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Sodium 4-phenylbutyrate protects against cerebral ischemic injury

Xin Qi1, Toru Hosoi, Yasunobu Okuma

  • 1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.

Molecular Pharmacology
|July 1, 2004
PubMed

Insights

Sodium 4-phenylbutyrate (4-PBA) shows neuroprotective effects against cerebral ischemic injury. This chemical chaperone reduces endoplasmic reticulum stress and inflammation, offering a novel therapeutic approach for stroke treatment.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Sodium 4-phenylbutyrate (4-PBA) is a fatty acid used for urea cycle disorders, sickle cell disease, and thalassemia.
  • 4-PBA functions as a chemical chaperone, alleviating endoplasmic reticulum (ER) stress caused by misfolded proteins in conditions like cystic fibrosis and liver injury.

Purpose of the Study:

  • To evaluate the neuroprotective potential of 4-PBA against cerebral ischemic injury.
  • To investigate the mechanisms underlying 4-PBA's effects on ER stress and apoptosis in the context of brain ischemia.

Main Methods:

  • Utilized a mouse model of hypoxia-ischemia to assess pre- and post-treatment with 4-PBA.
  • Examined the impact of 4-PBA on ER-mediated apoptosis markers (eIF2alpha phosphorylation, CHOP, caspase-12) in vivo and in neuroblastoma cells.
  • Assessed 4-PBA's effects on inflammation markers (iNOS, TNF-alpha) in glial cells.

Main Results:

  • 4-PBA treatment significantly reduced infarction volume, swelling, apoptosis, and improved neurological function in a mouse model of cerebral ischemia.
  • 4-PBA suppressed ER stress-induced apoptosis by inhibiting key signaling pathways, including eIF2alpha phosphorylation and caspase-12 activation.
  • 4-PBA demonstrated anti-inflammatory effects by inhibiting iNOS and TNF-alpha expression in glial cells under hypoxic/reoxygenation conditions.

Conclusions:

  • Sodium 4-phenylbutyrate (4-PBA) exhibits significant neuroprotective effects against cerebral ischemic injury.
  • 4-PBA mitigates ischemia by inhibiting ER stress-mediated apoptosis and inflammation.
  • The findings suggest 4-PBA as a promising therapeutic agent for stroke, leveraging its chemical chaperone properties.

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