256 research outputs found

    Involvement of Astrocytes in the Process of Metabolic Syndrome

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    Astrocytes constitute a very heterogeneous population of cells, which regulate pH, extracellular levels of ions and neurotransmitters, and energy metabolism in addition to actively participating in neurotransmission. In situations of damage to the CNS, the typical response is the degree of reactive gliosis, which can form glial scars. On the other hand, chronic diseases such as obesity, type 2 diabetes, hypertension, and atherosclerosis have been causally related to low-grade chronic inflammation in various metabolic tissues. It has been pointed out that the identification of hypothalamic inflammatory alterations are triggered by overnutrition, orchestrated by the hypothalamic immune system, and sustained by the pathophysiology associated with the metabolic syndrome. We discuss here the effects of astrocytes and the main astrocyte mechanisms involved in the metabolic syndrome and its comorbidities

    Investigating reorganization of the motor cortices following stem cell therapy in a non-human primate model of cortical ischemia

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    Prior work demonstrated that impairments in fine motor function produced by a controlled ischemic lesion in monkey primary motor cortex were ameliorated by treatment with a cell drug product, CNTO 0007. This drug contains human umbilical tissue-derived cells, in a proprietary thaw and inject formulation. Brain tissue sections from subjects with and without CNTO 0007 therapy were processed immunohistochemically to identify neurons expressing c-Fos as a marker for neuronal activity. Neurons expressing c-Fos were quantified using unbiased stereology. The number of c-Fos positive neurons in dorsal pre-motor cortex ipsilateral to the lesion were greater in treated animals but only approached statistical significance. These findings suggest that cortical reorganization in the dorsal pre-motor cortex may underlie the observed functional recovery. However, c-Fos expressing neurons in other motor areas, such as the ventral pre-motor cortex, remain to be studied

    Glial Growth Factor 2 as a treatment in a monkey model of cortical injury

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    Cortical injuries, such as those caused by stroke and other insults, are the leading cause of death and disability worldwide. While thrombolytics can be used to restore blood flow immediately following the onset of symptoms of an ischemic stroke, there are currently no neurorestorative therapeutics that can enhance long-term recovery of function following injury. Neuregulins are a family of growth factors involved with the survival and function of neurons and glia. Glial Growth Factor 2 (GGF2) is an isoform of neuregulin-1 that has demonstrated significant effects in the recovery of function in rodent models of stroke. Histological analyses suggest GGF2 promotes recovery by enhancing endogenous mechanisms to reduce inflammation and promote plasticity. To further explore the efficacy of GGF2, we used our rhesus monkey model of cortical injury and fine motor impairment to compare the rate and pattern of recovery in monkeys treated with GGF2. Twenty-four young adult male monkeys (ages 4-10 years old) were pre-trained on our task of fine motor function of the hand before undergoing surgery to produce a cortical lesion limited to the hand representation of the primary motor cortex on one side. Intravenous (IV) administration of GGF2 (0.5 mg/kg) began 24 hours after surgery and continued daily for 7 days. This was followed by 21 days of sub-cutaneous administration of GGF2 at two different dose levels (0.1 mg/kg or 0.3 mg/kg). Post-operative testing began two weeks after the lesion and continued for 12 weeks. All trials were video recorded and latency to retrieve a reward was quantitatively measured to assess the trajectory of post-operative response latency and grasp pattern compared to pre-operative levels. The results showed no significant differences between the groups in the recovery of fine motor function. Moreover, all vehicle control monkeys returned to their pre-operative levels of latency and grasp pattern despite no significant differences in lesion volume from the experimental groups. In addition to measures of behavioral recovery, we processed the brain tissue with immunohistochemistry to investigate the role of GGF2 treatment in reducing the pro-inflammatory response of microglia and enhancing axonal sprouting and synaptogenesis following injury. All groups had a greater density of Iba1+ microglia in the perilesional grey matter and sublesional white matter, but there were no significant differences in the numerical density or phenotypes of microglia between the groups. We also found no significant differences in axonal sprouting between the groups. However, GGF2 treatment did enhance expression of synaptophysin in the contralesional hemisphere of monkeys that received subcutaneous doses of GGF2 following the initial 7 days of intravenous GGF2 treatment. This suggests that high dose GGF2 treatment may enhance plasticity of compensatory circuits involving the intact hemisphere and that this effect is dose dependent. In addition, we followed up these analyses using a subset of monkeys from the larger GGF2 study to optimize and validate a method that labels newly synthesized myelin. This is accomplished by in vivo administration of a choline analog, propargylcholine (P-Cho) that labels newly synthesized myelin and can be visualized post-mortem. Our results demonstrate effective and stable incorporation of P-Cho with post injection survival of 1 to 6 weeks. Using this method to quantify new myelin after cortical injury to the primary motor cortex, showed significantly greater P-Cho labeling and co-localization with myelin basic protein (MBP) in the white matter underlying the ipsilesional hemisphere when compared with the contralesional hemisphere. This validates P-Cho for assessing myelin plasticity in a nonhuman primate brain and how it might be used to assess therapeutics aimed at inducing remyelination and enhancing myelin synthesis. Finally, this dissertation also includes the comparison of sex differences in recovery of motor function after cortical injury. In a cohort of aged male and female monkeys, postmortem analysis showed no differences in lesion volume between the males and females. However, behaviorally, the females returned to their pre-operative latency and grasp patterns significantly faster and more completely than the males. These findings demonstrate the need for additional studies to further investigate the role of estrogens and other sex hormones that may differentially affect recovery outcomes in the primate brain. Collectively, the results presented in this dissertation highlight the complexity of evaluating treatments and mechanisms underlying recovery of function by enhancing neuroplasticity. Specifically, we were unable to effectively evaluate GGF2 as a treatment due to the behavioral recovery of all control monkeys. Follow up studies should investigate treatment with GGF2 in aging monkeys and compare the results with our findings. Additionally, it is necessary to further explore the recovery of fine motor function in young monkeys. Finally, our study showing sex differences in recovery of function provides evidence that sex hormones may play a significant role in providing neuroprotection in the aging brain following cortical injury. Future studies should measure post-operative estrogen levels and evaluate supplementation as a potential treatment option

    A New Perspective on the Modulation of the Blood Brain Barrier: The Role of Nutrition and Environmental Factors

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    Kan beyin bariyeri (KBB), toksik bileşiklerin ve patojenlerin kandan beyne geçişini engelleyen, besin ögelerinin ise beyne iletilmesini sağlayan merkezi sinir sistemi (MSS) ve periferik sinir sistemi arasında regüle edilen oldukça seçici ve dinamik endotel bir bariyerdir. Kan beyin bariyeri, sinaptik ve nöronal işlevlerin sağlıklı bir biçimde yerine getirilmesi için beyin homeostazını sağlar. Kan beyin bariyeri işlevlerini sıkı bağlantı proteinleri (tight junctions), astrositler, perisitler gibi nörovasküler ünitenin elemanları vasıtasıyla gerçekleştirir. Beslenme, nöronal aktivite ve yaşlanma, hava kirliliği, ağır metallere maruziyet, sigara, alkol, stres, egzersiz gibi çevresel faktörler kan beyin bariyeri modülasyonunda rol oynamaktadır. Nöroinflamasyon, beyinde gerçekleşen hasarı takiben gelişen koordine bir yanıttır. Değişen beyin homeostazına yanıt olarak kan beyin bariyeri geçirgenliğine etki eden bir dizi inflamatuar mediatör salınır. Diyetin bileşimi, antioksidan bileşenler, nutrasötikler, vitaminler gibi çeşitli diyete bağlı faktörler nöroinflamasyona etki ederek kan beyin bariyeri geçirgenliğinde rol oynamaktadır. Diyet içerdiği yararlı bileşenler ile nöroprotektif olabilirken, kan beyin bariyerinde nöroinflamasyona neden olarak MSS’de yıkıcı etkilere de neden olabilir. Beslenmenin nörodejeneratif hastalıkların önlenmesinde, gelişiminde, progresyonunda ve tedavisindeki etkisi araştırmacılar için merak uyandıran yeni bir alandır. Besinlerin ve beslenme alışkanlıklarının kan beyin bariyeri modülasyonuna etkisinin ele alınması hastalık-diyet etkileşimine yeni bir bakış açısı sağlayacaktır

    Mitochondria and Brain Disorders

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    The mitochondrion is a unique and ubiquitous organelle that contains its own genome, encoding essential proteins that are major components of the respiratory chain and energy production system. Mitochondria play a dominant role in the life and function of eukaryotic cells including neurons and glia, as their survival and activity depend upon mitochondrial energy production and supply. Besides energy production, mitochondria also play a vital role in calcium homeostasis and may induce apoptosis by excitotoxicity. Mitochondrial dysfunction is related to common neurological diseases, such as Parkinson's disease, Alzheimer's disease, Friedreich's ataxia, Huntington's disease, and Multiple Sclerosis. An efficient treatment of mitochondrial dysfunction would open new horizons in the therapeutic perspectives of a substantial number of inflammatory and degenerative neurological disorders

    INSULIN ACTIONS ON HIPPOCAMPAL NEURONS

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    Aging is the main risk factor for cognitive decline. The hippocampus, a brain region critical for learning and memory formation, is especially vulnerable to normal and pathological age-related cognitive decline. Dysregulation of both insulin and intracellular Ca2+ signaling appear to coexist and their compromised actions may synergistically contribute to neuronal dysfunction with aging. This dissertation focused on the interaction between insulin, Ca2+ dysregulation, and cognition in hippocampal neurons by examining the contributions of insulin to Ca2+ signaling events that influence memory formation. I tested the hypothesis that insulin would increase cognition in aged animals by altering Ca2+-dependent physiological mechanisms involved in learning. The possible effects of insulin on learning and memory in young and aged rats were studied. In addition, the effects of insulin on the Ca2+-dependent afterhyperpolarization in CA1 pyramidal hippocampal neurons from young and aged animals were compared. Further, primary hippocampal cultures were used to examine the possible effects of insulin on voltage-gated Ca2+ channel activity and Ca2+-induced Ca2+-release; mechanisms known to influence the AHP. We found that intranasal insulin improved memory in aged F344 rats. Young and aged F344 rats were treated with Humalog®, a short-acting insulin analog, or Levemir®, a long-acting insulin analog. The aged rats performed similar to young rats in the Morris Water Maze, a hippocampal dependent spatial learning and memory task. Electrophysiological recordings from CA1 hippocampal neurons revealed that insulin reduced the age-related increase in the Ca2+-dependent afterhyperpolarization, a prominent biomarker of brain aging that is associated with cognitive decline. Patch clamping recording from hippocampal cultured neurons showed that insulin reduced Ca2+ channel currents. Intracellular Ca2+ levels were also monitored using Fura-2 in response to cellular depolarization. Results indicated that a reduction in Ca2+-induced Ca2+-release from intracellular stores occurred in the presence of insulin. These results suggest that increasing brain insulin levels in aged rats may have improved memory by reducing the AHP and intracellular Ca2+concentrations. This study indicates a possible mechanism responsible for the beneficial effects of intranasal insulin on cognitive function absorbed in selective Alzheimer’s patients. Thus, insulin therapy may reduce or prevent age-related compromises to Ca2+ regulatory pathways typically associated with cognitive decline

    Impact of Metabolic Syndrome on Neuroinflammation and the Blood–Brain Barrier

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    Metabolic syndrome, which includes diabetes and obesity, is one of the most widespread medical conditions. It induces systemic inflammation, causing far reaching effects on the body that are still being uncovered. Neuropathologies triggered by metabolic syndrome often result from increased permeability of the blood–brain-barrier (BBB). The BBB, a system designed to restrict entry of toxins, immune cells, and pathogens to the brain, is vital for proper neuronal function. Local and systemic inflammation induced by obesity or type 2 diabetes mellitus can cause BBB breakdown, decreased removal of waste, and increased infiltration of immune cells. This leads to disruption of glial and neuronal cells, causing hormonal dysregulation, increased immune sensitivity, or cognitive impairment depending on the affected brain region. Inflammatory effects of metabolic syndrome have been linked to neurodegenerative diseases. In this review, we discuss the effects of obesity and diabetes-induced inflammation on the BBB, the roles played by leptin and insulin resistance, as well as BBB changes occurring at the molecular level. We explore signaling pathways including VEGF, HIFs, PKC, Rho/ROCK, eNOS, and miRNAs. Finally, we discuss the broader implications of neural inflammation, including its connection to Alzheimer’s disease, multiple sclerosis, and the gut microbiome

    Adapentpronitrile, a New Dipeptidyl Peptidase-IV Inhibitor, Ameliorates Diabetic Neuronal Injury Through Inhibiting Mitochondria-Related Oxidative Stress and Apoptosis

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    Our previous studies indicated that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor, has a hypoglycemic effect and ameliorates rat pancreatic β cell dysfunction in type 2 diabetes mellitus through inhibiting DPP-IV activity. However, the effect of adapentpronitrile on the neurodegenerative diseases has not been studied. In the present study, we first found that adapentpronitrile significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (Aβ) expression in the hippocampus and cortex in the high fat diet/STZ rat model of diabetes. Furthermore, adapentpronitrile significantly attenuated oxidative stress, downregulated expression of the pro-apoptotic proteins BAX, cytochrome c, caspase-9, and caspase-3, and upregulated expression of the anti-apoptotic protein Bcl-2, although there was no effect on GLP-1R expression. At 30 min post-injection of adapentpronitrile (50 mg/kg) via the tail vein, its concentration in normal rat brain was 0.2034 ± 0.0094 μg/g. Subsequently, we further confirmed the neuroprotective effects and mechanism of adapentpronitrile in HT22 cells treated with high glucose (HG) and aluminum maltolate [Al(mal)3] overload, respectively. Our results showed significant decreases in mitochondrial membrane potential (MTP) and Bcl-2 expression, accompanied by a significant increase in apoptosis, reactive oxygen species (ROS) generation, and the expression of pro-apoptotic proteins in HT22 cells exposed to these stimuli. Adapentpronitrile treatment protected against neuronal injury, suppressed ROS generation, and reduced MTP and mitochondrial apoptosis in HT22 cells; however, DPP-IV activity was not detected. Our results suggest that adapentpronitrile protects against diabetic neuronal injury, at least partially, by inhibiting mitochondrial oxidative stress and the apoptotic pathway in a DPP-IV-independent manner

    Investigating Neurovascular Function in Pre-Clinical Models of Alzheimer’s Disease & Atherosclerosis

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    Background: Neurovascular coupling (NVC) is essential to brain health and the breakdown of NVC is proposed to be a key pathological factor in the development of Alzheimer’s disease (AD), vascular dementia (VaD) and other cerebrovascular diseases. Importantly; as we age, the presence of two or more comorbidities is common and this often leads to clinical complications. Whilst preclinical models of human disease are numerous and have supported basic and translational neuroscience immensely over the past few decades, models of comorbidity are few and often neglected when it is important to study comorbidity to reflect clinical presentations in patients. This project will focus on examining neurovascular function in 3 different preclinical models of AD, atherosclerosis (ATH) and comorbid AD & ATH (MIX). Aims & Objectives: I) To investigate neurovascular function at an early-AD timepoint (6m) in the J20-hAPP model of AD (J20-AD); when amyloid-beta deposits begin to form, using a chronic surgery recovered animal protocol. Neurovascular function will be assessed by 2D- optical imaging spectroscopy (2D-OIS) to measure cortical haemodynamics, in addition to using multichannel microelectrodes to obtain neural multi-unit activity (MUA). II) To investigate neurovascular function in a novel experimental model of ATH using the rAAV8-mPCSK9- D377Y + Western Diet model (PCSK9-ATH). III) To create a mixed comorbid model of AD and ATH (J20-PCSK9-MIX) and to investigate neurovascular function in this novel model. IV) To assess neuropathology and neuroinflammation from brain tissue in the 3 disease models. Results: Firstly, at an early stage, J20-AD mice exhibit enhanced evoked-haemodynamic responses associated with neural hyperexcitability. They also display a unique time- dependent elevation of baseline blood volume under normobaric hyperoxia. Secondly, PCSK9-ATH display reduced evoked-responses and show signs of neurovascular dysfunction associated with increased IL1β & TNFα-neuroinflammation. Thirdly, J20-PCSK9-MIX comorbid mice have a trebling of Aβ plaques in the hippocampus, although, without any further worsening of neurovascular function in the cortex compared to J20-AD mice, although all 3 disease models show a trend towards the reduced washout of HbR, which indicates metabolic inefficiency and inadequate oxygen delivery to neurons. Finally, electrode insertion into the brain (causing mild brain injury) leads to cortical spreading depression (CSD) to occur in all mice, with the most severe CSD occurring in J20-AD and PCSK9-ATH mice, and this may be related to levels of IL1β neuroinflammation, though this needs to be confirmed. Conclusions: These results provide novel insights in all 3 disease models which have important translational implications by highlighting distinct therapeutic targets and strategies. The results also show the importance of neurovascular function in dementia and targeting impairments to neurovascular function early on may be key to slowing down the onset and progression of dementia

    Pathogenesis of Encephalitis

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    Many infectious agents, such as viruses, bacteria, and parasites, can cause inflammation of the central nervous system (CNS). Encephalitis is an inflammation of the brain parenchyma, which may result in a more advanced and serious disease meningoencephalitis. To establish accurate diagnosis and develop effective vaccines and drugs to overcome this disease, it is important to understand and elucidate the mechanism of its pathogenesis. This book, which is divided into four sections, provides comprehensive commentaries on encephalitis. The first section (6 chapters) covers diagnosis and clinical symptoms of encephalitis with some neurological disorders. The second section (5 chapters) reviews some virus infections with the outlines of inflammatory and chemokine responses. The third section (7 chapters) deals with the non-viral causative agents of encephalitis. The last section (4 chapters) discusses the experimental model of encephalitis. The different chapters of this book provide valuable and important information not only to the researchers, but also to the physician and health care workers
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