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J. Lasseck, P. Grieshaber, U. Goebel, G. Martin, S. Thanos, S. Di Giovanni, W. Lagrèze; Valproic Acid-Mediated Neuroprotection and Neuroregeneration in Optic Nerve Injury Is Associated With CREB-Induction and Activation of pERK1/2. Invest. Ophthalmol. Vis. Sci. 2009;50(13):124.
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Valproic acid (VPA) has recently been found to have neuroprotective effects in neurodegenerative conditions. In addition to its anticonvulsive effects, VPA inhibits histone-deacetylases (HDAC) and delays apoptosis in degenerating neurons. We investigated, whether VPA protects retinal ganglion cells (RGCs) from cell death and enhances axonal regeneration after optic nerve crush (ONC). Furthermore, we analysed potential molecular targets involved in VPA-mediated protection, including its role in modifying histone-acetylation levels.
We performed ONC on the left eye of rats, receiving either VPA or Ringer`s solution subcutaneously (300 mg/kg twice daily) or intravitreally (single postlesional injection). Densities of fluorogold labeled RGCs were analysed after 5 or 8 days. Retinal tissue was additionally harvested and processed to (1) quantify axon growth in retinal explants, (2) evaluate caspase-3 activity, (3) analyse transcription factor cAMP response element binding protein (CREB), and (4) determine acetylated histone 3, 4 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2.
5 and 8 days after ONC, 93% and 58% RGCs survived after subcutaneous VPA treatment in comparison to Ringer`s solution (62% and 37% viable RGCs, p<0.001), respectively. Likewise, a single intravitreal injection of VPA immediately after injury significantly protected more RGCs from death. Injured RGCs treated with VPA showed enhanced regeneration of their axons in culture in comparison to the crushed controls receiving Ringer. In addition, RGCs of the corresponding right eye of VPA treated rats were transferred into a regenerative state. VPA-mediated neuroprotection and regeneration was accompanied by decreased caspase-3 activity, induction of CREB, activation of pERK1/2 but not by altered histone-acetylation.
The VPA-mediated neuroprotection after ONC involves multiple mechanisms, but not histone-acetylation levels, which were not significantly altered. In summary, VPA may represent a new therapeutic option to foster both neuroprotection and axon regeneration following ONC.
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