Signaling via NF-kappaB in the nervous system

Nuclear factor kappa B (NF-kappaB) is an inducible transcription factor present in neurons and glia. Recent genetic models identified a role for NF-kappaB in neuroprotection against various neurotoxins. Furthermore, genetic evidence for a role in learning and memory is now emerging. This review highlights our current understanding of neuronal NF-kappaB in response to synaptic transmission and summarizes potential physiological functions of NF-kappaB in the nervous system. This article contains a listing of NF-kappaB activators and inhibitors in the nervous system, furthermore specific target genes are discussed. Synaptic NF-kappaB activated by glutamate and Ca2+ will be presented in the context of retrograde signaling. A controversial role of NF-kappaB in neurodegenerative diseases will be discussed. A model is proposed explaining this paradox as deregulated physiological NF-kappaB activity, where novel results are integrated, showing that p65 could be turned from an activator to a repressor of anti-apoptotic genes.

Effects of Ischemia and Reperfusion on P2X(2) Receptor Expressing Neurons of the Rat Ileum Enteric Nervous System

Purpose We investigated the effects of ischemia/reperfusion in the intestine (I/R-i) on purine receptor P2X(2)-immunoreactive (IR) neurons of the rat ileum. Methods The superior mesenteric artery was occluded for 45 min with an atraumatic vascular clamp and animals were sacrificed 4 h later. Neurons of the myenteric and submucosal plexuses were evaluated for immunoreactivity against the P2X(2) receptor, nitric oxide synthase (NOS), choline acetyl transferase (ChAT), calbindin, and calretinin. Results Following I/R-i, we observed a decrease in P2X(2) receptor immunoreactivity in the cytoplasm and surface membranes of neurons of the myenteric and submucosal plexuses. These studies also revealed an absence of calbindin-positive neurons in the I/R-i group. In addition, the colocalization of the P2X(2) receptor with NOS, ChAT, and calretinin immunoreactivity in the myenteric plexus was decreased following I/R-i. Likewise, the colocalization between P2X(2) and calretinin in neurons of the submucosal plexus was also reduced. In the I/R-i group, there was a 55.8% decrease in the density of neurons immunoreactive (IR) for the P2X(2) receptor, a 26.4% reduction in NOS-IR neuron, a 25% reduction in ChAT-IR neuron, and a 47% reduction in calretinin-IR neuron. The density of P2X(2) receptor and calretinin-IR neurons also decreased in the submucosal plexus of the I/R-i group. In the myenteric plexus, P2X(2)-IR, NOS-IR, ChAT-IR and calretinin-IR neurons were reduced in size by 50%, 49.7%, 42%, and 33%, respectively, in the I/R-i group; in the submucosal plexus, P2X(2)-IR and calretinin-IR neurons were reduced in size by 56% and 72.6%, respectively. Conclusions These data demonstrate that ischemia/reperfusion of the intestine affects the expression of the P2X(2) receptor in neurons of the myenteric and submucosal plexus, as well as density and size of neurons in this population. Our findings indicate that I/R-i induces changes in P2X(2)-IR enteric neurons that could result in alterations in intestinal motility.

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)

Can geometric indices of heart rate variability predict improvement in autonomic modulation after resistance training in chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is associated with autonomic dysfunctions that can be evaluated through heart rate variability (HRV). Resistance training promotes improvement in autonomic modulation; however, studies that evaluate this scenario using geometric indices, which include nonlinear evaluation, thus providing more accurate information for physiological interpretation of HRV, are unknown. This study aimed to investigate the influence of resistance training on autonomic modulation, using geometric indices of HRV, and peripheral muscle strength in individuals with COPD. Fourteen volunteers with COPD were submitted to resistance training consisting of 24 sessions lasting 60 min each, with a frequency of three times a week. The intensity was determined as 60% of one maximum repetition and was progressively increased until 80% for the upper and lower limbs. The HRV and dynamometry were performed at two moments, the beginning and the end of the experimental protocol. Significant increases were observed in the RRtri (4·81 ± 1·60 versus 6·55 ± 2·69, P = 0·033), TINN (65·36 ± 35·49 versus 101·07 ± 63·34, P = 0·028), SD1 (7·48 ± 3·17 versus 11·04 ± 6·45, P = 0·038) and SD2 (22·30 ± 8·56 versus 32·92 ± 18·78, P = 0·022) indices after the resistance training. Visual analysis of the Poincare plot demonstrated greater dispersion beat-to-beat and in the long-term interval between consecutive heart beats. Regarding muscle strength, there was a significant increase in the shoulder abduction and knee flexion. In conclusion, geometric indices of HRV can predict improvement in autonomic modulation after resistance training in individuals with COPD; improvement in peripheral muscle strength in patients with COPD was also observed.

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.

Spinal cord injury: assessment of autonomic state-dependent control of cardiovascular system and body core temperature

Spinal cord injury (SCI) results not only in paralysis; but it is also associated with a range of autonomic dysregulation that can interfere with cardiovascular, bladder, bowel, temperature, and sexual function. The entity of the autonomic dysfunction is related to the level and severity of injury to descending autonomic (sympathetic) pathways. For many years there was limited awareness of these issues and the attention given to them by the scientific and medical community was scarce. Yet, even if a new system to document the impact of SCI on autonomic function has recently been proposed, the current standard of assessment of SCI (American Spinal Injury Association (ASIA) examination) evaluates motor and sensory pathways, but not severity of injury to autonomic pathways. Beside the severe impact on quality of life, autonomic dysfunction in persons with SCI is associated with increased risk of cardiovascular disease and mortality. Therefore, obtaining information regarding autonomic function in persons with SCI is pivotal and clinical examinations and laboratory evaluations to detect the presence of autonomic dysfunction and quantitate its severity are mandatory. Furthermore, previous studies demonstrated that there is an intimate relationship between the autonomic nervous system and sleep from anatomical, physiological, and neurochemical points of view. Although, even if previous epidemiological studies demonstrated that sleep problems are common in spinal cord injury (SCI), so far only limited polysomnographic (PSG) data are available. Finally, until now, circadian and state dependent autonomic regulation of blood pressure (BP), heart rate (HR) and body core temperature (BcT) were never assessed in SCI patients. Aim of the current study was to establish the association between the autonomic control of the cardiovascular function and thermoregulation, sleep parameters and increased cardiovascular risk in SCI patients.

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.

The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep

STUDY OBJECTIVES: Periodic leg movements in sleep (PLMS) are frequently accompanied by arousals and autonomic activation, but the pathophysiologic significance of these manifestations is unclear. DESIGN: Changes in heart rate variability (HRV), HRV spectra, and electroencephalogram (EEG) spectra associated with idiopathic PLMS were compared with changes associated with isolated leg movements and respiratory-related leg movements during sleep. Furthermore, correlations between electromyographic activity, HRV changes, and EEG changes were assessed. SETTING: Sleep laboratory. PATIENTS: Whole-night polysomnographic studies of 24 subjects fulfilling the criteria of either periodic leg movements disorder (n = 8), obstructive sleep apnea syndrome (n = 7), or normal polysomnography (n = 9) were used. MEASUREMENTS AND RESULTS: Spectral HRV changes started before all EEG changes and up to 6 seconds before the onset of all types of leg movements. An initial weak autonomic activation was followed by a sympathetic activation, an increase of EEG delta activity, and finally a progression to increased higher-frequency EEG rhythms. After movement onset, HRV indicated a vagal activation, and, the EEG, a decrease in spindle activity. Sympathetic activation, as measured by HRV spectra, was greater for PLMS than for all other movement types. In EEG, gamma synchronization began 1 to 2 seconds earlier for isolated leg movements and respiratory-related leg movements than for PLMS. Significant correlations were found between autonomic activations and electromyographic activity, as well as between autonomic activations and EEG delta activity, but not between higher-frequency EEG rhythms and EMG activity or HRV changes. CONCLUSIONS: These results suggest a primary role of the sympathetic nervous system in the generation of PLMS.

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.