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This paper describes the conditions under which autoimmune T cells enter the central nervous system to attack the local tissue. During a prodromal period preceding the onset of neurological disease, the CNS tissue is converted from its physiological immune-hostile state to an immune-friendly state. At the same time, in the peripheral immune system, activated autoimmune T cells undergo profound changes that allow them to enter through the blood-brain barrier and to finally interact with local autoantigen-presenting cells. Antigen recognition leads to T cell activation and the secretion of inflammatory mediators that are responsible for the development of the inflammatory lesions and the neurological deficits.

In order to stress the role and importance of memory in human nervous system, this first paper intends to show how it appeared during evolution with the cortex of brain hemispheres and how its significant growth is the cause (and not consequence) of hominization. This growth seems related to a discontinuation of the fetal period during gestation. It leads to birth before the brain is mature, substituting a genetic maturation by an epigenetic maturation through learning. This discontinuation of pregnancy is related to a purely mechanical and obstetrical cause, depending on maternal pelvis. Evolution from quadrupedia to bipedia transformed the pelvis, obliging the newborn to make his way not downward but forward, through a narrow inextensible pass. This history of memory, showing its role in human species evolution, may lead to a reflection on its role in the evolution of all the species possessing a cortex. Above all, it will allow to understand how and in which way human brain is a sort of machine totally associated with memory.

Some of the results formerly included in the dossiers under the heading of 'General Pharmacology: Central Nervous System' were intended to document most of the information now covered by the CNS Safety Pharmacology. This paper allows to point out some general experimental conditions relating to the choice of (1) suitable animal species whose use should be advocated, (2) the route by which the effects of the drugs should be studied and (3) the controls of the experimental context (surroundings, temperature, schedules of the trials, interference with food-intake episodes, influence of noises and smells, expertise of the experimental staff) likely to optimize the predictive value of the trials. Besides the core of investigations recommended by most of the regulatory authorities (changes in gross behaviour, motor coordination, locomotor activity, interaction with hypnotics, convulsant potential), the need to include or not some investigations such as EEG studies and the prediction of adverse events, such as anxiolytic and amnesia potentials, is considered. The place, within the scope of CNS Safety Pharmacology, of studies intended to document the potential for drug abuse and dependence is mentioned and some information given about the methods generally used.

The dynamic regulation of neurotransmitters and their receptors is an important component of the process of coping and stress adaptation. Among the central neurochemical systems, CRF and the renin-angiotensin may represent major modulatory systems involved in the adaptation of an organism to chronic stress, balancing the response demands that the stressor places on the central nervous system with the potentially detrimental effects that a sustained stress response may produce. As such, the study of these two systems with respect to their neurotransmitters and receptors will allow us to achieve a better perspective on the mechanisms responsible for effective short-term coping with stress as well as long-term adaptation and restoration in response to chronic or repeated stress. It will then be possible to verify the level of activation of different components of the central pathways involved in the mediation of stress responses in rat strains which develop hypertension following chronic exposure to stress. The primary objective of the present paper is to review some facts on the contribution of the central renin-angiotensin system on the regulatory mechanisms involved in the mediation of physiological responses to stress and on the involvement of these neurons in the CNS adaptation in rat strains that are developing hypertension when chronically exposed to stress. Neurons that are expressing angiotensin-receptors may be important in the short-term adaptation to stress by potentiating sympathoadrenal and/or hypophyseo-pituitary-adrenal responses. These same neurons may also participate in long-term stress-adaptation by altering gene expression of their angiotensin receptors. Moreover, these processes represent potential points of dysregulation in the case of extreme, repeated or prolonged stress, and thus in the development of stress-related pathological states such as hypertension and heart diseases.

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.

This paper describes the synthesis and the pharmacological characteristics of the first radioiodinated ligand of central 5-HT3 receptors: [125I]iodo-zacopride. Specific sites having a high affinity (Kd = 4.3 nM) for [125I]iodo-zacopride have been found in membranes from the rat entorhinal cortex. In addition, a highly significant correlation (r = 0.995) existed between the Ki of several 5-HT-related drugs for displacing both [125I]iodo-zacopride from its specific binding sites, and [3H]zacopride from 5-HT3 receptors. Finally, [125I]iodo-zacopride was successfully used for the autoradiographic mapping of 5-HT3 receptors in the rat central nervous system.

Introduction. The risk factors for multiple sclerosis (MS) and cancer overlap to a large extent. The objective of our study was to estimate the prevalence and risk ratios (RR) of cancers in patients with MS and to identify which types of cancer have the lowest frequency. Materials and methods. We carried out research of the literature in the PubMed, Medline, and Google Academic databases, with the aim of identifying large-scale studies addressing the link between different cancers and MS. From 411 relevant articles, we selected 13 scientific papers for further analysis, comprising 109,276 patients diagnosed with MS from different countries. Results. Of all MS patients, 5.1% were diagnosed with a certain type of cancer compared to 5.5% in the general population; the cancers with the lowest incidence were respiratory, digestive, and blood cancers. Conclusions. The results of our analysis suggested that MS patients are less exposed to respiratory, digestive, and blood cancers, but more research is needed to understand if some disease-modifying therapies play a role in this regard.

Abstract: Objective: To understand the physiopathology and the consequences of a traumatic spinal cord injury after the acute phase. The aim is to describe the preoperative management of these patients and the various anaesthetic techniques available. Data source: The data were retrieved from the PubMed data base, papers from the major French anaesthesiology and intensive care conventions, publications from the French medico-surgical encyclopaedia, combined with reference analysis of major articles in this field. Results: In France, there are 40,000 patients with traumatic spinal cord injury. These lesions lead to major handicap and frequent complications particularly urologic and orthopaedic ones. These patients often require surgical procedures under anaesthesia. Besides neurological deficits, the spinal cord injury leads to an imbalance between sympathetic and parasympathetic nervous systems with serious dysautonomic complications. During surgery, anaesthesia is necessary to prevent this autonomic dysreflexia. All anaesthetic techniques are usable and effective, subject to their careful implementation for those patients with cardiovascular and respiratory restricted adaptation. The use of suxamethonium can induce fatal hyperkaliemia for up to 10 years after the initial injury, with maximal frequency at six months post-trauma. Conclusion: Notwithstanding insensitivity resulting from a spinal cord lesion, it is necessary to anaesthetize these patients before all surgical procedures. [Copyright &y& Elsevier]

Abstract: This paper describes the conditions under which autoimmune T cells enter the central nervous system to attack the local tissue. During a prodromal period preceding the onset of neurological disease, the CNS tissue is converted from its physiological immune-hostile state to an immune-friendly state. At the same time, in the peripheral immune system, activated autoimmune T cells undergo profound changes that allow them to enter through the blood-brain barrier and to finally interact with local autoantigen-presenting cells. Antigen recognition leads to T cell activation and the secretion of inflammatory mediators that are responsible for the development of the inflammatory lesions and the neurological deficits. To cite this article: H. Wekerle, C. R. Biologies 330 (2007). [Copyright &y& Elsevier]

The article offers information on a study on new protein vectors for physiologically transferring therapeutic agents to the central nervous system. It informs that the blood-brain barrier (BBB) protects the central nervous system and is formed by endothelial cells of the brain capillaries for survival and functioning of the brain. It also informs that peptide vectors can be used as drug delivery systems for treating diseases like cancer or neurodegenerative disorders.