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Valproic acid or sodium valproate is a widely used drug in the treatment of epilepsy, although it also appears to have anxiolytic and sedative properties derived from its agonistic action on the GABAergic system. To analyze these potential effects of the drug, we conducted three experiments with rats using procedures designed to assess anxiety in rodents. In the first experiment, with a fear conditioning procedure, three groups of male rats were included that received either 100 mg/kg or 300 mg/kg of valproate or an equivalent volume of saline solution. In Experiment 2, recording spontaneous activity in an open field, we compared the effects of valproic acid (300 mg/kg) on male and female rats. In the third experiment, we analyzed the effect of valproic acid using a novelty-induced hypophagia test and tested again for potential differences as a function of the sex of the animals. The results showed an anxiolytic effect restricted to the 300 mg/kg dose of the drug in Experiment 1. Such an effect was restricted to the female sample in Experiment 2, but in the third experiment affected both sexes. As for the sedative effect, it was observed in all experiments irrespective of the sex of the rats. These findings hold significant implications for the treatment of anxiety disorders since valproate may offer a novel therapeutic approach for anxiety-related conditions with distinct benefits and fewer side effects. However, clinical studies are needed to validate the translation of these findings from animal models to human patients.

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Focal cortical dysplasia (FCD) is a structural lesion that is the most common anatomical lesion identified in children, and the second most common in adults with drug-resistant focal-onset epilepsy. These lesions vary in size, location, and histopathological manifestations. FCDs are classified into three subtypes associated with loss-of-function mutations in PI3K/AKT, TSC1/TSC2, RHEB, and DEPDC/NPRL2/NPRL3. During the decades of research into FCD, experimental models have played an irreplaceable role in the research design of studies investigating disease pathogenesis, pathophysiology, and treatment. Further, the establishment of FCD experimental models has moved the field forward by (1) revealing the cellular processes and signaling pathways underlying FCD pathogenesis and (2) varying the methods and materials to study the function of FCD proteins. Currently, FCD experimental models are predominantly murine, with each model providing unique insights into FCD lesions. This review briefly summarizes the pathology and molecular functions of FCD, further comparing the available modeling methods and indexes, as well as the utilization of models, followed by an analysis of the similarities, advantages, and disadvantages between these models and human FCD.

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This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.

Asunto(s)

Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Nebivolol , Carga de Parásitos , Toxoplasmosis Animal , Animales , Nebivolol/farmacología , Nebivolol/uso terapéutico , Ratones , Toxoplasmosis Animal/tratamiento farmacológico , Toxoplasmosis Animal/parasitología , Encéfalo/parasitología , Encéfalo/patología , Encéfalo/efectos de los fármacos , Femenino , Neuronas/efectos de los fármacos , Neuronas/parasitología , Etanolaminas/farmacología , Etanolaminas/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Resultado del Tratamiento , Óxido Nítrico/metabolismo , Toxoplasma/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo

RESUMEN

BACKGROUND AND AIMS: We previously identified small molecules predicted to reverse an ileal gene signature for future Crohn's Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA). METHODS: Induced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without ETYA pre-treatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO pro-fibrotic gene expression and collagen content. RESULTS: iPSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome secreted products, and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and pro-fibrotic gene expression pathways in LPS stimulated macrophages. Co-culture of LPS-primed macrophages with HIO led to up-regulation of fibroblast activation genes including ACTA2 and COL1A1, and an increase in HIO collagen content. ETYA pre-treatment prevented pro-fibrotic effects of LPS-primed macrophages. CONCLUSIONS: ETYA inhibits pro-fibrotic effects of LPS-primed macrophages upon co-cultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.

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BACKGROUND: Anastomotic leaks remain one of the most dreaded complications in gastrointestinal surgery causing significant morbidity, that negatively affect the patients' quality of life. Experimental studies play an important role in understanding the pathophysiological background of anastomotic healing and there are still many fields that require further investigation. Knowledge drawn from these studies can lead to interventions or techniques that can reduce the risk of anastomotic leak in patients with high-risk features. Despite the advances in experimental protocols and techniques, designing a high-quality study is still challenging for the investigators as there is a plethora of different models used. AIM: To review current state of the art for experimental protocols in high-risk anastomosis in rats. METHODS: This systematic review was performed according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. To identify eligible studies, a comprehensive literature search was performed in the electronic databases PubMed (MEDLINE) and Scopus, covering the period from conception until 18 October 2023. RESULTS: From our search strategy 102 studies were included and were categorized based on the mechanism used to create a high-risk anastomosis. Methods of assessing anastomotic healing were extracted and were individually appraised. CONCLUSION: Anastomotic healing studies have evolved over the last decades, but the findings are yet to be translated into human studies. There is a need for high-quality, well-designed studies that will help to the better understanding of the pathophysiology of anastomotic healing and the effects of various interventions.

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Interest in the right ventricle has substantially increased due to advances in knowledge of its pathophysiology and prognostic implications across a wide spectrum of diseases. However, we are still far from understanding the multiple mechanisms that influence right ventricular dysfunction, its evaluation continues to be challenging, and there is a shortage of specific treatments in most scenarios. This review article aims to update knowledge about the physiology of the right ventricle, its transition to dysfunction, diagnostic tools, and available treatments from a translational perspective.

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

Asunto(s)

Cardiotónicos , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo

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Cancer-associated cachexia represents a multifactorial syndrome mainly characterized by muscle mass loss, which causes both a decrease in quality of life and anti-cancer therapy failure, among other consequences. The definition and diagnostic criteria of cachexia have changed and improved over time, including three different stages (pre-cachexia, cachexia, and refractory cachexia) and objective diagnostic markers. This metabolic wasting syndrome is characterized by a negative protein balance, and anti-cancer drugs like chemotherapy or immunotherapy exacerbate it through relatively unknown mechanisms. Due to its complexity, cachexia management involves a multidisciplinary strategy including not only nutritional and pharmacological interventions. Physical exercise has been proposed as a strategy to counteract the effects of cachexia on skeletal muscle, as it influences the mechanisms involved in the disease such as protein turnover, inflammation, oxidative stress, and mitochondrial dysfunction. This review will summarize the experimental and clinical evidence of the impact of physical exercise on cancer-associated cachexia.

Asunto(s)

Caquexia , Ejercicio Físico , Músculo Esquelético , Neoplasias , Caquexia/etiología , Caquexia/terapia , Caquexia/metabolismo , Humanos , Neoplasias/complicaciones , Neoplasias/metabolismo , Neoplasias/terapia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Animales , Terapia por Ejercicio , Estrés Oxidativo , Inflamación/metabolismo

RESUMEN

Metastatic hormone-naïve prostate cancer (mHNPC) is often the initial form of presentation for metastatic prostate cancer and encompasses a heterogeneous patient population with high inter-patient heterogeneity in prognosis and response to therapy. A more precise treatment of mHNPC, guided by evidence-based biomarkers, remains an unmet medical need. In addition, the limited number of representative laboratory models of mHNPC hampers the translation of basic research into clinical applications. We provide a comprehensive overview of the clinical and biological features that characterize mHNPC, highlight molecular data that could explain the unique prognostic characteristics of mHNPC, and identify key open questions.

Asunto(s)

Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Metástasis de la Neoplasia

RESUMEN

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies.

RESUMEN

The blood-brain barrier (BBB) is a highly selective membrane that regulates the passage of substances between the bloodstream and the brain, thus safeguarding the central nervous system. This chapter provides an overview of current experimental models and detection methods utilized to study the BBB, along with the implementation of sensors and biosensors in BBB research. We discuss static and dynamic BBB models, highlighting their respective advantages and limitations. Additionally, we examine various detection methods employed in BBB research, including those specific to static and dynamic models. Furthermore, we explore the applications of physical sensors and biosensors in BBB models, focusing on their roles in monitoring barrier integrity and function. We also discuss recent advancements in sensor integration, such as robotic interrogators and integrated electrochemical and optical biosensors. Finally, we present a brief conclusion and future outlook, emphasizing the importance of continued innovation in BBB research to advance our understanding of neurological disorders and drug development.

Asunto(s)

Técnicas Biosensibles , Barrera Hematoencefálica , Barrera Hematoencefálica/metabolismo , Humanos , Técnicas Biosensibles/métodos , Animales , Dispositivos Laboratorio en un Chip

RESUMEN

PURPOSE OF REVIEW: Resistant Hypertension (RH) poses a significant public health challenge, contributing to increased mortality, cardiovascular events and organ damage. Both clinical and experimental research are striving for higher standards in a translational manner to integrate new findings and confirm hypotheses. Considering that many are the aspects of RH that are still under investigation, this review aims to shed light on the advances made in experimental research concerning RH. It seeks to underscore the pivotal role of experimental studies in shaping clinical practices and also explore future perspectives. RECENT FINDINGS: It is important to emphasize the significance of experimental models, primarily for advancing our understanding: experimental models have greatly contributed to our comprehension of the underlying mechanisms in RH, including factors like sympathetic activation, endothelial dysfunction and structural vessel abnormalities. Secondly, for assessing treatment approaches: animal models have also played a crucial role in evaluating the potential effectiveness of diverse treatment approaches for RH. These encompass both pharmacological options, involving combinations of established drugs or novel pharmaceuticals, and non-pharmacological alternatives, which include surgical procedures like renal denervation, medical devices like baroreceptor stimulators, and lifestyle modifications. The most lacking component in translational research is the fact that there is no well-established animal model that perfectly replicates RH. Consequently, alternative strategies, including the combination of models, must be considered. What remains clear is that the development of animal models closely mimicking RH holds the promise of providing valuable insights into the essential mechanisms and responses necessary to combat or slow the global progression of RH.

RESUMEN

Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a potent therapeutic strategy to boost white matter repair in the injured preterm brain. Using a double-hit mouse model of diffuse white matter injury, we previously showed that the efficacy of MSC treatment was time dependent, with a significant decrease in functional and histological improvements after the postponement of cell administration. In this follow-up study, we aimed to investigate the mechanisms underlying this loss of therapeutic efficacy. Additionally, we optimized the regenerative potential of MSCs by means of genetic engineering with the transient hypersecretion of beneficial factors, in order to prolong the treatment window. Though the cerebral expression of known chemoattractants was stable over time, the migration of MSCs to the injured brain was partially impaired. Moreover, using a primary oligodendrocyte (OL) culture, we showed that the rescue of injured OLs was reduced after delayed MSC coculture. Cocultures of modified MSCs, hypersecreting IGF1, LIF, IL11, or IL10, with primary microglia and OLs, revealed a superior treatment efficacy over naïve MSCs. Additionally, we showed that the delayed intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, improved myelination and the functional outcome in EoP mice. In conclusion, the impaired migration and regenerative capacity of intranasally applied MSCs likely underlie the observed loss of efficacy after delayed treatment. The intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, is a promising optimization strategy to prolong the window for effective MSC treatment in preterm infants with EoP.

Asunto(s)

Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratones , Trasplante de Células Madre Mesenquimatosas/métodos , Secretoma/metabolismo , Modelos Animales de Enfermedad , Oligodendroglía/metabolismo , Oligodendroglía/citología , Humanos , Técnicas de Cocultivo , Microglía/metabolismo , Ratones Endogámicos C57BL

RESUMEN

Since the establishment of a clear link between maternal alcohol consumption during pregnancy and certain birth defects, the research into the treatment of FASD has become increasingly sophisticated. The field has begun to explore the possibility of intervening at different levels, and animal studies have provided valuable insights into the pathophysiology of the disease, forming the basis for implementing potential therapies with increasingly precise mechanisms. The recent reports suggest that compounds that reduce the severity of neurodevelopmental deficits, including glial cell function and myelination, and/or target oxidative stress and inflammation may be effective in treating FASD. Our goal in writing this article was to analyze and synthesize current experimental therapeutic interventions for FASD, elucidating their potential mechanisms of action, translational relevance, and implications for clinical application. This review exclusively focuses on animal models and the interventions used in these models to outline the current direction of research. We conclude that given the complexity of the underlying mechanisms, a multifactorial approach combining nutritional supplementation, pharmacotherapy, and behavioral techniques tailored to the stage and severity of the disease may be a promising avenue for further research in humans.

RESUMEN

The joint workshop between U.S. and Japanese researchers, supported by The U.S.-Japan Brain Research Cooperative Program, convened in January 2023 at Keio University Mita campus in Tokyo, Japan. The workshop had a threefold objective. Firstly, it aimed to facilitate robust exchanges between U.S. and Japanese researchers engaged in Neurovascular Unit (NVU) research, enhancing the global network of scholars in the field. Secondly, it aimed to encourage the initiation of collaborative research projects, fostering interdisciplinary efforts and synergistic advancements in understanding the brain vascular physiology and central nervous system. Lastly, the workshop emphasized the nurturing of young researchers, recognizing their pivotal role in shaping the future of NVU research. Throughout the workshop, participants discussed fundamental aspects of the NVU, exploring its complex connections and vital functions. By sharing their expertise and insights, the workshop attendees sought to uncover novel approaches to mitigate the burden of neurological diseases for individuals worldwide. This report provides a summary of the presentations and discussions held during the workshop, showcasing the collective efforts and progress made by the participants.

Asunto(s)

Encéfalo , Humanos , Japón , Estados Unidos , Encéfalo/fisiología , Investigación Biomédica

RESUMEN

Hearing loss is a common side effect of many tumor treatments. However, hearing loss can also occur as a direct result of certain tumors of the nervous system, the most common of which are the vestibular schwannomas (VS). These tumors arise from Schwann cells of the vestibulocochlear nerve and their main cause is the loss of function of NF2, with 95 % of cases being sporadic and 5 % being part of the rare neurofibromatosis type 2 (NF2)-related Schwannomatosis. Genetic variations in NF2 do not fully explain the clinical heterogeneity of VS, and interactions between Schwann cells and their microenvironment appear to be critical for tumor development. Preclinical in vitro and in vivo models of VS are needed to develop prognostic biomarkers and targeted therapies. In addition to VS, other tumors can affect hearing. Meningiomas and other masses in the cerebellopontine angle can compress the vestibulocochlear nerve due to their anatomic proximity. Gliomas can disrupt several neurological functions, including hearing; in fact, glioblastoma multiforme, the most aggressive subtype, may exhibit early symptoms of auditory alterations. Besides, treatments for high-grade tumors, including chemotherapy or radiotherapy, as well as incomplete resections, can induce long-term auditory dysfunction. Because hearing loss can have an irreversible and dramatic impact on quality of life, it should be considered in the clinical management plan of patients with tumors, and monitored throughout the course of the disease.

Asunto(s)

Pérdida Auditiva , Audición , Neuroma Acústico , Humanos , Neuroma Acústico/patología , Neuroma Acústico/fisiopatología , Neuroma Acústico/complicaciones , Pérdida Auditiva/fisiopatología , Pérdida Auditiva/etiología , Pérdida Auditiva/patología , Animales , Neurilemoma/patología , Neurilemoma/complicaciones , Neurilemoma/terapia , Nervio Vestibulococlear/patología , Nervio Vestibulococlear/fisiopatología , Factores de Riesgo , Neurofibromatosis 2/genética , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/patología , Neurofibromatosis 2/fisiopatología , Neurofibromatosis 2/terapia , Meningioma/patología , Meningioma/fisiopatología , Meningioma/complicaciones

RESUMEN

Alzheimer's disease (AD) poses a significant public health problem, affecting millions of people across the world. Despite decades of research into therapeutic strategies for AD, effective prevention or treatment for this devastating disorder remains elusive. In this review, we discuss the potential of photobiomodulation (PBM) for preventing and alleviating AD-associated pathologies, with a focus on the biological mechanisms underlying this therapy. Future research directions and guidance for clinical practice for this non-invasive and non-pharmacological therapy are also highlighted. The available evidence indicates that different treatment paradigms, including transcranial and systemic PBM, along with the recently proposed remote PBM, all could be promising for AD. PBM exerts diverse biological effects, such as enhancing mitochondrial function, mitigating the neuroinflammation caused by activated glial cells, increasing cerebral perfusion, improving glymphatic drainage, regulating the gut microbiome, boosting myokine production, and modulating the immune system. We suggest that PBM may serve as a powerful therapeutic intervention for AD.

Asunto(s)

Enfermedad de Alzheimer , Terapia por Luz de Baja Intensidad , Enfermedad de Alzheimer/radioterapia , Enfermedad de Alzheimer/terapia , Terapia por Luz de Baja Intensidad/métodos , Animales , Humanos , Modelos Animales de Enfermedad , Investigación Biomédica Traslacional/métodos

RESUMEN

Ischemic stroke research has enabled significant advancements in diagnosis, treatment, and management of this debilitating disease, yet challenges remain standing in the way of better patient prognoses. In this narrative review, a fictional case illustrates challenges and uncertainties that medical professionals still face - penumbra identification, lack of neuroprotective agents, side-effects of tissue plasminogen activator, dearth of molecular biomarkers, incomplete microvascular reperfusion or no-reflow, post-recanalization hyperperfusion, blood pressure management and procedural anesthetic effects. The current state of the field is broadly reviewed per topic, with the aim to introduce a broad audience (scientist and clinician alike) to recent successes in translational stroke research and pending scientific queries that are tractable for preclinical assessment. Opportunities for co-operation between clinical and experimental stroke experts are highlighted to increase the size and frequency of strides the field makes to improve our understanding of this disease and ways of treating it.

Asunto(s)

Accidente Cerebrovascular Isquémico , Investigación Biomédica Traslacional , Humanos , Investigación Biomédica Traslacional/métodos , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Animales , Isquemia Encefálica/terapia , Isquemia Encefálica/tratamiento farmacológico

RESUMEN

The route of administration of implanted cells may affect the outcome of cell therapy by directing cell migration to the damaged site. However, the question of the relationship between the route of administration, the efficacy of colonisation of a given organ, and the efficacy of cell therapy has not been resolved. The aim of the study was to localise transplanted intravenously and intraperitoneally human amniotic epithelial cells (hAECs) in the tissues of mice, both healthy and injured, in an animal experimental model of acute liver failure (ALF). Mice intoxicated with D-Galactosamine (D-GalN) at a dose of 150 mg/100 g body weight received D-GalN alone or with a single dose of hAECs administered by different routes. Subsequently, at 6, 24, and 72 h after D-GaIN administration and at 3, 21, and 69 h after hAEC administration, lungs, spleen, liver, and blood were collected from recipient mice. The degree of liver damage and regeneration was assessed based on biochemical blood parameters, histopathological evaluation (H&E staining), and immunodetection of proliferating (Ki67+) and apoptotic (Casp+) cells. The biodistribution of the administered cells was based on immunohistochemistry and the identification of human DNA. It has been shown that after intravenous administration, in both healthy and intoxicated mice, most of the transplanted hAECs were found in the lungs, while after intraperitoneal administration, they were found in the liver. We concluded that a large number of hAECs implanted in the lungs following intravenous administration can exert a therapeutic effect on the damaged liver, while the regenerative effect of intraperitoneally injected hAECs on the liver was very limited due to the relatively lower efficiency of cell engraftment.

RESUMEN

Traumatic brain injury (TBI) is one of the most common pathological conditions impacting the central nervous system (CNS). A neurological deficit associated with TBI results from a complex of pathogenetic mechanisms including glutamate excitotoxicity, inflammation, demyelination, programmed cell death, or the development of edema. The critical components contributing to CNS response, damage control, and regeneration after TBI are glial cells-in reaction to tissue damage, their activation, hypertrophy, and proliferation occur, followed by the formation of a glial scar. The glial scar creates a barrier in damaged tissue and helps protect the CNS in the acute phase post-injury. However, this process prevents complete tissue recovery in the late/chronic phase by producing permanent scarring, which significantly impacts brain function. Various glial cell types participate in the scar formation, but this process is mostly attributed to reactive astrocytes and microglia, which play important roles in several brain pathologies. Novel technologies including whole-genome transcriptomic and epigenomic analyses, and unbiased proteomics, show that both astrocytes and microglia represent groups of heterogenic cell subpopulations with different genomic and functional characteristics, that are responsible for their role in neurodegeneration, neuroprotection and regeneration. Depending on the representation of distinct glia subpopulations, the tissue damage as well as the regenerative processes or delayed neurodegeneration after TBI may thus differ in nearby or remote areas or in different brain structures. This review summarizes TBI as a complex process, where the resultant effect is severity-, region- and time-dependent and determined by the model of the CNS injury and the distance of the explored area from the lesion site. Here, we also discuss findings concerning intercellular signaling, long-term impacts of TBI and the possibilities of novel therapeutical approaches. We believe that a comprehensive study with an emphasis on glial cells, involved in tissue post-injury processes, may be helpful for further research of TBI and be the decisive factor when choosing a TBI model.