GAPDH-targeted therapy - A new approach for secondary damage after traumatic brain injury on rats

Biochemical and Biophysical Research Communications
Vladimir F LazarevBoris A Margulis

Abstract

Massive neuronal death caused by a neurodegenerative pathology or damage due to ischaemia or traumatic brain injury leads to the appearance of cytosolic proteins in the extracellular space. We found that one of the most abundant cellular polypeptides, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), appearing in the medium of dying cells or body fluids is able to form aggregates that are cytotoxic to adjacent cells. Since we previously showed that the hydrocortisone derivative RX624 can inhibit the ability of GAPDH to transport the enzyme complex with polyglutamine and reduce the cytotoxicity of the complex, we explored the effects of GAPDH on SH-SY5Y neuroblastoma cells. We found that the latter treated with particular forms of GAPDH molecules die with a high efficiency, suggesting that the exogenous enzyme does kill adjacent cells. RX624 prevented the interaction of exogenous GAPDH with the cell membrane and reduced the level of death by more than 10%. We also demonstrated the efficiency of RX624 treatment in a rat model of traumatic brain injury. The chemical blocked the formation of GAPDH aggregates in the brain, inhibited the cytotoxic effects of cerebrospinal fluid and rescued the motor function of injured rats. Importan...Continue Reading

Citations

May 10, 2019·International Journal of Molecular Sciences·Kamal M YakoubValentina Di Pietro
May 7, 2020·Pharmaceutics·Vladimir F LazarevBoris A Margulis
May 6, 2020·Pharmaceutics·Elizaveta A DutyshevaVladimir F Lazarev
May 6, 2021·Biomedicines·Hilary Y LiuElias Aizenman

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