Valproate, the popular antidepressant, is known as an inducer of autism. It has many kinds of physiological properties, including the inhibition of histone deacetylase (HDAC). Recently we reported valproate application to rat fetus caused developmental changes in cerebellar cortex. In treated cerebellum, the dendrites of Purkinje cells elongated earlier than in vehicles. Using the enzyme-linked photo assay device, it was observed that some neurotransmitter releases were changed.
In this study, we report the effects of two other HDAC inhibitors to cerebellar development and compare them with the effect of valproate. The HDACs are classified into three main groups, Class I to III, and Class I includes HDAC1, HDAC2, HDAC3, and HDAC8. Valproate is possible to inhibit Class I HDACs. Suberoylanilide hydroxamic acid, SAHA, is major anticancer drug, and possible to inhibit Class I and II. Trichostatin A, TSA, is also Class I inhibitor.
Valproate application to embryonic day 16 p.o. increased GABA release even from early developing periods, and changed its releasing spatial pattern. ATP release with glutamate stimulation was also increased earlier. In addition, Purkinje cells in the Valproate-applied rat elongate their dendrites all over the molecular layer even in P12. SAHA applied to same embryonic day i.p., increased ATP release and elongated the dendrites of Purkinje cells earlier, however, the effects was less than VPA. The effects of TSA were observable but slight.
These three HDAC inhibitors have different organic structures. Valproate belongs to the aliphatic acid compounds, while SAHA and TSA belongs to hydroxamic acids. In addition, their physiological spectrum was different but all of them would promote the neuronal differentiation.