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Abc act-The high affinity uptake system for L-glutamate and L-aspartate in rs cerebral cortex may not be specific for these likely excitatory synaptic transmitters, as threo-3hydroxy-DL-aspartate, L-cysteinesulphinate, L-cysteate and D-aspartate strongly inhibit the observed high affinity uptake of ~-[~H]glutamate by rat brain slices in a manner consistent with linear competitive inhibition. These substances should therefore be considered as possible substrates for the transport system. Each of these four acidic amino acids excites central neurones in a manner similar to excitation induced by L-glutamate, and as each might occur in brain tissue, their possible synaptic role should be investigated.L-Glutamate high affinity uptake was shown to be sodium-dependent, but under certain conditions appeared to be less sensitive than GABA uptake to changes in the external sodium ion concentration, and to drugs which modify sodium ion movements. This may be relevant to the efficiency of the glutamate uptake process during synaptic depolarization induced by glutamate.L-Glutamate high affinity uptake was inhibited in a relatively nonspecific manner by a variety of drugs including mercurials and some electron transport inhibitors.L-GLUTAMATE and L-aspartate are likely to be excitatory synaptic transmitters in the mammalian central nervous system (CURTIS and JOHNSTON, 1970). These acidic amino acids depolarize feline spinal neurones when administered extracellularly by electrophoresis from multi-barelled micropipettes (CURTIS, PHILLIS and WATKINS, 1960) and this depolarizing action is potentiated by the simultaneous administration of p-chloromercuriphenylsulphonate (CURTIS, DUGGAN and JOHNSTON, 1970). These observations, together with the lack of effect of substances known to inhibit Lglutamate-metabolizing enzymes on L-glutamate-induced depolarization (CURTIS et al., 1960), have been interpreted on the basis of active transport being partially responsible for the removal of L-glutamate from the synaptic environment (CURTIS et al., 1970). L-Glutamate is taken up actively into brain slices (STERN, EGGLESTON, HEMS and KREBS, 1949; BLASBERG and LAJTHA, 1966), by at least two kinetically distinct transport systems (LOGAN and SNYDER, 1971). Both these transport systems can be inhibited by p-chloromercuriphenylsulphonate (BALCAR and JOHNSTON, 1972).The system of higher affinity for L-glutamate, but not that of lower affinity, appears to be associated with a unique population of nerve terminals which can be separated from other terminals that concentrate other synaptic transmitters, such as GABA and noradrenaline (WOFSEY, KUHAR and SNYDER, 1971). We have examined a variety of amino acids, other putative transmitters, drugs and inorganic ions, for their ability to inhibit the high affinity uptake of ~-[~H]glutamate (and ~-['H]aspartate) in slices of rat cerebral cortex. This study was aimed at finding (i) possible substrates, which should strongly inhibit the observed uptake of ~-f~H]glutamate in a competi-Abbreviation used ICso, i...

1. In the mammalian central nervous system, GABA is the main inhibitory neurotransmitter. GABA is a highly flexible molecule and, thus, can exist in many low-energy conformations. Conformationally restricted analogues of GABA have been used to help identify three major GABA receptors, termed GABAA, GABAB and GABAC receptors. 2. GABAA and GABAC receptors are members of a super-family of transmitter-gated ion channels that include nicotinic acetylcholine, strychnine-sensitive glycine and 5HT3 receptors. GABAA receptors are hetero-oligomeric Cl- channels that are selectively blocked by the alkaloid bicuculline and modulated by steroids, barbiturates and benzodiazepines. To date, 16 human GABAA receptor cDNA have been cloned. 3. GABAB receptors are seven transmembrane receptors that are coupled to G-proteins and activate second messenger systems and Ca2+ and K+ ion channels. To date, three GABAB receptor proteins have been cloned and these resemble metabotropic glutamate receptors. GABAB receptors are hetero-oligomeric receptors made up of a mixture of a combination of the subunits. These receptors are selectively activated by (-)-baclofen and CCGP27492 and are blocked by phaclofen, the phosphonic acid analogue of baclofen. 4. In contrast, GABAC receptors represent a relatively simple form of transmitter-gated Cl- channel made up of a single type of protein subunit. Two human GABAC receptor cDNA have been cloned. These receptors are not blocked by bicuculline nor are they modulated by steroids, barbiturates or benzodiazepines. Instead, GABAC receptors are selectively activated by the conformationally restricted analogues of GABA in the folded conformation cis-4-aminocrotonic acid and (1s,2R)-2-(aminomethyl)-1-carboxycyclopropane. (1,2,5,6-Tetrahydropyridine-4-yl)methylphosphinic acid, a methylphosphinic acid analogue of GABA in a partially folded conformation, is a selective antagonist at GABAC receptors.

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Objective To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management.Design Multicentre, parallel group, observer blind, randomised controlled trial. Setting 39 UK hospitals, recruiting from June 2009 to November 2012.Participants 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 prednisolone).Intervention Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively.Main outcome measures The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months).Results Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 prednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was −0.21 (1.00) cm2/day in the ciclosporin group compared with −0.14 (0.42) cm2/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm2/day, 95% confidence interval −0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in the prednisolone group.Conclusion Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes. Treatment decisions for individual patients may be guided by the different side effect profiles of the two drugs and patient preference. Trial registration Current Controlled Trials ISRCTN35898459.