Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke
| Autor: | Richard Stewart, Chandan K. Sen, Savita Khanna, Hallie Harris, Maria H.H. Balch, Cameron Rink, Surya Gnyawali, James Spieldenner |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glutamic Acid Phytoestrogens Pharmacology Biochemistry Neuroprotection Biochanin A Brain Ischemia 03 medical and health sciences chemistry.chemical_compound Transactivation Mice 0302 clinical medicine Genetics Medicine Animals Aspartate Aminotransferases Receptor skin and connective tissue diseases Molecular Biology Stroke Gene knockdown business.industry Research Glutamate receptor Isoflavones medicine.disease Mice Inbred C57BL 030104 developmental biology Neuroprotective Agents chemistry business 030217 neurology & neurosurgery Biotechnology |
| Popis: | In the pathophysiologic setting of cerebral ischemia, excitotoxic levels of glutamate contribute to neuronal cell death. Our previous work demonstrated the ability of glutamate oxaloacetate transaminase (GOT) to metabolize neurotoxic glutamate in the stroke-affected brain. Here, we seek to identify small-molecule inducers of GOT expression to mitigate ischemic stroke injury. From a panel of phytoestrogen isoflavones, biochanin A (BCA) was identified as the most potent inducer of GOT gene expression in neural cells. BCA significantly increased GOT mRNA and protein expression at 24 h and protected against glutamate-induced cell death. Of note, this protection was lost when GOT was knocked down. To validate outcomes in vivo, C57BL/6 mice were intraperitoneally injected with BCA (5 and 10 mg/kg) for 4 wk and subjected to ischemic stroke. BCA levels were significantly increased in plasma and brain of mice. Immunohistochemistry demonstrated increased GOT protein expression in the brain. BCA attenuated stroke lesion volume as measured by 9.4T MRI and improved sensorimotor function-this protection was lost with GOT knockdown. BCA increased luciferase activity in cells that were transfected with the pERRE3tk-LUC plasmid, which demonstrated transactivation of GOT. This increase was lost when estrogen-related receptor response element sites were mutated. Taken together, BCA represents a natural phytoestrogen that mitigates stroke-induced injury by inducing GOT expression.-Khanna, S., Stewart, R., Gnyawali, S., Harris, H., Balch, M., Spieldenner, J., Sen, C. K., Rink, C. Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke. |
| Databáze: | OpenAIRE |
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