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 been demonstrated recently 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 eukaryotic initiation factor 2␣ phosphorylation, CCAAT/enhancerbinding protein homologous protein 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 nitricoxide synthase and tumor necrosis factor-␣ 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 the treatment of stroke.

Epigenetic Mechanisms in Cerebral Ischemia

“…53,61,102 The elevation of two further molecules is attenuated in this setting: cyclooxygenase 2 (COX2), 47 which accelerates the production of prostanoids and free radicals, as well as iNOS. 47,61 iNOS catalyzes the production of nitric oxide and constitutes an essential mediator of the immune response. Its knockdown was shown to ameliorate the overall damage caused by ischemia.…”

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

“…We therefore set out to determine whether cell death following ER stress is inhibited by the specific δPKC inhibitor peptide, δV1-1 [14]. Tunicamycin (Tm), a pharmacological agent inhibiting N-linked protein glycosylation, is commonly used to induce ER stress and subsequent cell death [4,[19][20][21]. Release of the cytosolic enzyme, lactose dehydrogenase (LDH), into the cell media is a marker of oncotic cell death.…”

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…Towards the normal tissues it not only shows little toxicity, but also provides protections against various stimuli [27][28][29][30][31][32]. The anticancer activity of PBA is generally attributed to its function as an HDACI [23,26].…”

“…The anticancer activity of PBA is generally attributed to its function as an HDACI [23,26]. However, multiple activities can be assigned to its protection of normal tissues, such as the activity of an HDACI [28], of a chemical chaperone [27,29,30], and of an ammonia sink [31,32].…”

“…Based on the previous reports that PBA protects normal tissues against oxidative stress [27,28], we envisioned a possibility that PBA might protect heart from ADR injury. In this study, we investigated the effects of PBA on acute ADR cardiotoxicity in wild type C57BL/6 mice, by echocardiographic characterization, ultrastructural pathology analysis, and measurement of serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities.…”