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• W2340987034 abstract "In summary our results indicate that VPA might be applicable to neurodegenerative diseases such as ALS. As multiple mechanism have been shown to be involved in ALS pathogenesis, a combination of several neuroprotective compounds with additive effects appears might be a promising strategy for future clinical trials. In our studies we proved that high concentrations of VPA, however, as well as KA application alone, led to dose-dependent loss of motor neurons as was shown by immunocytochemistry. In order to address a potential neuroprotective role of VPA in motor neurons, we first studied the interactions of highly purified populations of developing neurons under different culture conditions regarding cell survival and its dependency on glial feeding co-cultures, i.e. astrocytes or Schwann cells. Glial feeder layers significantly enhanced basal survival of motor neurons, and slightly protected them against KA neurotoxicity in presence of VPA. Calcium imaging experiments revealed no effect of VPA on calcium transients once motor neurons were spontaneously active (>10 days in culture). In non-spontaneously active motor neurons (<10 days in culture), however, KA induced intracellular calcium transients were significantly increased in presence of VPA. To overcome the problem of adverse effects of VPA administered in higher dosages, a number of chemical derivates of VPA have been synthesized. We focus on three out of a number of synthesized VPA derivates that have lately been under investigation: 3-propyl-heptanoic acid (3-PHA) and PE-4-yn enantiomers (R- and S- PE-4-yn). The survival of motor neurons under simultaneous application of KA and VPA derivates was not significantly increased.  Pre-incubation of the cells with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability against the KA-induced neurotoxic effect. The highest increase in motoneuron survival was seen after pre-incubation with S-PE-4-yn. We additionally tested the hypothesis of a correlation of the modulation of synaptic activity and a neuroprotective effect on motoneurons using whole cell patch clamp technique. The analysis of spontaneous synaptic activity in untreated cells and in presence of the test-compounds on glial feeder layers revealed a shift towards increased transsynaptic inhibition. VPA derivate, S-PE-4-yn reduced the frequency but not the amplitute of both spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in motoneurons cultured on glial feeder layers. Clearly, further studies are necessary to identify the exact mechanism of action of VPA and its derivates that are involved in beneficial action of potential neuroprotective effect." @default.
• W2340987034 created "2016-06-24" @default.
• W2340987034 creator A5026091750 @default.
• W2340987034 date "2009-01-01" @default.
• W2340987034 modified "2023-09-23" @default.
• W2340987034 title "The role of synaptic transmission in the pathophysiology and therapy of neurodegenerative disease, amyotrophic lateral sclerosis" @default.
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