4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2.

Abstract

Chronic cerebral hypoperfusion is believed to cause white matter lesions (WMLs), leading to cognitive impairment. Previous studies have shown that inflammation and apoptosis of oligodendrocytes (OLs) are involved in the pathogenesis of WMLs, but effective treatments have not been studied. In this study, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a chloride (Cl-) channel blocker, was injected into chronic cerebral ischemia-hypoxia rat models at different time points. Our results showed that DIDS significantly reduced the elevated mRNA levels and protein expression of chloride channel 2 (ClC-2) in neonatal rats induced by ischemia-hypoxia. Meanwhile, DIDS application significantly decreased the concentrations of reactive oxygen species (ROS); and the mRNA levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha TNF-α in neonatal rats with hypoxic-ischemic damage. Myelin staining was weaker in neonatal rats with hypoxic-ischemic damage compared to normal controls in corpus callosum and other white matter, which was ameliorated by DIDS. Furthermore, the elevated number of caspase-3 and neural/glial antigen 2 (NG-2) double-labeled positive cells was attenuated by DIDS after ischemia anoxic injury. Administration of DIDS soon after injury alleviated damage to OLs much more effectively in white matter. In conclusion, our study suggests that early application of DIDS after ischemia-hypoxia injury may partially protect developing OLs.

• Authors: Baixiong Zhao, Hongyu Quan, Teng Ma, Yanping Tian, Qiyan Cai, Hongli Li
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 5 Pg. 10457-69 (May 07 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25961953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens
• CLC-2 Chloride Channels
• Chloride Channels
• Clcn2 protein, rat
• Neuroprotective Agents
• Proteoglycans
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• chondroitin sulfate proteoglycan 4
• Nitric Oxide Synthase Type II
• Caspase 3
• 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid

Topics

• 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid (pharmacology, therapeutic use)
• Animals
• Antigens (metabolism)
• Apoptosis
• Brain (drug effects, growth & development, metabolism)
• CLC-2 Chloride Channels
• Caspase 3 (metabolism)
• Chloride Channels (antagonists & inhibitors, metabolism)
• Hypoxia-Ischemia, Brain (drug therapy, metabolism)
• Myelin Sheath (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Nitric Oxide Synthase Type II (metabolism)
• Proteoglycans (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)