scholarly journals Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity

2020 ◽  
Vol 22 (1) ◽  
pp. 211
Author(s):  
Josine E. G. Vaes ◽  
Chantal M. Kosmeijer ◽  
Marthe Kaal ◽  
Rik van Vliet ◽  
Myrna J. V. Brandt ◽  
...  
Keyword(s):  
Cortical Cell ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Preterm Neonates ◽  
Pathophysiological Mechanism ◽  
Cortical Interneuron ◽  
Developmental Disturbances ◽  
Cornu Ammonis ◽  
Regenerative Therapies ◽  
Interneuron Development

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.

Humoral Immunity in Heart Failure

2019 ◽  
Vol 19 (1) ◽  
pp. 14-18 ◽  
Author(s):  
Amrita Sarkar ◽  
Khadija Rafiq
Keyword(s):  
Heart Failure ◽  
Humoral Immunity ◽  
Treatment Strategies ◽  
Pathophysiological Mechanism ◽  
Peripheral Vascular ◽  
Cardiac Inflammation ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
New Treatment ◽  
Immunity Function

Cardiovascular Disease (CVD) is a class of diseases that involve disorders of heart and blood vessels, including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, which finally lead to Heart Failure (HF). There are several treatments available all over the world, but still, CVD and heart failure became the number one problem causing death every year worldwide. Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Cardiac inflammation is a major pathophysiological mechanism operating in the failing heart, regardless of HF aetiology. Disturbances of the cellular and humoral immune system are frequently observed in heart failure. This review describes how B-cells play a specific role in the heart failure states. There is an urgent need to identify novel therapeutic targets and develop advanced therapeutic strategies to combat the syndrome of HF. Understanding and describing the elements of the humoral immunity function are essential and may suggest potential new treatment strategies.

scholarly journals Ocular Toxoplasmosis: Mechanisms of Retinal Infection and Experimental Models

Parasitologia ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 50-60
Author(s):  
Veronica Rodriguez Fernandez ◽  
Giovanni Casini ◽  
Fabrizio Bruschi
Keyword(s):  
Ex Vivo ◽  
Cell Damage ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Ocular Toxoplasmosis ◽  
Cell Infection

Ocular toxoplasmosis (OT) is caused by the parasite Toxoplasma gondii and affects many individuals throughout the world. Infection may occur through congenital or acquired routes. The parasites enter the blood circulation and reach both the retina and the retinal pigment epithelium, where they may cause cell damage and cell death. Different routes of access are used by T. gondii to reach the retina through the retinal endothelium: by transmission inside leukocytes, as free parasites through a paracellular route, or after endothelial cell infection. A main feature of OT is the induction of an important inflammatory state, and the course of infection has been shown to be influenced by the host immunogenetics. On the other hand, there is evidence that the T. gondii phenotype also has an impact on the distribution of the pathology in different areas. Although considerable knowledge has been acquired on OT, a deeper knowledge of its mechanisms is necessary to provide new, more targeted treatment strategies. In particular, in addition to in vitro and in vivo experimental models, organotypic, ex vivo retinal explants may be useful in this direction.

scholarly journals Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

2010 ◽  
Vol 31 (1) ◽  
pp. 17-35 ◽  
Author(s):  
Martin Lauritzen ◽  
Jens Peter Dreier ◽  
Martin Fabricius ◽  
Jed A Hartings ◽  
Rudolf Graf ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Disorders ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Neuronal Damage ◽  
Ion Homeostasis ◽  
Large Body ◽  
Treatment Strategies ◽  
Pathophysiological Mechanism

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

2021 ◽  
Vol 19 ◽  
Author(s):  
Aditya A Singh ◽  
Akash Kharwar ◽  
Manoj P. Dandekar
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Neurotrophic Factors ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Cerebral Stroke ◽  
Post Stroke ◽  
Stroke Models

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

scholarly journals Exogenous Application of Proteoglycan to the Cell Surface Microenvironment Facilitates to Chondrogenic Differentiation and Maintenance

2020 ◽  
Vol 21 (20) ◽  
pp. 7744
Author(s):  
Teruaki Masutani ◽  
Shuhei Yamada ◽  
Akira Hara ◽  
Tatsuji Takahashi ◽  
Paul G Green ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tyrosine Kinases ◽  
Endochondral Ossification ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Dimensional Structure ◽  
Pathophysiological Mechanism ◽  
Nasal Cartilage ◽  
Chondroprogenitor Cells ◽  
Extracellular Matrix Components

Osteoarthritis (OA), a disease that greatly impacts quality of life, has increasing worldwide prevalence as the population ages. However, its pathogenic mechanisms have not been fully elucidated and current therapeutic treatment strategies are inadequate. In recent years, abnormal endochondral ossification in articular cartilage has received attention as a pathophysiological mechanism in OA. Cartilage is composed of abundant extracellular matrix components, which are involved in tissue maintenance and regeneration, but how these factors affect endochondral ossification is not clear. Here, we show that the application of aggrecan-type proteoglycan from salmon nasal cartilage (sPG) exhibited marked proliferative capacity through receptor tyrosine kinases in chondroprogenitor cells, and also exhibited differentiation and three-dimensional structure formation via phosphorylation of Insulin-like Growth Factor-1 Receptor and Growth Differentiation Factor 5 expression. Furthermore, sPG inhibited calcification via expression of Runx2 and Col10 (factors related to induction of calcification), while increasing Mgp, a mineralization inhibitory factor. As a result of analyzing the localization of sPG applied to the cells, it was localized on the surface of the cell membrane. In this study, we found that sPG, as a biomaterial, could regulate cell proliferation, differentiation and calcification inhibition by acting on the cell surface microenvironment. Therefore, sPG may be the foundation for a novel therapeutic approach for cartilage maintenance and for improved symptoms in OA.

scholarly journals Thiamine Deficiency Induced Neurochemical, Neuroanatomical, and Neuropsychological Alterations: A Reappraisal

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Raffaele Nardone ◽  
Yvonne Höller ◽  
Monica Storti ◽  
Monica Christova ◽  
Frediano Tezzon ◽  
...  
Keyword(s):  
Thiamine Deficiency ◽  
Cortical Cell ◽  
Cell Loss ◽  
Brain Regions ◽  
Experimental Models ◽  
Neurological Sequela ◽  
Thalamic Nuclei ◽  
Chronic Alcoholic ◽  
Ethanol Abuse ◽  
And Function

Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans.

In silico design of treatment strategies in wound healing and bone fracture healing

2010 ◽  
Vol 368 (1920) ◽  
pp. 2683-2706 ◽  
Author(s):  
L. Geris ◽  
R. Schugart ◽  
H. Van Oosterwyck
Keyword(s):  
Mathematical Models ◽  
Fracture Healing ◽  
Bone Fracture ◽  
In Silico ◽  
Healing Process ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Bone Fracture Healing ◽  
Impaired Healing ◽  
Healing Processes

Wound and bone fracture healing are natural repair processes initiated by trauma. Over the last decade, many mathematical models have been established to investigate the healing processes in silico , in addition to ongoing experimental work. In recent days, the focus of the mathematical models has shifted from simulation of the healing process towards simulation of the impaired healing process and the in silico design of treatment strategies. This review describes the most important causes of failure of the wound and bone fracture healing processes and the experimental models and methods used to investigate and treat these impaired healing cases. Furthermore, the mathematical models that are described address these impaired healing cases and investigate various therapeutic scenarios in silico . Examples are provided to illustrate the potential of these in silico experiments. Finally, limitations of the models and the need for and ability of these models to capture patient specificity and variability are discussed.

scholarly journals Novel urinary markers: taurine, dopamine and L-fucose levels in predicting neonatal seizures

Biomedicine ◽  
2021 ◽  
Vol 41 (4) ◽  
pp. 732-736
Author(s):  
Varashree B. S. ◽  
Sravya Poduri ◽  
Leslie Edward Lewis ◽  
Vijetha Shenoy Belle
Keyword(s):  
Neonatal Period ◽  
Treatment Strategies ◽  
Recurrence Risk ◽  
Neonatal Seizure ◽  
Pathophysiological Mechanism ◽  
Limited Efficacy ◽  
Ethical Approval ◽  
Urine Levels ◽  
Normal Controls ◽  
Apparently Healthy

Introduction and Aim: Neonatal seizure is an age specific neurological emergency. Their unique pathophysiological mechanism has become subject of interest for many research studies. The recurrence risk for seizures is high during neonatal period and currently used treatment strategies have limited efficacy in preventing it. From past decades although the treatment has not changed, there is a gradual progress in various mechanisms that are involved in generation of seizures and their response to anti-epileptics. With the emergence of new biochemical parameters for risk assessment in patients with seizures, there is a strong need for their comparative evaluation in order to evaluate their potential clinical application. So, this study was carried out to compare the urine levels of taurine, dopamine and fucose in assessing their role in mechanism of seizure.   Materials and Methods: After obtaining ethical approval and consent from parents total 43 neonates, urine taurine, dopamine and fucose were measured in 24 cases of seizures and 19 apparently healthy normal controls. Dopamine and Taurine were measured using ELISA and L-fucose by Dische and Shettles method.   Results: The median level of urine fucose was significantly higher in male neonates, taurine was significantly decreased in cases compared to that of controls. Males had higher preponderance to develop seizures. The median levels of urine dopamine were high in cases compared to controls but has not showed any significance.   Conclusion: Amino acid like taurine, carbohydrate moiety like fucose and a neuromodulator like dopamine may have a mechanistic role in development of seizures in neonatal period.

scholarly journals Activin receptor ALK4 coordinates extracellular signals and intrinsic transcriptional programs to regulate development of cortical somatostatin interneurons

2019 ◽  
Author(s):  
Christina Göngrich ◽  
Favio A. Krapacher ◽  
Hermany Munguba ◽  
Diana Fernández-Suárez ◽  
Annika Andersson ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Gene Promoter ◽  
Double Positive ◽  
Activin Receptor ◽  
Cortical Interneuron ◽  
Extracellular Signals ◽  
Inhibitory Circuitry ◽  
Cortical Interneurons ◽  
Interneuron Development

AbstractAlthough the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific loses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

scholarly journals Wnt1 Neuroprotection Translates into Improved Neurological Function during Oxidant Stress and Cerebral Ischemia ThroughAKT1and Mitochondrial Apoptotic Pathways

2010 ◽  
Vol 3 (2) ◽  
pp. 153-165 ◽  
Author(s):  
Zhao Zhong Chong ◽  
Yan Chen Shang ◽  
Jinling Hou ◽  
Kenneth Maiese
Keyword(s):  
Oxidative Stress ◽  
Oxidant Stress ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Neurological Function ◽  
Cellular Protection ◽  
Cellular Targets ◽  
Endogenous Expression

Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression ofWnt1or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.

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