imaging evaluations. Information on the presence of headache, neuropsychomotor development (NPMD), low back pain, joint deformity, ligament laxity and lower limb discrepancy was collected. Imaging abnormalities of the axial skeleton and CNS were investigated by whole spine digital radiography, craniocervical junction CT and brain and spine MRI. The diagnostic criteria for CNS injury were abnormal clinical and/or radiographic examination of the CNS. Brain injury included malacia, encephalopathies and malformation. Spinal cord injury included malacia, hydrosyringomyelia and spinal cord injury without radiographic abnormalities. CNS injury was diagnosed in more than 25% of GSD patients. Spinal cord injury was found in 21.7% of patients, and brain injury was found in 5.9%. The presence of low back pain, os odontoideum and abnormal NPMD remained independently associated with CNS injury in the multivariable analysis. Early identification of these abnormalities may have some role in preventing compressive CNS injury, which is a priority in GSD patients.

Acute Central Nervous System Trauma in the Field.

Acute central nervous system (CNS) trauma in the field is best approached by a systematic and thorough physical and neurologic examination that allows the practitioner to localize the brain or spinal cord injury. The skull and vertebral canal are complex 3-dimensional structures, and orthogonal radiographic views are necessary for an accurate diagnosis. Therapeutics aimed at decreasing pain, inflammation, and edema or increased intracranial pressure in the case of traumatic brain injury should be administered. Survival and return to athleticism can be achieved even in moderate-to-severe traumatic CNS injury with appropriate medical management.

Long non-coding RNAs mediate cerebral vascular pathologies after CNS injuries.

Central nervous system (CNS) injuries are one of the leading causes of morbidity and mortality worldwide, accompanied with high medical costs and a decreased quality of life. Brain vascular disorders are involved in the pathological processes of CNS injuries and might play key roles for their recovery and prognosis. Recently, increasing evidence has shown that long non-coding RNAs (lncRNAs), which comprise a very heterogeneous group of non-protein-coding RNAs greater than 200 nucleotides, have emerged as functional mediators in the regulation of vascular homeostasis under pathophysiological conditions. Remarkably, lncRNAs can regulate gene transcription and translation, thus interfering with gene expression and signaling pathways by different mechanisms. Hence, a deeper insight into the function and regulatory mechanisms of lncRNAs following CNS injury, especially cerebrovascular-related lncRNAs, could help in establishing potential therapeutic strategies to improve or inhibit neurological disorders. In this review, we highlight recent advancements in understanding of the role of lncRNAs and their application in mediating cerebrovascular pathologies after CNS injury.

A novel injury paradigm in the central nervous system of adult Drosophila: molecular, cellular and functional aspects.

The mammalian central nervous system (CNS) exhibits limited regenerative capacity and the mechanisms that mediate its regeneration are not fully understood. Here, we present a novel experimental design to damage the CNS by using a contusion injury paradigm. The design of this protocol allows the study of long-term and short-term cellular responses, including those of the CNS and the immune system, and of any implications regarding functional recovery. We demonstrate for the first time that adult Drosophilamelanogaster glial cells undergo spontaneous functional recovery following crush injury. This crush injury leads to an intermediate level of functional recovery after damage, which is ideal to screen for genes that facilitate or prevent the regeneration process. Here, we validate this model and analyse the immune responses of glial cells as a central regulator of functional regeneration. Additionally, we demonstrate that glial cells and macrophages contribute to functional regeneration through mechanisms involving the Jun N-terminal kinase (JNK) pathway and the Drosophila protein Draper (Drpr), characteristic of other neural injury paradigms. We show that macrophages are recruited to the injury site and are required for functional recovery. Further, we show that the proteins Grindelwald and Drpr in Drosophila glial cells mediate activation of JNK, and that expression of drpr is dependent on JNK activation. Finally, we link neuron-glial communication and the requirement of neuronal vesicular transport to regulation of the JNK pathway and functional recovery. This article has an associated First Person interview with the first author of the paper.

A1/A2 astrocytes in central nervous system injuries and diseases: Angels or devils?

Astrocytes play a pivotal role in maintaining the central nervous system (CNS) homeostasis and function. In response to CNS injuries and diseases, reactive astrocytes are triggered. By purifying and genetically profiling reactive astrocytes, it has been now found that astrocytes can be activated into two polarization states: the neurotoxic or pro-inflammatory phenotype (A1) and the neuroprotective or anti-inflammatory phenotype (A2). Although the simple dichotomy of the A1/A2 phenotypes does not reflect the wide range of astrocytic phenotypes, it facilitates our understanding of the reactive state of astrocytes in various CNS disorders. This article reviews the recent evidences regarding A1/A2 astrocytes, including (a) the specific markers and morphological characteristics, (b) the effects of A1/A2 astrocytes on the neurovascular unit, and (c) the molecular mechanisms involved in the phenotypic switch of astrocytes. Although many questions remain, a deeper understanding of different phenotypic astrocytes will eventually help us to explore effective strategies for neurological disorders by targeting astrocytes.

Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression.

OBJECTIVE: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. METHODS: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. FINDINGS: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/µL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.

Meningeal Multipotent Cells: A Hidden Target for CNS Repair?

Traditionally, the primary role of the meninges is thought to be structural, i.e., to act as a surrounding membrane that contains and cushions the brain with cerebrospinal fluid. During development, the meninges is formed by both mesenchymal and neural crest cells. There is now emerging evidence that subsets of undifferentiated stem cells might persist in the adult meninges. In this mini-review, we survey representative studies of brain-meningeal interactions and discuss the hypothesis that the meninges are not just protective membranes, but instead contain multiplex stem cell subsets that may contribute to central nervous system (CNS) homeostasis. Further investigations into meningeal multipotent cells may reveal a "hidden" target for promoting neurovascular remodeling and repair after CNS injury and disease.

Clinical study and observation on the effect of hemoperfusion therapy treatment on central nervous system injury in patients with 2,4-dichlorophenoxyacetic acid poisoning.

OBJECTIVE: To evaluate the curative effect of hemoperfusion therapy on central nervous system injury in patients with 2,4-dichlorophenoxyacetic acid poisoning. PATIENTS AND METHODS: A total of 60 patients with 2,4-dichlorophenoxyacetic acid poisoning were enrolled in this study. They were admitted to the Emergency Department of Qinghai Provincial People's Hospital from 2015 to 2018 and were randomly divided into two groups by random number table method. One group was control group (routine treatment group), and the other group was the treatment group (hemoperfusion therapy was added on the basis of routine treatment). Glasgow coma score (GCS), APACHE II score, and MMSE score were used to evaluate the effects before treatment and 7 days after treatment. The results were statistically analyzed. RESULTS: After treatment, GCS in the treatment group was higher than that in the control group, while APACHE II score was lower than that in the control group, and MMSE score was significantly higher than that in the control group, with statistically significant difference (p<0.05). The effective rate in the control group was only 26.67%, and that in the treatment group was 86.67%, with statistically significant difference (c2=19.62, p<0.001). CONCLUSIONS: Hemoperfusion therapy can promote the recovery of central nervous system in patients with 2,4-dichlorophenoxyacetic acid poisoning, reduce the injury of other organs, and significantly reduce the mortality of patients.

Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication.

Understanding how injury to the central nervous system induces de novo neurogenesis in animals would help promote regeneration in humans. Regenerative neurogenesis could originate from glia and glial neuron-glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila to search for genes functionally related to the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Both loss and over-expression of ia-2 induced neural stem cell gene expression, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic analysis and lineage tracing, we demonstrate that Ia-2 and Kon regulate Drosophila insulin-like peptide 6 (Dilp-6) to induce glial proliferation and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia and reprogrammes glia into neural stem cells for regeneration.

The intrinsic axon regenerative properties of mature neurons after injury.

Thousands of nerve injuries occur in the world each year. Axon regeneration is a very critical process for the restoration of the injured nervous system's function. However, the precise molecular mechanism or signaling cascades that control axon regeneration are not clearly understood, especially in mammals. Therefore, there is almost no ideal treatment method to repair the nervous system's injury until now. Mammalian axonal regeneration requires multiple signaling pathways to coordinately regulate gene expression in soma and assembly of the cytoskeleton protein in the growth cone. A better understanding of their molecular mechanisms, such as axon regeneration regulatory signaling cascades, will be helpful in developing new treatment strategies for promoting axon regeneration. In this review, we mainly focus on describing these regeneration-associated signaling cascades, which regulate axon regeneration.

The Role of Astrocytes in the Modulation ofK+-Cl--Cotransporter-2 Function.

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K+-Cl--cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression.

Neuroprotective Effects of Curcumin-Loaded Emulsomes in a Laser Axotomy-Induced CNS Injury Model.

PURPOSE: Curcumin, a polyphenol isolated from the rhizomes of turmeric, holds great potential as a neuroprotective agent in addition to its anti-inflammatory and antioxidant characteristics. The poor bioavailability and low stability of curcumin are the greatest barriers to its clinical use. This study aims to investigate the neuroprotective effect of curcumin on axonal injury, by delivering the lipophilic polyphenol to a primary hippocampal neuron culture by means of a lipid-based drug delivery system, named emulsomes. METHODS: To study neuroregeneration ex vivo, an injury model was established through single-cell laser axotomy on hippocampal neurites. Upon treatment with curcumin-loaded emulsomes (CurcuEmulsomes), curcumin and CurcuEmulsome uptake into neurons was verified by three-dimensional Z-stack images acquired with confocal microscopy. Neuron survival after axonal injury was tracked by propidium iodide (PI) and Hoechst staining. Alterations in expression levels of physiological markers, such as anti-apoptotic marker Bcl2, apoptotic marker cleaved caspase 3, neuroprotective marker Wnt3a and the neuronal survival marker mTOR, were investigated by immunocytochemistry analyses. RESULTS: The results indicated significant improvement in the survival rate of injured neurons upon CurcuEmulsome treatment. Bcl2 expression was significantly higher for injured neurons treated with curcumin or CurcuEmulsome. Reduction in caspase 3 expression was seen in both curcumin and CurcuEmulsome treatment, whereas there were no significant changes in Wnt3a and mTOR expression. CONCLUSION: The established laser-axotomy model was proven as a reliable methodology to study neurodegenerative models ex vivo. CurcuEmulsomes delivered curcumin to primary hippocampal neurons successfully. Treated with CurcuEmulsomes, injured hippocampal neurons benefit from the neuroprotective effects of curcumin, exhibiting a higher survival rate and increased anti-apoptotic marker levels.

When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification.

PURPOSE OF REVIEW: Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. RECENT FINDINGS: Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-ß1-mediated pathways. This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients.