Received for publication April 9, 2004.
Revised June 7, 2004.
Accepted for publication June 28, 2004.

Sodium 4-phenylbutyrate protects against cerebral ischemic injury

Abstract

Sodium 4-phenylbutyrate (4-PBA) is a low-molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease and thalassemia. It has recently been demonstrated that 4-PBA can act as a chemical chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling and apoptosis, and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eIF-2 phosphorylation, CHOP induction and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric oxide synthase (iNOS) and TNF in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia and its use as a chemical chaperone would provide a novel approach for therapy of stroke.

Key words: Apoptosis, Ischemia/Reperfusion