Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity

BACKGROUND AND PURPOSE Amyloid-β (Aβ) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aβ aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aβ1-42 and cell-derived Aβ oligomers. EXPERIMENTAL APPROACH Surface plasmon resonance studies measured binding of SEN1269 to Aβ1–42. Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ1–42–induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aβ1–42 and cell-derived Aβ oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats. KEY RESULTS SEN1269 demonstrated direct binding to monomeric Aβ1–42, produced a concentration-related blockade of Aβ1–42 aggregation and protected neuronal cell lines exposed to Aβ1–42. In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ1–42 and cell-derived Aβ oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aβ oligomers. CONCLUSIONS AND IMPLICATIONS SEN1269 protected cells exposed to Aβ1–42, displayed central activity with respect to reducing Aβ-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aβ-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aβ-mediated synaptic toxicity as potential neuroprotective agents for treating AD

Integration and modulation of chemical and electrical synaptic transmission in sympathetic preganglionic neurones in vitro

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of H-1 receptors

The role of histamine in regulating excitability of sympathetic preganglionic neurons (SPNs) and the expression of histamine receptor mRNA in SPNs was investigated using whole-cell patch-clamp electrophysiological recording techniques combined with single-cell reverse transcriptase polymerase chain reaction (RT-PCR) in transverse neonatal rat spinal cord slices. Bath application of histamine (100 mu M) or the H-1 receptor agonist histamine trifluoromethyl toluidide dimaleate (HTMT; 10 mu M) induced membrane depolarization associated with a decrease in membrane conductance in the majority (70%) of SPNs tested, via activation of postsynaptic H-1 receptors negatively coupled to one or more unidentified K+ conductances. Histamine and HTMT application also induced or increased the amplitude and/or frequency of membrane potential oscillations in electrotonically coupled SPNs. The H-2 receptor agonist dimaprit (10 mu M) or the H-3 receptor agonist imetit (100 nM) were without significant effect on the membrane properties of SPNs. Histamine responses were sensitive to the H-1 receptor antagonist triprolidine (10 mu M) and the nonselective potassium channel blocker barium (1 mM) but were unaffected by the H-2 receptor antagonist tiotidine (10 mu M) and the H-3 receptor antagonist, clobenpropit (5 mu M). Single cell RT-PCR revealed mRNA expression for H-1 receptors in 75% of SPNs tested, with no expression of mRNA for H-2, H-3, or H-4 receptors. These data represent the first demonstration of H-1 receptor expression in SPNs and suggest that histamine acts to regulate excitability of these neurons via a direct postsynaptic effect on H-1 receptors