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PubMed1999

Effects of antihypertensive therapies on the sympathetic nervous system.

The sympathetic nervous system is a major modulator of cardiovascular function. Over the past three decades, numerous studies, using various methodologies, have reported the existence of a variety of pre- and postsynaptic sympathetic dysfunctions in essential hypertension. Most of these abnormalities facilitate sympathetic neurotransmission, resulting in a chronic increase in the sympathetic tone and reactivity in a significant proportion of hypertensive patients. Chronic sympathetic activation is also associated with major alterations in the balance among postsynaptic adrenergic receptors in cardiovascular tissues. Indeed, an attenuation of beta-adrenergic function and a potentiation of alpha1-adrenergic function has been demonstrated in cardiovascular tissues in hypertensive patients, suggesting the development of a sympathetic postsynaptic alpha1 dominance during the development and evolution of hypertension. Chronic activation of the sympathetic system is deleterious and could contribute to the development of most cardiovascular complications associated with hypertension. One of the major aims of antihypertensive therapy should thus be to attenuate pre- or postsynaptic sympathetic tone. Most antihypertensive drugs have been found to improve either pre- or postsynaptic sympathetic function in hypertensive patients. At the presynaptic level, diuretics were found to increase the liberation of noradrenalin, presumably through baroreflex sympathetic activation. In contrast, beta-blockers were shown to attenuate noradrenalin release from sympathetic nerves by blocking presynaptic facilitatory beta-receptors, thus reducing the sympathetic tone on postsynaptic receptors. Similarly, angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor antagonists have been found to reduce sympathetic reactivity by acting on the central nervous system, but also by blocking AT1-mediated facilitatory mechanisms located on sympathetic fibres and in the adrenal medulla. Short acting dihydropyridine calcium channel blockers (CCBs) were found to enhance noradrenalin release from sympathetic nerves, but longer acting CCBs seems to have variable effects. Indeed, while the chronic slow release formulation of nifedipine gastrointestinal therapeutic system (GITS) did not raise circulating noradrenalin levels, treatment with amlodipine increased circulating noradrenalin levels, suggesting that nifedipine GITS is neutral on the sympathetic tone but that amlodipine chronically activates the sympathetic system. At the postsynaptic level, however, dihydropyridine CCBs were shown to attenuate the sympathetic tone on alpha1-adrenoceptors. In conclusion, it appears that most antihypertensive drugs interfere with pre- or postsynaptic sympathetic mechanisms and that these mechanisms could contribute to their hypotensive effects.

Adrenergic Antagonists↗
PubMed2003

Differentiation of neurospheres from the enteric nervous system.

The enteric nervous system (ENS) derives from neural crest cells, which migrate from the neural tube into the developing gut. The neuronal and glial precursor cells migrate mainly from the oral towards the anal end of the gastrointestinal tract. So far, knowledge about the multipotent influences upon the ENS development, especially its neurotrophic support, derives mainly from knock-out models. The in vitro technique of isolating enteric neuronal precursor cells allows to study the effects of various factors upon their appropriate development in more detail. We therefore adapted the method of growing neurospheres, which are agglomerates of neuronal precursor cells and differentiated neurones and glial cells, from the central nervous system (CNS) for the ENS. The gut of NMRI mice at E12 were dissected, mildly dissociated and plated in 25-cm(2) culture flasks. The cultures were maintained in N1 supplemented DMEM/F12 medium with the appropriate neurotrophin cocktails (bFGF, GDNF, Neurturin, CNTF). After several days in culture most of the cells die, while the surviving cells form clusters from which domes, and later spheres arise. The spheres could be harvested and processed for further experiments. First investigations revealed, that the amount of precursor cells was much less in enteric neurospheres as seen in corresponding cultures from the CNS. We found about 43% HNK-1-NCAM+ in enteric and approximately 90% Nestin-+ cells in midbrain neurospheres. Differentiation studies of the enteric neurospheres showed that especially ciliary neurotrophic factor (CNTF) increased the number of enteric neurones (PGP positive), while the amount of HNK-1 precursor cells decreased under the influence of all tested neurotrophins but GDNF. The culture of the freshly dissociated enteric neurospheres in a three-dimensional matrix yielded a secondary network which allows to investigate the pattern formation of the ENS. The generation of enteric neurospheres and the following differentiation and 3D culture in vitro can increase our knowledge of the amount and time point of neurotrophic as well as the ECM-protein influence upon the appropriate development of the ENS.

Animals↗
PubMed1993

Essential organization of the sympathetic nervous system.

The sympathetic nervous system consists of efferent neurones supplying the viscera. The cell bodies of preganglionic neurones are located in four areas in the thoracolumbar cord; however, the majority are found in the IML. Various tracing techniques have provided information concerning the location of the cell bodies of sympathetic preganglionic neurones projecting into various nerves and ganglia and regulating the adrenal gland, the kidney and the sympathetic supply to skeletal muscle. Numerous supraspinal neurones project to the neuropil surrounding sympathetic preganglionic neurones and may form synaptic contacts with these neurones. The areas of the brain that project to the IML appear to be part of a network of reciprocally connected supraspinal cell groups. Although much emphasis has been placed on the importance of the RVLM in the mediation of tonic and phasic inputs to sympathetic preganglionic neurones, it appears that other areas are of significant import; the RVLM should not be considered to be 'the vasomotor centre'. Spinal and cranial afferents influence the sympathetic nervous system. Baroreceptor afferents terminate in the NTS and may utilize an excitatory amino acid as their neurotransmitter. However, a number of neuropeptides are also associated with these afferents. Neurones within the NTS project to a number of brain stem areas thought to be involved in the regulation of sympathetic activity; consequently the baroreceptor reflex may be mediated over a number of parallel pathways involving both supraspinal and spinal sites of inhibition. Many neurotransmitters are thought to regulate the activity of sympathetic preganglionic neurons: monoamines, peptides and amino acids. Matching the chemical content of the cell bodies of neurones within a particular cell group with physiological characteristics is a challenging task; some barosensitive neurones of the RVLM do not appear to be adrenergic although they are in the midst of the C1 adrenergic cell group. Besides acetylcholine and noradrenaline, neurotransmission in the periphery appears to involve numerous peptides and ATP.

Animals↗
PubMed2003

Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration.

OBJECTIVE: HIV-1 encephalopathy (HIVE) is associated with high levels of viral RNA in the central nervous system (CNS). Highly active antiretroviral therapy (HAART) effectively reduces HIV replication in both plasma and cerebrospinal fluid (CSF). Some individuals, however, exhibit delayed CSF HIV RNA suppression in the presence of rapid plasma responses. We investigated the reasons for this discrepancy. DESIGN: CSF and plasma were collected prospectively in paired samples before and once or several times during HAART in 40 HIV-positive subjects. Ten had HIVE and 30 patients were neurologically asymptomatic or had non-HIVE neurological manifestations. METHODS: The slopes of viral RNA decay during HAART were compared between the compartments. The presence of HIVE was defined by clinical standards and its severity categorized according to the Memorial Sloan Kettering score. CSF and plasma levels of antiretroviral drugs were measured. Viral drug resistance during HAART in CSF and plasma was analysed both genotypically and phenotypically. RESULTS: Slow CSF viral decay and a high degree of compartmental discordance (slopeCSF/slopeplasma) were both significantly correlated with HIVE (P < 0.00002). There was no correlation of a rapid CSF response with Centers for Disease Control and Prevention stage, CD4 cell count, or with the number of antiretroviral compounds and their known CSF penetration. Slow CSF viral decay was associated with neither low levels of antiretroviral drugs in the CSF or plasma, nor with viral drug resistance. CONCLUSIONS: None of the treatment-associated variables, but only the presence of HIVE, was associated with delayed virus elimination during HAART in the CSF. This suggests a distinct pattern of viral replication in the CNS in HIVE.

AIDS Dementia Complex↗
PubMed2026

Targeting Gasdermins for Therapeutic Interventions in Central Nervous System Injury.

Central nervous system (CNS) injuries are the leading cause of permanent disability and premature death in adults worldwide, with their incidence continuing to rise amid social development. These injuries not only severely impair the quality of life but also impose a heavy burden on the global public health system. Current clinical interventions, such as decompression and thrombolysis, can alleviate primary injury but fail to effectively reverse the secondary neuroinflammatory damage. Traditional anti-inflammatory therapies, which cannot block the upstream source of the inflammatory cascade, have led to repeated failures in global clinical translation research over the past decades. Gasdermins were first characterized in studies of systemic inflammatory diseases. These proteins form transmembrane pores to drive the release of proinflammatory factors and inflammatory cell death, serving as key mediators of host innate immunity. Recent studies have revealed that gasdermins play critical roles in regulating the initiation and amplification of neuroinflammation following CNS injury. To clarify the therapeutic potential of gasdermins as targets for injury repair, this review systematically summarizes the structure and function of gasdermins, as well as their cell-specific activation and regulatory mechanisms. We further elaborate on their pathological roles in these injuries and the corresponding therapeutic strategies, aiming to provide a theoretical reference for basic research and clinical translation in this field.

Humans↗
PubMed2001

The role of the nervous system in hypertension.

The central nervous system plays an important role in the minute-to-minute regulation of arterial pressure, but its contribution to chronic regulation of arterial pressure is less clear. A nervous system role in essential hypertension in humans has been postulated for decades, but conclusive data on the relationship has been lacking. However, several lines of evidence in animal models and in humans suggest that the sympathetic nervous system is a primary contributor to the development and maintenance of some forms of essential hypertension. The primary final common pathway for the nervous system's contribution to hypertension is the sympathetic nervous system. Sympathetic nervous system overactivity may result from either inappropriately elevated sympathetic drive from brain centers, an increase in synaptically released neurotransmitters in the periphery, or amplification of the neurotransmitter signal at the target tissue. This review examines recent evidence for the central and peripheral nervous systems' roles in hypertension, and considers recent findings in this area that suggest that sex steroids and circadian rhythms are important considerations in the nervous system's regulation of arterial pressure.

Animals↗
PubMed1991

[The transition zone of the central nervous system-peripheral nervous system of the adult rat; ultrastructural and immunocytochemical studies: a new function of the astroglia?].

At the transition between central nervous system (CNS) and peripheral nervous system (PNS), the CNS compartment forms cone-shaped incursions into the peripheral part of the dorsal root. The ultrastructural study of the CNS-PNS transitional zone shows that this region is particularly rich in astrocyte processes. In an attempt to investigate the possible role of the CNS-PNS interface astrocytes in myelin formation, a photonic microscopy immunocytochemical study has been done with anti-GFAP and anti-MBP sera. The CNS glial expansion shows an important GFAP immunoreactivity with intimate association between astrocyte processes and myelinated axons. This may indicate that the transitional myelin originates from astrocytes. The same region is also MBP-positive. Two explanations are considered: some astrocytes form transitional myelin sheathes and express MBP epitopes, or oligodendrocytes, with cell bodies distant from the CNS-PNS interface, send myelinating cytoplasmic expansions which are not shown by the techniques we used.

Animals↗
PubMed2001

Primary nervous-system lymphoma.

Primary nervous-system lymphoma is a rare type of non-Hodgkin lymphoma, which is confined to the nervous system. This disease is managed quite differently from the usual treatment of either primary brain tumours or systemic non-Hodgkin lymphoma. Although whole-brain radiotherapy results in responses in more than 90% of cases, this treatment is associated with high relapse rates and with delayed neurotoxicity in elderly patients. First-generation chemotherapy regimens used successfully in systemic non-Hodgkin lymphoma (eg cyclo-phosphamide, adriamycin, vincristine, and prednisone) are ineffective in primary nervous-system lymphoma, partly because of the blood-brain barrier. Median survival of patients treated with radiotherapy alone or chemotherapy plus radiotherapy is similar, and ranges from 10 to 16 months. The addition of methotrexate-based chemotherapy has improved survival for these patients, extending median survival to more than 30 months. When used alone, methotrexate-based chemotherapy is associated with significantly fewer treatment-associated toxic effects. Leptomeningeal lymphoma and intraocular lymphoma are topics of particular relevance in primary nervous-system lymphoma and are addressed in this review.

Age Factors↗
PubMed2003

Anteroposterior patterning in hemichordates and the origins of the chordate nervous system.

The chordate central nervous system has been hypothesized to originate from either a dorsal centralized, or a ventral centralized, or a noncentralized nervous system of a deuterostome ancestor. In an effort to resolve these issues, we examined the hemichordate Saccoglossus kowalevskii and studied the expression of orthologs of genes that are involved in patterning the chordate central nervous system. All 22 orthologs studied are expressed in the ectoderm in an anteroposterior arrangement nearly identical to that found in chordates. Domain topography is conserved between hemichordates and chordates despite the fact that hemichordates have a diffuse nerve net, whereas chordates have a centralized system. We propose that the deuterostome ancestor may have had a diffuse nervous system, which was later centralized during the evolution of the chordate lineage.

Animals↗
PubMed2004

Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement.

Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.

Adolescent↗
PubMed2001

Receptor-mediated interaction between the sympathetic nervous system and immune system in inflammation.

The sympathetic nervous system plays a central role in establishing communication between the central nervous system and the immune system during inflammation. Inflammation activates the sympathetic nervous system, which causes release of the transmitters of the sympathetic nervous system in the periphery. The transmitters of the sympathetic nervous system are the catecholamines noradrenaline and adrenaline and the purines ATP, adenosine, and inosine. Once these transmitters are released, they stimulate both presynaptic receptors on nerve terminals and post-synaptic receptors on immune cells. The receptors that are sensitive to catecholamines are termed adrenoceptors, whereas the receptors that bind purines are called purinoceptors. Stimulation of the presynaptic receptors exerts an autoregulatory effect on the release of transmitters. Ligation of the postsynaptic receptors on inflammatory cells modulates the inflammatory activities of these cells. The present review summarizes some of the most important aspects of the current state of knowledge about the interactions between the sympathetic nervous system and the immune system during inflammation with a special emphasis on the role of adreno and purinoceptors.

Animals↗
PubMed1995

Cerebrospinal fluid analysis in systemically ill children without central nervous system disease.

OBJECTIVE: Experience led us to question the applicability of standards for normal cerebrospinal fluid (CSF), originally developed in healthy children, to children with systemic illness but without central nervous system (CNS) infection. The purpose of this study was to test our hypothesis that systemically ill children, in the absence of CNS infection, have an elevated CSF white blood cell count and a greater percentage of neutrophils than accepted norms. METHODS: We enrolled 345 patients in the following diagnostic categories: infants 1 month of age or younger with possible sepsis (n = 95), patients older than 1 month of age with possible sepsis (n = 155), patients with a focus of infection in close proximity to the CNS (n = 51), and patients presenting with seizures and fevers (n = 45). Sociodemographic data and results of CSF examination were abstracted from the medical records. Statistical analysis systems were used for data processing. RESULTS: The CSF white blood cell count did not significantly differ from standards except for a lower mean count in the group presenting with seizures. The percent of CSF neutrophils was significantly greater than standards, however, for those patients older than 1 month of age with possible sepsis, those with a focus of infection in close proximity to the CNS, and those presenting with seizures. Data analysis by quantiles shows only 25% to 50% of patients, in each of the diagnostic categories, meeting the current definition of normal CSF neutrophil count. CONCLUSIONS: Our results show that a mean of at least 5% neutrophils may be present in the CSF with a diagnosis of fever without a source, a focus of infection in close proximity to the CNS, or a seizure with fever in the absence of CNS infection. These data support tailoring treatment based on clinical assessment rather than what is considered an abnormal CSF neutrophil count by current standards.

Central Nervous System Diseases↗
PubMed2003

Role of semaphorins in the adult nervous system.

In the developing nervous system, extending axons are directed towards their appropriate targets by a myriad of attractive and repulsive guidance cues. Work in the past decade has significantly advanced our understanding of these molecules and has made it increasingly clear that their function is not limited to the guidance of growing axons during embryogenesis. Axon guidance cues fulfill additional roles in angiogenesis, cell migration and the immune system, and often display sustained expression in adulthood. Here we focus on the semaphorin (Sema) family and review their proposed functions in the adult nervous system. Several semaphorin family members continue to be expressed in the adult brain and spinal cord, and increasing evidence indicates that their expression is regulated upon nervous system injury in rodents and in neuropathology in humans. The available evidence suggests that semaphorins might significantly contribute to the maintenance and stability of neuronal networks. Furthermore, semaphorins could play important roles in the regeneration, or failure thereof, of neuronal connections. In the future, genetic manipulation of semaphorins and their receptors in the adult intact and injured nervous system should provide a deeper insight into the mechanisms by which semaphorin signaling contributes to structural plasticity and regeneration in the adult brain.

Animals↗
PubMed1990

Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement.

Paired serum and cerebrospinal fluid (CSF) specimens from 14 patients with systemic lupus erythematosus (SLE) and central nervous system (CNS) involvement were studied for interleukin-6 (IL-6) activity using the IL-6-dependent murine hybridoma, MH60.BSF2. We also studied 23 patients with noninflammatory neurologic diseases, and 9 SLE patients without CNS involvement. CSF IL-6 activity was elevated only in SLE patients with CNS involvement, although there was no significant difference in serum IL-6 activity among the 3 groups. CSF IL-6 activity was not correlated with either the CSF-serum albumin quotient (Q albumin; an indicator of blood-brain barrier function) or serum IL-6 activity in SLE patients with CNS involvement. The CSF IL-6 activity decreased significantly when CNS manifestations subsided after successful treatment. These results indicate that determination of CSF IL-6 activity may be useful in the evaluation of CNS disease activity in SLE. Moreover, the data confirm the presence of immune system activation within the CNS in patients with SLE-associated CNS disease.

Antibodies, Monoclonal↗