Previous studies by us have strongly indicated a role for the N-methyl-D-aspartate (NMDA) receptor in the pathogenesis of experimental allergic encephalomyelitis (EAE) and, moreover, the loss of blood-brain barrier (BBB) integrity implicit in the disease. The current investigation has used the NMDA receptor antagonist memantine to modify the neurological course of EAE and, in particular, prevent BBB breakdown. Memantine was administered orally either semiprophylactically, from day 7 postinoculation (PI), or therapeutically, 10 to 11 days PI. Semiprophylactic administration of drug at 60 mg/kg b.wt. significantly restored BBB integrity, reduced symptoms, and limited inflammatory lesions (p Ͻ 0.05), when assessed 12 days PI. Higher concentrations of memantine did not notably advance disease improvements observed at 60 mg/kg b.wt., and 40-mg/kg b.wt. doses only reduced histological scores (p Ͻ 0.05).Therapeutic application of memantine was found to be as effective as semiprophylactic dosing. Administration of drug at 60 mg/kg b.wt. was demonstrated as the optimum dose, significantly reducing disease, BBB permeability, and lesions (p Ͻ 0.01). Extended studies revealed that, after cessation of memantine treatment using either dosing regime, any subsequent appearance of disease was suppressed in severity and duration. We have provided further strong evidence in support of a role for the NMDA receptor in the development of EAE and, in particular, the loss of BBB function and recruitment of inflammatory cells. Moreover, memantine is therapeutically efficacious, suggesting the NMDA receptor as a viable pharmacological target for future treatment of human neurological conditions such as multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS). The condition predominantly affects young adults and is characterised by immunological and inflammatory changes in the periphery and CNS that contribute to neurovascular disruption, haemopoietic cell invasion of target tissues, and demyelination of nerve fibres which culminate in neurological deficits that relapse and remit or are progressive. The main features of MS can be reproduced in the inducible animal counterpart, experimental autoimmune encephalomyelitis (EAE). The search for new MS treatments invariably employs EAE to determine drug activity and provide a rationale for exploring clinical efficacy. The preclinical development of compounds for MS has generally followed a conventional, immunotherapeutic route. However, over the past decade, a group of compounds that suppress EAE but have no apparent immunomodulatory activity have emerged. These drugs interact with the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-isoxazolepropionic acid (AMPA)/kainate family of glutamate receptors reported to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. The review considers the importance of the glutamate receptors in EAE and MS pathogenesis. The use of receptor antagonists to control EAE is also discussed together with the possibility of therapeutic application in demyelinating disease.

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Objective To determine the distribution of platelet volumes and numbers through pregnancy, and to compare these to changes in platelet volumes and numbers in women with pre‐eclampsia. Subjects Four hundred twenty‐eight women with normal pregnancy from whom four or more platelet measurements were available were identified. 74 women with pre‐eclampsia (blood pressure 140/90 mmHg, at least 0.5g protein/24 h urine collection) from whom platelet measurements were available between 27 and 30 weeks of gestation were identified. Results Mean platelet volume and platelet number remained constant in normal pregnancies between the first trimester and the end of pregnancy. A persistent increase of 0.8 fl ( 90th centile) in mean platelet volume was found in 14 out of 15 pre‐eclamptic patients between 24 weeks and 38 weeks of gestation and in only 13 of 428 normal pregnant individuals. Platelet numbers were decreased by 50 × 109/l (i.e. to less than the 10th centile) in 12 of the 15 patients with pre‐eclampsia. 10% of the normal pregnant population showed a similar decline in platelet numbers showing that changes in platelet numbers may be a less accurate assessment of the development of pre‐eclampsia. Conclusion We suggest that longitudinal determination of platelet volumes may be of use in identifying those women at risk of pre‐eclampsia.

Adrenomedullin (AM) is a novel vasodilatatory peptide which acts primarily through the calcitonin receptor-like receptor (CLR) in combination with either receptor-activity-modifying-protein (RAMP) 2 or 3 (forming receptors, AM(1) and AM(2) respectively). AM plays an important role during inflammation, with its expression increasing following cytokine treatment, promoting macrophage action in situ and high expression by T cells during hypoxic conditions. Examination of T cell AM receptor expression has previously been incomplete, hence we here consider the presentation of AM receptors and their responsiveness to AM and glucocorticoids (GC). AM receptor expression was examined by PCR and flow cytometry in primary human T cells, revealing that RAMP2, 3 and CLR are physiologically expressed in unstimulated T cells, both intracellularly and on the cell surface. PHA stimulation decreased receptor proteins, significantly so for CLR and RAMP3. Incubation with AM elicited limited receptor alterations however, GC treatment (10(-6) M; 24 h) markedly affected cell surface expression, significantly increasing receptor components in unstimulated cells and significantly decreasing the same in stimulated T cells. Our findings indicate that human T cells utilize both AM(1) and AM(2) receptors, which are GC-sensitive in an activation-state dependent manner.