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Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels.
Neuroscience. 2008 Dec 10; 157(4):884-94.N

Abstract

The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (KATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of KATP channel openers is available. We hypothesized that pretreatment with a KATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new KATP channel opener, which is selective for SUR2 type KATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood-brain barrier, water content, Na+ and Ca2+ concentration, and activities of Na+,K+-ATPase, Ca2+-ATPase and Mg2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K(ATP) channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K(ATP) channels, suggesting a new therapeutic strategy for stroke treatment.

Authors+Show Affiliations

Department of Environmental Medicine, Tianjin Institute of Hygiene and Environmental Medicine, Tianjin 300050, China.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18951957

Citation

Zhu, H-L, et al. "Iptakalim Protects Against Hypoxic Brain Injury Through Multiple Pathways Associated With ATP-sensitive Potassium Channels." Neuroscience, vol. 157, no. 4, 2008, pp. 884-94.
Zhu HL, Luo WQ, Wang H. Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. Neuroscience. 2008;157(4):884-94.
Zhu, H. L., Luo, W. Q., & Wang, H. (2008). Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. Neuroscience, 157(4), 884-94. https://doi.org/10.1016/j.neuroscience.2008.09.033
Zhu HL, Luo WQ, Wang H. Iptakalim Protects Against Hypoxic Brain Injury Through Multiple Pathways Associated With ATP-sensitive Potassium Channels. Neuroscience. 2008 Dec 10;157(4):884-94. PubMed PMID: 18951957.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. AU - Zhu,H-L, AU - Luo,W-Q, AU - Wang,H, Y1 - 2008/10/01/ PY - 2008/01/13/received PY - 2008/09/17/revised PY - 2008/09/18/accepted PY - 2008/10/28/pubmed PY - 2009/4/16/medline PY - 2008/10/28/entrez SP - 884 EP - 94 JF - Neuroscience JO - Neuroscience VL - 157 IS - 4 N2 - The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (KATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of KATP channel openers is available. We hypothesized that pretreatment with a KATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new KATP channel opener, which is selective for SUR2 type KATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood-brain barrier, water content, Na+ and Ca2+ concentration, and activities of Na+,K+-ATPase, Ca2+-ATPase and Mg2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K(ATP) channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K(ATP) channels, suggesting a new therapeutic strategy for stroke treatment. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/18951957/Iptakalim_protects_against_hypoxic_brain_injury_through_multiple_pathways_associated_with_ATP_sensitive_potassium_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(08)01402-4 DB - PRIME DP - Unbound Medicine ER -