Treatment Of Nervous System Diseases Research Articles

Muscarinic Acetylcholine Receptors: New Potential Therapeutic Targets in Antinociception and in Cancer Therapy

The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren's diseases). This review will focus on the potential implications of muscarinic receptors in tumour progression and in nociception and the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864 ) have also been demonstrated to arrest tumour progression in nude mice. Moreover muscarinic agonists such as vedaclidine, CMI- 936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates.

A Look Inside

Standard neurobiology textbooks commonly do not contain a chapter on cancer, and the word might not even appear in the index. Its absence cannot be explained simply on the grounds that the subject falls more appropriately within the clinical realm, because you will find chapters devoted to various other nervous system diseases. Could this intellectual blind spot result from the fact that mature neurons, being post-mitotic, do not succumb to the disease? This absence in most texts is curious, considering the severe functional implications. The word is sometimes used metaphorically to connote an unstoppable process of destruction, and indeed some forms of brain cancer present the most dire prognosis of any cancer. But more importantly the neglect of this subject is curious, because on a molecular and cellular level, cancer is the result of biological processes that are at the forefront of modern neurobiological research. These include such current hot-topic areas as intraand inter-cellular signaling networks, regulation of gene transcription, control of cellular differentiation, regulation of cell motility, migration and cell death; the secretion and response to growth factors, and interactions with the vascular and immune systems. Finally, the current enthusiasm and promising research on the use of stem cells for therapeutic treatment of nervous system disease has brought us face-to-face with our ignorance in this area, as we find that many types of stem cells transplanted into the brain form tumors. This issue of Neuron Glia Biology contains a special collection of original research papers on cancer in the peripheral and central nervous system and a review on the subject. These papers are introduced below by Special Feature Editor, Philip Lee.

Melanocortins and the Treatment of Nervous System Disease: Potential Relevance to the Skin?

For several decades melanocortins have been implicated in the modulation of brain function. More recently, this idea has been supported by the identification and cloning of melanocortin (MC) receptors in the nervous system. MCs stimulate axonal growth in fetal neural tissue or in neural cell lines in culture. This feature was utilized in screening their neurotrophic or neuroprotection potential in animal studies of nervous system disease (peripheral nerve and spinal cord trauma, toxic and metabolic neuropathies, EAN, EAE, etc.). Some of these effects may be mediated by MC4 receptor activation, although as yet unknown receptors may also be involved (for instance, protection by Org 2766). To what extent MC-nervous system effects are related to known effects of MCs in skin- and neuro-immune systems, remains to be discovered. Nevertheless, it is of interest to note that activation of brain MC4 receptors profoundly affects care behavior for the body surface (skin and fur). The excessive grooming response in rodents exhibits a remarkable functional correlation with MSH activity in a brain-skin axis.

Philadelphia Infirmary for Nervous Diseases: America's original model of institutional neurology.

The role and contributions of the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases in the development of neurology in 19th-century America are described. American neurology was largely born during the Civil War through the work of S.W. Mitchell at Turner's Lane Hospital. With the closing of this military facility, the United States was left without an institution dedicated to neurologic research and the treatment of nervous system diseases. Nineteenth century archival data, including original Trustees' minutes, annual board of managers reports, patient case books, and published research from the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases were studied. The Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases promoted the development of neurology in the United States through three main activities. First, it offered patients with primary nervous system diseases, arthritis, and orthopedic disorders specialized care that was unavailable at medical universities. Second, its medical staff, especially Mitchell, provided opportunities for advanced neurologic education. Postgraduate physicians interested in neurologic disease attended formal lectures and directly participated in the operation of outpatient clinics and inpatient rounds. Finally, its formalized record system in the form of case books facilitated neurologic research. These records formed the basis of landmark publications by Mitchell, Sinkler, Osler, and others on rest therapy, spastic palsies, chorea, and other topics. As America's first and comprehensive peacetime neurologic facility, the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases fostered the evolution of neurology as a separate, viable specialty in the post-Civil War period and provided a particular focus for the study of interactions among orthopedic, nutritional, and neurologic disorders.

CSF, plasma viral load and HIV associated dementia.

Plasma viral burden has proven valuable in predicting the future course of systemic HIV related disease and the response to treatment. It is not known whether plasma or cerebrospinal fluid (CSF) viral burden can be used to predict onset of or response to treatment of nervous system disease. We propose a model of viral load mediated neurotoxicity underlying peripheral and central HIV associated neurological disease. The objective of this preliminary study was to assess the relationship of HIV associated neurological disease to quantitative viral load in plasma and CSF. 47 subjects (HIV- = 10, HIV+ = 37) participated in the study. Plasma and CSF samples were collected within a 3 h window. RT-PCR (Roche Amplicor Monitor) was utilized to assess HIV-1 RNA viral load in both plasma and cell free (centrifuged) CSF. Subjects underwent concurrent comprehensive neurological and neuropsychological evaluations. In general, systemic viral load, as measured in plasma, was greater than that found in cell free CSF. Cell free CSF HIV RNA viral load was significantly correlated with neurological dysfunction, whereas plasma viral load was not. The sole subject with an elevated CSF viral load (> 5 Log 10), had HIV associated dementia (HAD) on clinical examination.

Growth factor therapy

Neurotrophic factors are molecules that specifically promote neuronal survival, axonal growth, and synaptic plasticity. Different populations of neurons respond to specific neurotrophic factors, thereby providing potential tools for targeting various neurological disorders. In animal models of human diseases—including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), stroke, spinal cord injury, and peripheral neuropathy—neurotrophic factors have convincingly exhibited the ability to promote neuronal rescue, elicit axonal growth, and generate functional recovery. Yet clinical trials of neurotrophic factors have yielded little success to date, demonstrating preliminary efficacy for the treatment of peripheral neuropathy but failing to show benefit in several other neurological diseases. An emerging concept in the application of this extremely powerful and promising class of molecules for the treatment of nervous system disease is that their mode of delivery to the nervous system is critical: neurotrophic factors must be delivered specifically and accurately to neuronal targets, a difficult feat when delivering large molecules across the blood–brain barrier. Several novel approaches for delivering neurotrophic factors to the nervous system are under development, including gene therapy, focal intraparenchymal brain infusion, carrier-mediated transport, and small molecular analogs to neurotrophic factors that can cross the blood–brain barrier. These approaches are likely to establish neurotrophic factors as a mainstay of neurological therapy in the future, providing not only a means of compensating for nervous system disease once it has occurred, but for the first time, preventing or reducing the rate of disease progression. MRDD Research Reviews 1998;4:212–222. © 1998 Wiley-Liss, Inc.

Estructura y funciones de la macroglía en el sistema nervioso central. Respuesta a procesos degenerativos

Glial cells have been known for a long time. For many years they have been considered to be merely a support for the structure of nervous tissue. Our limited knowledge of these cells has been mainly due to different methodological problems which made it impossible to discover more about their origin and physiology. Now, however, thanks to the development of immunocytochemical techniques, it has been possible to determine their structure, and their function have been discovered thanks to the modern molecular biology techniques. Thus the importance of the glia in the nervous system, both in normal and in pathological conditions, is now realized. In recent years increasing interest has been shown in the functional role played by macroglia (astrocytes and oligodendrocytes). Although astrocytes and oligodendrocytes have been classified into different types, according to their morphology, these cells are functionally very heterogeneous depending on the microenvironment in which they are found. However, this is only a measure of the number of key processes in which they participate to the correct functionality of central nervous system. The diversity of processes in which astrocytes and oligodendrocytes are involved shows that these cells can respond in different ways to neurodegenerative situations, both normal and pathological, in order to maintain the structural integrity of cerebral tissue. Although the role played by oligodendrocytes is less well-known than that played by astrocytes, both cell types may be perfect targets for treatment of nervous system diseases, and also of the neurodegenerative changes due to ageing.

The potential of melanotropins in the treatment of nervous system diseases.

Annals of the New York Academy of SciencesVolume 680, Issue 1 p. 401-411 The Potential of Melanotropins in the Treatment of Nervous System Diseases WILLEM HENDRIK GISPEN, WILLEM HENDRIK GISPEN Department of Medical Pharmacology Rudolf Magnus Institute Vondellaan 6 3521 GD Utrecht, the NetherlandsSearch for more papers by this author WILLEM HENDRIK GISPEN, WILLEM HENDRIK GISPEN Department of Medical Pharmacology Rudolf Magnus Institute Vondellaan 6 3521 GD Utrecht, the NetherlandsSearch for more papers by this author First published: May 1993 https://doi.org/10.1111/j.1749-6632.1993.tb19698.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume680, Issue1The Melanotropic PeptidesMay 1993Pages 401-411 RelatedInformation