Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus

Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus.

Histopathological, immunohistochemical, and molecular study of BHV-5 infection in the central nervous system of experimentally infected calves

Bovine meningoencephalitis caused by BHV-5, a double-stranded DNA enveloped virus that belongs to the family Herpesviridae and subfamily Alphaherpesvirinae, is an important differential diagnosis of central nervous diseases. The aim of this study was to describe the histological changes in the central nervous system of calves experimentally infected with BHV-5 and compare these changes with the PCR and IHC results. Formalin-fixed paraffin-embedded central nervous system samples from calves previously inoculated with BHV-5 were microscopically evaluated and tested using IHC and PCR. All the animals presented with nonsuppurative meningoencephalitis. From 18 evaluated areas of each calf, 32.41% and 35.19% were positive by IHC and PCR, respectively. The telencephalon presented more accentuated lesions and positive areas in the PCR than other encephalic areas and was the best sampling area for diagnostic purposes. Positive areas in the IHC and PCR were more injured than IHC and PCR negative areas. The animal with neurological signs showed more PCR- and IHC-positive areas than the other animals.

Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection

Alterations in extracellular matrix (ECM) expression in the central nervous system (CNS) usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN) and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients, T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN) and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with a4+ and a5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were a6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections.

Cardiovascular and autonomic modulation by the central nervous system after aerobic exercise training

The autonomic nervous system plays a key role in maintaining homeostasis under normal and pathological conditions. The sympathetic tone, particularly for the cardiovascular system, is generated by sympathetic discharges originating in specific areas of the brainstem. Aerobic exercise training promotes several cardiovascular adjustments that are influenced by the central areas involved in the output of the autonomic nervous system. In this review, we emphasize the studies that investigate aerobic exercise training protocols to identify the cardiovascular adaptations that may be the result of central nervous system plasticity due to chronic exercise. The focus of our study is on some groups of neurons involved in sympathetic regulation. They include the nucleus tractus solitarii, caudal ventrolateral medulla and the rostral ventrolateral medulla that maintain and regulate the cardiac and vascular autonomic tonus. We also discuss studies that demonstrate the involvement of supramedullary areas in exercise training modulation, with emphasis on the paraventricular nucleus of the hypothalamus, an important area of integration for autonomic and neuroendocrine responses. The results of these studies suggest that the beneficial effects of physical activity may be due, at least in part, to reductions in sympathetic nervous system activity. Conversely, with the recent association of physical inactivity with chronic disease, these data may also suggest that increases in sympathetic nervous system activity contribute to the increased incidence of cardiovascular diseases associated with a sedentary lifestyle.

Effects of seasonal variation on the central nervous system activity of Ocimum gratissimum L. essential oil

Ocimum gratissimum L. (Lamiaceae) and other species of the same genus are used as medicines to treat central nervous system (CNS) diseases, commonly encountered in warm regions of the world. The chemical composition of Ocimum gratissimum essential oil varies according to their chemotypes: timol, eugenol or geraniol. In this study, the essential oil type eugenol was extracted by hydrodistillation in each of the four seasons of the year. Activity upon CNS was evaluated in the open-field and rota-rod tests; sleeping time induced by sodium pentobarbital (PBS, 40 mg/kg, intraperitoneally, i.p.) and anticonvulsant activity against seizures induced by both pentylenetetrazole (PTZ; 85 mg/kg, s.c.) and maximal electroshock (MES, 50 mA, 0.11 s) were determined. Essential oils obtained in each season were effective in increasing the sleeping duration and a preparation obtained in Spring was able to protect animals against tonic seizures induced by electroshock. In each season, eugenol and 1,8-cineole were the most abundant compounds, and in Spring the essential oil presented the greatest relative percentage of sesquiterpenes, suggesting that these compounds could explain the differences observed in the biological activity in essential oils obtained in different seasons of the year. (c) 2005 Elsevier B.V.. All rights reserved.

Histopathological, immunohistochemical, and molecular study of BHV-5 infection in the central nervous system of experimentally infected calves

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Innovative analytical methods for Central Nervous System Drug analysis in biological fluids

During recent years a consistent number of central nervous system (CNS) drugs have been approved and introduced on the market for the treatment of many psychiatric and neurological disorders, including psychosis, depression, Parkinson disease and epilepsy. Despite the great advancements obtained in the treatment of CNS diseases/disorders, partial response to therapy or treatment failure are frequent, at least in part due to poor compliance, but also genetic variability in the metabolism of psychotropic agents or polypharmacy, which may lead to sub-therapeutic or toxic plasma levels of the drugs, and finally inefficacy of the treatment or adverse/toxic effects. With the aim of improving the treatment, reducing toxic/side effects and patient hospitalisation, Therapeutic Drug Monitoring (TDM) is certainly useful, allowing for a personalisation of the therapy. Reliable analytical methods are required to determine the plasma levels of psychotropic drugs, which are often present at low concentrations (tens or hundreds of nanograms per millilitre). The present PhD Thesis has focused on the development of analytical methods for the determination of CNS drugs in biological fluids, including antidepressants (sertraline and duloxetine), antipsychotics (aripiprazole), antiepileptics (vigabatrin and topiramate) and antiparkinsons (pramipexole). Innovative methods based on liquid chromatography or capillary electrophoresis coupled to diode-array or laser-induced fluorescence detectors have been developed, together with the suitable sample pre-treatment for interference removal and fluorescent labelling in case of LIF detection. All methods have been validated according to official guidelines and applied to the analysis of real samples obtained from patients, resulting suitable for the TDM of psychotropic drugs.

Regulation of immune cell entry into the central nervous system

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS to not disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses can be mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly controlling immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier, which protect the CNS from the constantly changing milieu within the bloodstream, also strictly control immune cell entry into the CNS. Under physiological conditions, immune cell migration into the CNS is kept at a very low level. In contrast, during a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis, immunocompetent cells readily traverse the BBB and likely also the choroid plexus and subsequently enter the CNS parenchyma or CSF spaces. This chapter summarizes our current knowledge of immune cell entry across the blood CNS barriers. A large body of the currently available information on immune cell entry into the CNS has been derived from studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Therefore, most of this chapter discussing immune cell entry during CNS pathogenesis refers to observations in the EAE model, allowing for the possibility that other mechanisms of immune cell entry into the CNS might apply under different pathological conditions such as bacterial meningitis or stroke.

Experimental pneumococcal meningitis causes central nervous system pathology without inducing the 72-kd heat shock protein

We examined whether experimental pneumococcal meningitis induced the 72-kd heat shock protein (HSP72), a sensitive marker of neuronal stress in other models of central nervous system (CNS) injury. Brain injury was characterized by vasculitis, cerebritis, and abscess formation in the cortex of infected animals. The extent of these changes correlated with the size of the inoculum (P less than 0.003) and with pathophysiologic parameters of disease severity, i.e., cerebrospinal fluid (CSF) lactate (r = 0.61, P less than 0.0001) and CSF glucose concentrations (r = -0.55, P less than 0.0001). Despite the presence of numerous cortical regions having morphologic evidence of injury, HSP72 was not detected in most animals. When present, only rare neurons were HSP72 positive. Western blot analysis of brain samples confirmed the paucity of HSP72 induction. The lack of neuronal HSP72 expression in this model suggests that at least some of the events leading to neuronal injury in meningitis are unique, when compared with CNS diseases associated with HSP72 induction.

Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

Juvenile onset central nervous system folate deficiency and rheumatoid arthritis.

Isolated cerebral folate deficiency was detected in a 13-year-old girl with cognitive and motor difficulties and juvenile rheumatoid arthritis. Her serum contains autoantibodies that block membrane-bound folate receptors that are on the choroid plexus and diminish the uptake of folate into the spinal fluid. Whereas her serum folate exceeded 21 ng/mL, her spinal fluid contained 3.2 ng/mL of 5-methyltetrahydrofolate as a consequence of the autoantibodies diminishing the uptake of this folate.

Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke

Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood-brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T-cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro inflammation: A common denominator for stroke, multiple sclerosis and Alzheimer's disease, guest edited by Helga de Vries and Markus Swaninger.

Viral Escape in the Central Nervous System with Multidrug-Resistant Human Immunodeficiency Virus-1

In this study, we report the case of a patient infected with human immunodeficiency virus (HIV)-1 who developed ataxia and neurocognitive impairment due to viral escape within the central nervous system (CNS) with a multidrug-resistant HIV-1 despite long-term viral suppression in plasma. Antiretroviral therapy optimization with drugs with high CNS penetration led to viral suppression in the CSF, regression of ataxia, and improvement of neurocognitive symptoms.

Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results.