VALPROATE – A FATTY ACID DERIVATIVE WITH MULTIPLE EFFECTS

INTRODUCTION

An imbalance between HDACs and HATs regulates the levels of acetylation of the histone proteins and subsequent transcription of genes. If the HDAC levels are high the deacetylation of the lysine residues are promoted. This affects large number of intracellular functions like apoptosis, differentiation, cellular proliferation etc. In order to control the levels of HDACs scientists have designed HDAC inhibitors. Valproate is one among them.

VALPROATE ACTS SYNERGISTICALLY WITH ADRIAMYCIN

Valproate was administered along with adriamycin on MUTZ-1 cell line and its effects on tumor suppression were analyzed. The growth of the tumor cells was discovered through flow cytometry and growth curve was drawn. The growth inhibition rates were analysed at various concentrations. Valproate alone was unable to stimulate the process of apoptosis but when it worked in combination with adriamycin the rate of apoptosis was found to be increased. This research showed that this combination of inhibitors was very effective in controlling myelodysplastic syndrome [1].

VALPROATE AND NEURODEGENERATIVE DISORDERS

Neurodegenerative disorders like Alzheimer's disease are associated with loss in the neuronal tissues. The main reason behind the Neuritic plaques is the secretion of Aβ –protein. This protein is produced as an out come of the endoproteolytic cleavages of type 1 APP by the secretase enzyme (β- and γ- isoforms). In case of Alzheimer's disease this cleavage fails and it leads to the accumulation of Aβ protein. Valproic acid has been used in case of bipolar disorder. This inhibitor inhibits calcium, potassium and sodium channels within the membrane. It increases the transmission of γ-aminobutyric acid and activates the kinases which control the function of AP-1 protein. Valproic acid interferes with neurotrophic responses. It alters the activity of HDACs and GSK-3. It acts similar to trichostatin A in increasing the expression of β-catenin and hence regulating the Wnt pathway. The analysis of the neuronal function of HDAC inhibitors revealed that they promote synaptogenesis through acetylation of the histone proteins. This improves ones memory and learning capacity. In case of Alzheimer's disease, studies have shown that VPA controls the cleavage of APP via γ-secretase enzyme. This enzyme is in turn under the control of GSK-3β. In mice this inhibitor increased the memory hence suggesting that it can be an efficient antiamyloid therapy [2]. It can be used as an anticonvulsant and stimulator of the process of apoptosis and differentiation within cancerous cells. Clinical trials have been done in cases of myelodysplastic problem and myeloid leukemia. It was administered alone and in combination with inhibitors (which have all-trans retinoic acid structure). The combination of inhibitors synergistically improved the hematologic condition [3].

VALPROATE DOWNREGULATES VEGF RECEPTOR

Multiple myeloma cells express VEGFR-1 protein under in vitro conditions. Upon administration of VPA the growth of these cells was inhibited in a dose dependent manner. Upon exposure for longer hours (48 hours) the rate of apoptosis was also found to be increased. The expression of VEGFR-1 was reduced after the administration of VPA [4].

CONCLUSION

VPA is a fatty acid (short chain in length) derivative. It shows significant positive effects on various cellular functions like proliferation, differentiation, immunogenicity and apoptosis.

REFERENCES

1. Yu C, Chen BA, et al. [Sodium valproate synergizes adriamycin to inhibit proliferation and induce apoptosis in myelodysplastic syndrome cell line]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008 Jun; 16(3):555-60.

2. Qing H, He G, et al. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 2008 Nov 24; 205(12):2781-9.

3. Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer 2007 Sep 1; 110(5):943-54.

4. Dong XF, Song Q, et al. Histone deacetylase inhibitor valproic acid inhibits proliferation and induces apoptosis in KM3 cells via downregulating VEGF receptor. Neuro Endocrinol Lett 2007 Dec; 28(6):775-80.