Physiological and pathological roles of interleukin-6 in the central nervous system

The cytokine interleukin-6 (IL-6) is an important mediator of inflammatory and immune responses in the periphery. IL-6 is produced in the periphery and acts systemically to induce growth and differentiation of cells in the immune and hematopoietic systems and to induce and coordinate the different elements of the acute-phase response. In addition to these peripheral actions, recent studies indicate that IL-6 is also produced within the central nervous system (CNS) and may play an important role in a variety of CNS functions such as cell-to-cell signaling, coordination of neuroimmune responses, protection of neurons from insult, as well as neuronal differentiation, growth and survival. IL-6 may also contribute to the etiology of neuropathological disorders. Elevated levels of IL-6 in the CNS are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis. Moreover, several studies have shown that chronic overexpression of IL-6 in transgenic mice can lead to significant neuroanatomical and neurophysiological changes in the CNS similar to that commonly observed in various neurological diseases. Thus, it appears that IL-6 may play a role in both physiological and pathophysiological processes in the CNS.     

Remyelination of the central nervous system

The three typical stages in the clinical course of multiple sclerosis (relapse, persistent disability and progression) can be explained on the basis of inflammation, demyelination and failure of repair leading to axon degeneration and astrocytosis. Strategies are being evaluated for limiting the inflammatory process using immunological treatments and these may have unexpected dividends in promoting endogenous remyelination. Increasing knowledge on glial lineages and axon-glial interactions needed for stable myelination also offer the prospect for enhancing remyelination through growth factor therapy and cell implantation.     

Tumors of the central nervous system

Neoplasia of the central nervous system (CNS) can be divided into two main categories: nonpituitary CNS neoplasia and pituitary adenomas. Nonpituitary CNS neoplasias are generally compressive in nature, although some are also invasive. The majority of reported CNS tumors are secondary with only a few originating from nervous tissue. Pituitary adenomas predominantly occur in the pars intermedia of the older horse. Clinical signs, diagnostic testing, and possible treatments are discussed.     

Cytokine actions in the central nervous system

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimer's disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-gamma), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-beta), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

Glutamate receptors in the central nervous system

A lot of clinical processes following excessive stimulation of glutamate receptors seem to participate in pathophysiology of numerous acute and chronic neurological disorders. The whole of these reactions has been named as "glutamate cascade", because of the central role of glutamate in initiation and intensification of these processes. In this article, classification of different types of glutamate receptors and several hypotheses concerning mechanisms of glutamate neurotoxic activity are presented. A wide variety of neurological diseases, which etiologies are more or less connected with glutamate toxicity are discussed. At last, the future perspectives for treatment by drugs which action is thought to be mediated through glutamate receptors are presented.     

Stem cells in the central nervous system

In the vertebrate central nervous system, multipotential cells have been identified in vitro and in vivo. Defined mitogens cause the proliferation of multipotential cells in vitro, the magnitude of which is sufficient to account for the number of cells in the brain. Factors that control the differentiation of fetal stem cells to neurons and glia have been defined in vitro, and multipotential cells with similar signaling logic can be cultured from the adult central nervous system. Transplanting cells to new sites emphasizes that neuroepithelial cells have the potential to integrate into many brain regions. These results focus attention on how information in external stimuli is translated into the number and types of differentiated cells in the brain. The development of therapies for the reconstruction of the diseased or injured brain will be guided by our understanding of the origin and stability of cell type in the central nervous system.     

Aging and the central nervous system

This review of the literature on aging and the central nervous system attempts to cover the basic perameters investigated at both human and infrahuman levels for the better part of the last century. The results have indicated that there is a rather considerable lack of consistency in the data both within the frame of reference of a single species, and with regard to intraspecies comparisons. We have suggested that possible reasons for the contradictory findings would rest upon variability in techniques employed but, perhaps more importantly, on the failure of investigators in this area to standardize terminology. It is suggested that such a standardization might well be one of the more useful things to be accomplished in order to facilitate the interpretation of future work. The literature review first dealt with gross, i.e., macroscopic changes in brain morphology that could correlate with age, and then covered changes at the microscopic level. Finally, a brief review of the literature with regard to the biochemistry of aging was carried out. Implications of the data were noted where appropriate.     

Cyclooxygenases and the central nervous system

Prostaglandins (PGs) were first described in the brain by Samuelsson over 30 years ago (Samuelsson, 1964). Since then a large number of studies have shown that PGs are formed in regions of the brain and spinal cord in response to a variety of stimuli. The recent identification of two forms of cyclooxygenase (COX; Kujubu et al., 1991; Xie et al., 1991; Smith and DeWitt, 1996), both of which are expressed in the brain, along with superior tools for mapping COX distribution, has spurred a resurgence of interest in the role of PGs in the central nervous system (CNS). In this review we will describe new data in this area, focusing on the distribution and potential role of the COX isoforms in brain function and disease.     

Putative roles for the inducible transcription factor c-fos in the central nervous system: studies with antisense oligonucleotides

Although immediate-early genes such as c-fos are widely believed to play an important role in neuroplasticity, there is limited evidence to support involvement in the initiation of molecular events leading to medium- and long-term changes in brain function following a stimulus. Results using techniques such as transgenic knockout of the gene are often difficult to interpret. Antisense oligonucleotide technology offers an alternative. Infusion of antisense oligonucleotide to modify the expression of c-fos in the brain results in dramatic changes in rotation behaviour in animals challenged with psychostimulant drugs such as amphetamine. Similarly, the knockdown of c-fos expression using antisense oligonucleotides can also alter the rate of amygdala kindling in response to electrical stimulation of the brain. While studies using antisense oligonucleotides to knockdown c-fos expression provide evidence that the expression of c-fos plays an important role in regulating neuronal function, the use of antisense nucleotides has limitations and experiments must be very carefully controlled. Many details of antisense oligonucleotide actions remain unknown.     

Superficial hemosiderosis of the central nervous system

Superficial hemosiderosis (SH) of the CNS is a rare disease caused by repeated subarachnoid hemorrhage, with progressive superficial siderosis of the CNS. We report a patient with SH whose clinical picture was marked by progressive gait ataxia, hearing loss, dysarthria, and recurrent episodes of hemifacial spasm. Iron and ferritin levels in the CSF were significantly higher than in a control group of patients. Six month's treatment with the iron-chelating agent trientine dihydrochloride led to clinical improvement, with a concomitant reduction of CSF iron level. We suggest that, in addition to magnetic resonance imaging findings, CSF levels of iron and ferritin should be used as diagnostic criteria for SH, as well as to estimate the efficacy of iron chelation treatment.     

Autoantibodies in central nervous system lupus

Central nervous system (CNS) involvement in patients with lupus remains both a diagnostic and a therapeutic challenge. The role of autoantibodies in the pathogenesis of CNS lupus and/or as markers for disease activity is reviewed. Doubt is cast on the value of measuring anti-neuronal antibodies. Those antibodies binding ribosomal-P protein antigens or certain phospholipids appear to have greater utility, although even in these cases there is no uniform agreement as to their precise role in CNS disease induction, or how well antibody levels reflect disease activity.     

Primary lymphoma of the central nervous system

Eleven patients with primary lymphoma of the central nervous system were seen in the King Faisal Specialist Hospital and Research Centre, Saudi Arabia, between 1986 and 1992. None had previously received immunosuppressive therapy. All cases were confirmed by biopsy and histopathological studies. Of the eleven patients, six had debulking of the tumour, seven received radiation therapy and six received chemotherapy. This report confirms the very poor prognosis for patients with primary lymphoma of the central nervous system, with only a few long-term survivors.     

Stem cells of the central nervous system

BACKGROUND: The aim of the present study was to analyze whether minor differences in recipient body surface area have any predictive value on renal allograft evolution. METHODS: For this study, we considered 236 pairs of recipients who received a kidney from the same donor at our center between March 1985 and December 1995. Pairs in whom at least one patient presented any of the following events were excluded: graft loss during the first year of follow-up, diabetes mellitus, noncompliance with treatment, chronic pyelonephritis, and recurrent or de novo glomerulonephritis. Recipients of each pair were classified as large or small according to their body surface area (BSA). The percentage difference of BSA in each pair was calculated, and two cohorts of pairs were defined: BSA difference < or = 10% (n=76 pairs) and BSA difference >10% (n=70 pairs). RESULTS: The large recipients of the cohort with a BSA difference >10% showed a higher incidence of posttransplant delayed graft function (22/70 vs. 12/70, P=0.075), hypertension at 1 year of follow-up (51/70 vs. 35/70, P=0.006), and a higher serum creatinine level at 1-year follow-up (173 vs. 142 micromol/L, P=0.003), whereas in the cohort with a BSA difference < or = 10%, posttransplant evolution in large and small recipients was not different. Multivariate analysis showed that recipient BSA was an independent predictor of delayed graft function, posttransplant hypertension, and serum creatinine at 1-year follow-up. CONCLUSIONS: Relatively small differences in recipient BSA influence renal allograft evolution. Consequently, our data support that recipient size should be taken into consideration for renal allograft allocation.     

5 alpha-reductase isozymes in the central nervous system

The enzyme 5 alpha-reductase (5 alpha-R) activates several delta 4-3keto steroids to more potent derivatives which may also acquire new biological actions. Testosterone gives rise to the most potent natural androgen dihydrotestosterone (DHT), and progesterone to dihydroprogesterone (DHP), a precursor of the endogenous anxiolytic/anesthetic steroid tetrahydroprogesterone (THP). Two isoforms of 5 alpha-R, with a limited degree of homology, different biochemical properties and distinct tissue distribution have been cloned: 5 alpha-R type 1 and type 2. In androgen-dependent structures DHT is almost exclusively formed by 5 alpha-R type 2; 5 alpha-R type 1 is widely distributed in the body, with the highest levels in the liver, and may be involved in steroid catabolism. In the brain, the roles of the two isozymes are still largely unknown. This brief review will summarize recent experimental data from our laboratory which try to assign possible functional roles to the process of 5 alpha-reduction, and to the two 5 alpha-R isoforms in the CNS.     

Pediatric central nervous system tumors

Numerous collagenous structures must be reconstituted following injury to the skin in order to return function to this tissue. The basement membrane zone, vascular basement membranes, and the dense connective tissue of the dermis are examples of structures that contain a number of different collagen types and that may need replacement following injury. In addition, a scar is deposited at the site of damage in order to substitute for elements lost in the trauma and for elements that cannot be successfully replaced. Clearly, cells resident within the different compartments of the skin are able to synthesize and deposit collagen to reform these multiple structures. However, accumulating experimental evidence suggests that in addition to these resident cells, blood-borne cells may be responsible for the deposition of a portion of the newly synthesized collagen. Studies from this laboratory point to the activated monocyte as a potential source of collagen in the wound environment. Given the dynamics of the process, the hypothesis is proposed that during normal wound healing, the activated monocyte is a source of collagen essential for the rapid formation of a provisional matrix conducive for the subsequent formation of granulation tissue. Collagen synthesis also occurs by expanded populations of resident cells, under the influence of inflammatory cell-derived mediators, which results in the major accumulation of collagen during normal wound repair. However, if a chronic inflammatory state is initiated, the activated monocytes may remain in sufficient numbers to deposit collagen leading to a pathological lesion.     

MR imaging of the central nervous system in divers

BACKGROUND: Magnetic resonanse imaging (MRI) frequently reveals asymptomatic cerebral infarctions in the general population. HYPOTHESIS: The central nervous system (CNS) of divers is affected by a hyperbaric environment even if they are asymptomatic. METHODS: We examined 25 uniformed service divers by MRI and compared them with normal controls. RESULTS: Of 25 divers, 9 had CNS lesions vs. 2 of 25 controls (p = 0.02). There was a significant relationship between the CNS lesions, age, and smoking. CONCLUSION: The divers had a risk of accumulating CNS lesions. These results suggested that divers should undergo periodic medical evaluations and MRI brain scanning.     

Angiitis of the central nervous system in systemic diseases

PURPOSE: This review is aimed at presenting classification and diagnosis criteria of isolated central nervous system (CNS) angiitis, and at proposing guidelines for diagnosis and management of this disease. CURRENT KNOWLEDGE AND KEY POINTS: Isolated CNS angiitis are rare and most information has been provided by studies of very small series. Angiitis can be primitive or secondary to infectious, neoplastic diseases, or toxics. Clinical manifestations and radiologic abnormalities are not specific. A brain biopsy is therefore often required to confirm the diagnosis, as numerous non-inflammatory vascular diseases can mimic both clinically and radiologically isolated CNS angiitis. PERSPECTIVES AND PROJECTS: To help guide the diagnosis and therapeutical management of patients with CNS angiitis, strict classification criteria should be used: 1) rule out the various diseases that can mimic clinical and radiological CNS aspects related to isolated angiitis and differentiate "isolated CNS angiitis" from "CNS angiitis associated with systemic diseases"; 2) search for factors associated with the development of a "secondary CNS angiitis"; 3) check presumed mechanism at the origin of the cerebral vascular disease: "angiitis" versus "angiopathy"; 4) if the diagnosis of "primary CNS angiitis" is still suspected, it seems reasonable to perform cerebral and leptomeningeal biopsies. Treatment is still unknown and has to be discussed on a case by case basis according to the severity and progression of symptoms.