Analysis of Neuroprotective Effects of Valproic Acid on Primary Motor Neurons in Monoculture or Co-cultures with Astrocytes or Schwann Cells

Ragancokova, Daniela; Jahn, Klaus; Kotsiari, Alexandra; Schlesinger, Friedrich; Haastert, Kirsten; Stangel, Martin; Petri, Susanne; Krampfl, K.

doi:10.1007/s10571-009-9393-3

Cited by 11 publications

(10 citation statements)

References 33 publications

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“…All treatment described below were performed after 7 days in vitro (DIV 7). The purity of primary motor neuron cultures was determined by the ratio of SMI32 positive cells to DAPI stained nuclei, resulting in approximately 80% motor neurons [46], [47].…”

Section: Methodsmentioning

confidence: 99%

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Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

et al. 2013

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Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.

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Section: Methodsmentioning

confidence: 99%

“…Cell nuclei were stained with 4′, 6-diamidino-2-phenylindole (DAPI; Invitrogen, Darmstadt, Germany). Motor neuron and astrocyte survival was quantified by cell counting in 5 visual fields of each coverslip in a total of eight different preparations for both non-transgenic and transgenic cells, as previously described [46], [47].…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

et al. 2013

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“…Higher concentrations ([100 lM), however, were considerably toxic for primary motoneurons dissected from spinal cords. We had further shown dose dependent neurotoxic effects of the glutamate receptor agonist KA in three different motor neuron culture systems which validate them as a proper tool to study exitotoxicity in vitro and to screen potentially neuroprotective compounds (Ragancokova et al 2009). To overcome the problem of adverse effects of VPA administered in higher dosages, a number of chemical derivates of VPA have been synthesized.…”

Section: Discussionmentioning

confidence: 85%

“…In a previous study we had shown a dose-dependency of the effect of VPA on motoneuron survival and a marginal neuroprotective effect against KA-induced neurotoxicity in presence of glial cells (Ragancokova et al 2009). …”

Section: Resultsmentioning

confidence: 93%

“…Simultaneous incubation of DIV9 cell cultures was performed together with 30 lM KA and with 10 lM of VPA (a concentration which had previously shown the best neuroprotective effect) (Ragancokova et al 2009) or with 10 lM of the derivates: 3-propyl-heptanoic acid (3-PHA), R(? )-and S(-)-2-npentyl-4-pentynoic acid (R-and S-PE-4-yn).…”

Section: Neurotoxicity Experimentsmentioning

confidence: 99%

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Modulation of Synaptic Transmission and Analysis of Neuroprotective Effects of Valproic Acid and Derivates in Rat Embryonic Motoneurons

et al. 2010

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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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Valproic acid induces astrocyte‐dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI‐1 activity

Cho

Kwon

Choi

et al. 2013

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Tissue plasminogen activator (tPA) is expressed in several regions of brain and plays regulatory roles such as neurite outgrowth, synaptic plasticity and long term potentiation. The activity of tPA is regulated by an endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1), which is expressed mainly in astrocytes. Valproic acid (VPA), a histone deacetylase inhibitor that is used for the treatment of epilepsy and bipolar disorders, promotes neurite extension, neuronal growth and has neuroprotective effect in neurodegenerative diseases. In this study, we examined whether the neurite extension effects of VPA is mediated by modulating tPA/PAI-1 system. VPA dose-dependently increased tPA activity and decreased PAI-1 activity in rat primary astrocytes but not in neurons. PAI-1 protein level secreted into the culture medium but not tPA per se was decreased by VPA. In co-culture system or in neuronal culture stimulated with astrocyte conditioned media but not in pure neuronal cell culture, VPA induced neurite outgrowth via increased tPA activity due to the decreased PAI-1 activity in astrocytes. The decrease in PAI-1 activity and increased neurite extension was regulated via JNK mediated post-transcriptional pathway. The essential role of tPA/PAI-1 system in the regulation of VPA-mediated neurite extension was further demonstrated by experiments using astrocyte conditioned media obtained from tPA or PAI-1 knockout mice. Regulation of PAI-1 activity in astrocyte by VPA may affect both physiological and pathological processes in brain by upregulating tPA activity.

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Analysis of Neuroprotective Effects of Valproic Acid on Primary Motor Neurons in Monoculture or Co-cultures with Astrocytes or Schwann Cells

Cited by 11 publications

References 33 publications

Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

Modulation of Synaptic Transmission and Analysis of Neuroprotective Effects of Valproic Acid and Derivates in Rat Embryonic Motoneurons

Valproic acid induces astrocyte‐dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI‐1 activity

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