Modulation of Synaptic Transmission and Analysis of Neuroprotective Effects of Valproic Acid and Derivates in Rat Embryonic Motoneurons |
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Authors: | D Ragancokova Y Song H Nau R Dengler K Krampfl S Petri |
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Institution: | 1.Department of Neurology and Clinical Neurophysiology,Hannover Medical School,Hannover,Germany;2.Institute for Food Toxicology and Chemical Analysis,School of Veterinary Medicine,Hannover,Germany;3.Center for Systems Neuroscience (ZSN),Hannover,Germany |
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Abstract: | Amyotrophic lateral sclerosis is a devastating motoneuron disorder for which no effective treatment exists. There is some
evidence for neuroprotective effects of valproic acid (VPA). The beneficial effects, however, are limited due to the adverse
effects of VPA. To overcome this problem, a number of VPA derivates with fewer side effects have been synthesized. In the
present study, we investigated the viability of highly purified embryonic motoneurons cultured on glial feeder layers, composed
of either astrocytes or Schwann cells, or in monoculture, in presence of VPA and its three derivates 3-propyl-heptanoic acid
(3-PHA), PE-4-yn enantiomers (R- and S-PE-4-yn). An excitotoxic stimulus, kainate (KA), was added at day in vitro 9 (DIV9)
and the neuroprotective effect of either simultaneous incubation (DIV9) or pre-incubation (DIV1) of VPA and its derivates
was tested. The survival of motoneurons under simultaneous application of KA and VPA derivates was not remarkably increased.
Pre-incubation with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability
against the KA-induced neurotoxic effect. Our data suggest that the neuroprotective capacities of VPA and its three derivates
tested here drastically increase when they are added several days before KA. Most prominent neuroprotective effects were seen
for the PE-4-yn enantiomers. Patch-clamp experiments revealed an antiexcitotoxic effect of the S-PE-4-yn enantiomer that reduces
the frequency of postsynaptic currents and enhances the inhibitory postsynaptic transmission dependent on the co-culture condition. |
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