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Does the immune system communicate with the central nervous system? Interferon modifies central nervous activity.

The present investigation determined whether an immunomodulator agent modified the central nervous system activity as measured behaviorally and neurophysiologically. Two types of interferons (IFNs), alpha (alpha) and gamma (gamma), were applied locally (microiontophoretically) into various regions of the rat brain simultaneously with single neuron recording from the cerebral cortex, hippocampus, thalamus and hypothalamus. Of the various IFNs, only alpha-IFN altered single cell activity in all brain structures in a dose-dependent manner. Moreover, systemic administration of alpha-IFN altered the naloxone-induced abstinence syndrome in morphine-dependent rats. These observations suggest that immunomodulators such as alpha-IFN are capable of influencing directly central nervous system function as well as the immune system.

Animals↗

Functional organization of cotransmission systems: lessons from small nervous systems.

Small invertebrate nervous systems allow one to ask a series of questions concerning the functional roles of cotransmitters. This review outlines some of the implications of cotransmission for target selectivity in complex neuropils. We suggest the possibility that a unique constellation of cotransmitters in individual identified modulatory neurons allows a specificity of action even when peptides may act over an extended distance, and when individual modulatory substances may be released from several modulatory neurons.

Animals↗

Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction.

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoelectric focusing using immunoperoxidase staining techniques to detect oligoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid oligoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-interferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean +/- SD = 5.3 +/- 2.4), but was significantly elevated (mean +/- SD = 27.4 +/- 18.8, p less than 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myelopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.

Albumins↗

Cytopathology of the central nervous system. Part I. Utility of crush smear cytology in intraoperative diagnosis of central nervous system lesions.

OBJECTIVE: To evaluate the utility of rapid intraoperative crush smear cytologic diagnosis of central and peripheral nervous system lesions and to determine the accuracy and relevance of the accuracy of the intraoperative cytologic diagnosis when compared to the final paraffin section diagnosis. STUDY DESIGN: The crush (squash) smear technique was introduced at Sher-i-Kashmir Institute of Medical Sciences in May 2003. The 8 months of 2003 were used for standardization of the procedure. In 2004, 151 patients with open neurosurgical specimens or stereotactic biopsies were diagnosed intraoperatively by crush smears, and the diagnosis was compared with final diagnosis on paraffin sections of the same tissue samples. No supplementation of frozen sections was used. RESULTS: Of 151 cases, 144 were diagnosed accurately intraoperatively by crush smear cytology when compared with the respective paraffin section diagnoses. The diagnostic accuracy attained was 95.36%. Each case was diagnosed within 10 minutes after receipt of sample. Neurosurgical procedure (open or stereotaxy) did not affect diagnostic accuracy. CONCLUSION: In the expert hands of a pathologist with good exposure neurosurgical specimens, crush smear cytology is an accura and reliable procedure for the intraoperative diagnosis central nervous system tumors.

Adolescent↗

The effects of captopril on the renin-angiotensin system and the sympathetic nervous system during sodium nitroprusside-induced hypotension in the halothane-anesthetized rabbit.

Three groups of New Zealand white rabbits were used to study the effects of captopril on the renin-angiotensin system and sympathetic nervous system during sodium nitroprusside (SNP)-induced hypotension and halothane anesthesia. Two groups of rabbits (C and CH) were treated with captopril 2 mg/kg i.v. One captopril-treated group (CH) and the third, untreated group (H) received SNP to induce hypotension. In these two groups, the mean arterial blood pressure (MAP) was reduced by 40% for 150 min. Group C did not undergo SNP-induced hypotension and served to document the effects of captopril alone during the 150-min study period. Arterial blood samples for norepinephrine (NE), epinephrine (EPI), and plasma renin activity (PRA) were drawn prior to, during hypotension, and in the recovery period. The SNP dose required to maintain the hypotension was continuously recorded. NE, EPI, and PRA all increased in group H, indicating activation of both the renin-angiotensin system and the sympathetic system during hypotension. This was accompanied by a dramatic increase in SNP dose requirement. In the CH group, PRA levels rose sharply and remained elevated. Plasma NE levels increased, while EPI levels remained unchanged with a decline in the SNP dose requirement. The C group demonstrated a rise in PRA levels, accompanied by unchanged NE and EPI levels and MAP during the study period. Captopril administration decreased the SNP dose requirement and significantly decreased the sympathetic response (measured by NE and EPI levels) in group CH as compared to the H group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.

Adrenocorticotropic Hormone↗

Constant topological organization of the coleopteran metamorphosing nervous system: analysis of persistent elements in the nervous system of Tenebrio molitor.

Evidence is provided that the topological organization of the larval neuropil is preserved during metamorphosis of Tenebrio molitor. Constancies in neuronal organization were due in part to persistence of individual neurons whose morphologies were individually followed. It appears that the phenomenologically static situation of the metamorphosing neuropil is achieved by stabilization and regulation due to cellular interactions. Comparisons are made with features of hemimetabolan postembryogenesis.

Animals↗

Endopeptidase-24.11, a cell-surface peptidase of central nervous system neurons, is expressed by Schwann cells in the pig peripheral nervous system.

Endopeptidase-24.11 is a 90-kDa surface glycoprotein with the ability to hydrolyze a variety of biologically active peptides. Interest in this enzyme is based on the consensus that it may play a role in the termination of peptide signals in the central nervous system. In the present study, we have investigated the distribution of endopeptidase-24.11 in two nerves of the peripheral nervous system of newborn pigs: the sciatic, composed of a mixture of myelinated and nonmyelinated axons, and cervical sympathetic trunk in which greater than 99% of the axons are nonmyelinated. The endopeptidase was monitored enzymatically, as well as by immunoblotting and immunocytochemistry using mono- and polyclonal anti-endopeptidase antibodies. Endopeptidase-24.11 was detected in both the sciatic nerve and the cervical sympathetic trunk. Membrane preparations from sciatic nerve hydrolyzed 125I-insulin B-chain, and more than 50% of the activity was inhibited by phosphoramidon with an IC50 concentration of 3.2 nM. Moreover, a 90-kDa polypeptide was detected by immunoblotting of sciatic nerve membranes. The type of cells expressing the endopeptidase was determined by immunohistochemistry. In teased nerve preparations, these cells were identified morphologically as myelin- and non-myelin-forming Schwann cells. Endopeptidase-24.11 was also expressed by cultured Schwann cells from sciatic nerve and cervical sympathetic trunk maintained for 3 h in vitro. The presence of endopeptidase-24.11 on the Schwann cell surface raises the possibility of a potential role for the enzyme in nerve development and/or regeneration.

Animals↗

Drug delivery to the central nervous system: general principles and relevance to therapy for infections of the central nervous system.

Drug delivery to the central nervous system (CNS) is of vital concern to the therapy for primary CNS disorders and the development of drug neurotoxicity. The factors influencing drug entry into the CSF include the status of the blood-brain barrier (BBB) and lipid solubility, molecular weight, pKa, protein binding, and removal of the drug from the CSF by an exit pump in the choroid plexus. The most important of these factors is the status of the complex BBB systems. The morphologic equivalent of the BBB and its specialized functions (e.g., transport of D-glucose, amino acids, and ions) are discussed in depth. Methods developed for increasing drug delivery to the CNS by circumvention and/or manipulation of the BBB have included direct injection into the CSF, administration of prodrugs or chemical delivery systems, or reversible "opening" of the BBB by hyperosmotic agents, pentylenetetrazole, etoposide, DMSO, or other agents. The relevance of these general principles to selected examples of CNS infections (i.e., gram-negative aerobic bacillary meningitis and subacute encephalopathy associated with AIDS) is emphasized.

Anti-Infective Agents↗

The mast cells of the mammalian central nervous system. VI. Uptake of tritiated thymidine by mast cells, neurolipomastocytoid cells and other elements of the central nervous system.

The central nervous system (CNS) of two mammalian species was studied autoradiographically using tritium-labeled thymidine; the rat, whose brain contains few localized mast cells (MCs) but many ubiquitous neurolipomastocytoid cells (NLMs), and the guinea pig, whose brain contains only ubiquitous NLMs. A few guinea pigs were also injected with an MC discharger compound 48/80 and the response of the NLMs, which are thought to be allied to MCs, as well as of neuroglial and vascular endothelial cells, was noted. The rats were 3 days to 6 weeks old whereas all the guinea pigs were young adults. Both MCs and NLMs took up the label, and much more so in the babies, paralleling similar uptakes in only very small immature MCs outside the CNS. Neuroglial elements, especially subependymal and oligodendroglial, as well as endothelial, perivascular, leptomeningeal and ependymal cells demonstrated some uptake. This was considerably increased upon receipt of compound 48/80, especially in the case of the subependymal glia, the NLMs and the endothelial cells; capillary neoformations were seen in the spinal cords of guinea pigs that had shown signs of paralysis. The cause of this increase is discussed in terms of mild stress induced by that compound. The subependymal response is also discussed with reference to periventricular plaques seen in multiple sclerosis and lymphoreticular and glial tumors seen in that region. It is concluded that both MCs and NLMs are capable of DNA replication and mitosis in immature animals. The NLMs can also divide upon stimulation in adult CNS.

Animals↗

Gluten Ataxia and Post-Streptococcal Central Nervous System Syndromes: Emerging Immune-mediated Disorders of the Central Nervous System?

There is an "emerging concept" that central nervous system dysfunction can be caused by an aberrant immune response triggered by exogenous antigens such as the food allergen gluten or streptococcal infection. The hypothesis of a gluten sensitive ataxia remains unproven, but is worthy of consideration. The data in support of this hypothesis require critical review before any treatment recommendations can be formulated. The idea that anti-gliadin antibody seropositivity per se justifies the term "gluten sensitivity" is important because it offers potential therapeutic possibilities, including simple exclusion diets, for patients with anti-gliadin antibody-associated ataxia. Post-streptococcal basal ganglia dysfunction has various manifestations, all of which fall into a relatively well-defined symptom complex or syndrome. Anti-basal ganglia antibodies that are associated with serologic evidence of recent streptococcal infection are a potential diagnostic marker for this group of disorders, which includes Sydenham's chorea (SC) as the prototype. More recently subjects with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, Tourette's syndrome, obsessive-compulsive disorder and other movement disorders have been described in association with anti-basal ganglia antibodies. The apparent overlap between the clinical phenotype of SC, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, Tourette's syndrome, and obsessive-compulsive disorder suggests that they may represent one disease entity. The current working hypothesis is that antibodies induced in response to streptococcal infection cross-react with antigenic determinants in the basal ganglia resulting in basal ganglia dysfunction. Although the experimental evidence is incomplete, there is sufficient evidence to support immune-mediated basal ganglia dysfunction as an emerging clinical entity. This has important implications for the diagnosis and treatment of subjects with these disorders. The latter includes the judicious use of antibiotic prophylaxis and immunomodulatory therapies. Apart from the diagnosis and management of SC, no consensus exists regarding the diagnosis and management of the other clinical entities within this group of disorders.

Journal Article↗

Bcl-2 antisense oligonucleotides are effective against systemic but not central nervous system disease in severe combined immunodeficient mice bearing human t(14;18) follicular lymphoma.

The t(14;18) is present in 85-90% of follicular lymphomas. It results in overexpression of the Bcl-2 protein, which inhibits apoptosis and plays a role in lymphomagenesis. Bcl-2 antisense oligonucleotides (ODNs) down-regulate Bcl-2 expression and inhibit growth of the follicular lymphoma cell line WSU-FSCCL. In this study, we have established a human lymphoma xenograft model in severe combined immunodeficient (SCID) mice using the WSU-FSCCL cell line. s.c., i.v., or i.p. injection of WSU-FSCCL cells into SCID mice results in the development of disseminated tumors, with the liver, spleen, bone marrow, and lymph nodes as major sites of disease. Tumors were fatal in 7-14 weeks, depending on cell inoculum and route of administration. Immunohistochemistry, flow cytometry, and cytogenetic analysis confirmed the human B-cell origin of tumor cells in the xenograft. Phosphorothioate ODNs against the translation initiation site of bcl-2 mRNA in the antisense and mismatched antisense sequences were administered i.v. or i.p. to the xenograft models three times a week for 2 weeks, starting on day 7 after tumor injections. Antisense-treated animals had significantly longer survival (mean, 11.6 weeks) compared with 7.6 weeks for the control group and 7.5 weeks for the mismatched antisense-treated animals (P = 0.002 and 0.004, respectively). More significantly, a pathological examination showed no tumor in the liver, spleen, or bone marrow of the antisense group. However, subsequent experiments showed that the central nervous system was involved, causing mice to die although other sites were disease free. We conclude that bcl-2 antisense ODN therapy is effective against systemic FSCCL disease in SCID mice xenografts; however, it does not prevent disease dissemination into the central nervous system causing animal death.

Animals↗

Evidence for an endocannabinoid system in the central nervous system of the leech Hirudo medicinalis.

In invertebrates, like Hydra and sea urchins, evidence for a functional cannabinoid system was described. The partial characterization of a putative CB1 cannabinoid receptor in the leech Hirudo medicinalis led us to investigate the presence of a complete endogenous cannabinoid system in this organism. By using gas chromatography-mass spectrometry, we demonstrate the presence of the endocannabinoids anandamide (N-arachidonoylethanolamine, 21.5+/-0.7 pmol/g) and 2-arachidonoyl-glycerol (147.4+/-42.7 pmol/g), and of the biosynthetic precursor of anandamide, N-arachidonylphosphatidyl-ethanolamine (16.5+/-3.3 pmol/g), in the leech central nervous system (CNS). Anandamide-related molecules such as N-palmitoylethanolamine (32.4+/-1.6 pmol/g) and N-linolenoylethanolamine (5.8 pmol/g) were also detected. We also found an anandamide amidase activity in the leech CNS cytosolic fraction with a maximal activity at pH 7 and little sensitivity to typical fatty acid amide hydrolase (FAAH) inhibitors. Using an antiserum directed against the amidase signature sequence, we focused on the identification and the localization of the leech amidase. Firstly, leech nervous system protein extract was subjected to Western blot analysis, which showed three immunoreactive bands at ca. approximately 42, approximately 46 and approximately 66 kDa. The former and latter bands were very faint and were also detected in whole homogenates from the coelenterate Hydra vulgaris, where the presence of CB1-like receptors, endocannabinoids and a FAAH-like activity was reported previously. Secondly, amidase immunocytochemical detection revealed numerous immunoreactive neurons in the CNS of three species of leeches. In addition, we observed that leech amidase-like immunoreactivity matches to a certain extent with CB1-like immunoreactivity. Finally, we also found that stimulation by anandamide of this receptor leads, as in mammals, to inhibition of cAMP formation, although this effect appeared to be occurring through the previously described anandamide-induced and CB1-mediated activation of nitric oxide release. Taken together, these results suggest the existence of a complete and functional cannabinoid system in leeches.

Adenylyl Cyclases↗