Abstract:The neurotoxic effects of the dopamine-selective neurotoxin MPTP (15 mg/kg, s.c.), in mice, were totally prevented by systemic administration of salicylate (ED 5O = 40 mg/kg, i.p.), aspirin (ED50 = 60 mg/kg, i.p.), or the soluble lysine salt of aspirin, Aspegic (ED50 = 80 mg/kg, i.p.). The protective effects of aspirin are unlikely to be related to cyclooxygenase inhibition as paracetamol (100mg/kg, i.p.), diclofenac (100mg/kg, i.p.), ibuprofen (20 mg/kg, i.p.) and indomethacin (100 mg/kg, i.p.) were ineffective. Dexamethasone (3-30 mg/kg, i.p.), which, like aspirin and salicylate, has been reported to inhibit the transcription factor NF-,q3, was also ineffective. Aspirin or salicylate (100 beM) had no effect on dopamine uptake into striatal synaptosomes or on monoamine oxidase B activity. The neuroprotective effects of salicylate derivatives could perhaps be related to hydroxyl radical scavenging. This was suggested by the fact that hydroxylated metabolites of salicylate (2,3-and 2,5-dihydrobenzoic acid) were recovered in brain tissue following the combined administration of MPTP and aspirin to a greater extent than following aspirin alone. The surprising neuroprotective effects of aspirin in an animal model of Parkinson's disease warrant further clinical investigation.

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In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective a7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human a7 n-AChRs (K i of 2274 and 1471 nM, respectively). Ex vivo 3 [H]a-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 ¼ 8 mg/kg p.o.). In functional studies performed with human a7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity ¼ 51 and 36%, EC 50 ¼ 4.4 and 0.9 mM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small a-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic a7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 mM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the a7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dosedependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse a7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

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Sodium-activated potassium (K Na ) channels have been suggested to set the resting potential, to modulate slow afterhyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K Na channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 M was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC 50 ϭ 4.4 M and EC 50 ϭ 2.9 M, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the singlechannel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K Na channels and to increase the rheobase of action potential. This study identifies new K Na channel pharmacological tools, which will be useful for further Slack channel investigations.