Acta Pharmacologica Sinica 2007 August; 28 (8): 1097-1104; doi: 10.1111/j.1745-7254.2007.00624.x

Aim: To investigate the effects of lithium (Li) and prostaglandin A₁ (PGA₁) on the expression of heat shock factor 1 (HSF-1), heat shock proteins (HSP), and apoptosis protease activating factor-1 (Apaf-1) induced by permanent focal ischemia in rats).

Methods: The rats were pretreated with a subcutaneous (sc) injection of Li for 2 d or a single intracerebral ventricle (icv) administration of PGA₁ for 15 min before ischemic insult, or a combination of Li (sc, 1 mEq/kg, 2 d) and PGA₁ (icv, 15 min prior to ischemic insult). Brain ischemia was induced by the permanent middle cerebral artery occlusion (pMCAO). Twenty-four hours after the occlusion, the expression of HSF-1, HSP, and Apaf-1 in the ischemic striatum were examined with Western blot analysis.

Results: The expression of HSF-1, heme oxygenase-1 (HO-1), HSP90a, and Apaf-1 were significantly increased, but the expression of HSP90b was significantly decreased 24 h after the pMCAO. PGA₁ and Li and their combination significantly enhanced the ischemia-induced elevation in the levels of HSF-1, HO-1, and HSP90α, and recovered HSP90β expression, but decreased Apaf-1 levels in the ischemic striatum.

Conclusion: The present study demonstrates that PGA₁ and Li have synergistic effects on the enhancement of the expression of HSP, suggesting that the synergistic effects of PGA₁ and Li in the rat model of permanent focal cerebral ischemia may be mediated by the enhancement expression of HSP expression and the downregulation of Apaf-1. Our studies suggest that combined PGA₁ and Li may have potential clinical value for the treatment of stroke.

Keywords: prostaglandin A₁; lithium; oxidative stress; heat shock factor 1; cerebral ischemia; Apaf-1; HO-1; HSP90α; HSP90β