Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia.
OBJECTIVE
To examine the effects of a mixed formulation composed of prostaglandin E1 and lithium (PGE1+Li mixture) on brain damage after cerebral ischemia. The effects of the mixture on protein expression of heat shock proteins (HSPs), p53, and Bcl-2 were also determined.


METHODS
Brain ischemia was induced with a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were treated with a single intravenous administration of PGE1, lithium or a PGE1+Li mixture immediately after the ischemic insult. The infarct volume and motor behavior deficits were analyzed 24 h after the ischemic insult. The protein levels of HSP70, glucose-regulated protein 78 (GRP78), HSP60, Bcl-2, and p53 in the striatum of the ipsilateral hemisphere were examined using immunoblotting.


RESULTS
The mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg) reduced infarct volume and neurological deficits induced by focal cerebral ischemia. Moreover, the mixture had a greater neuroprotective effect against cerebral ischemia compared with PGE1 or lithium alone. The mixture was effective even if it was administered 3 h after ischemia. PGE1+Li also significantly upregulated cytoprotective HSP70, GRP78, HSP60, and Bcl-2 protein levels, while decreasing p53 expression.


CONCLUSIONS
These results demonstrated a PGE1+Li mixture with a therapeutic window of up to 3 h for clinical treatment of cerebral ischemia. The PGE1+Li mixture potentially exerts a protective effect after stroke through the induction of HSPs and Bcl-2 proteins.
Department of Pharmacology, Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
Rui
R
Sheng
Li-sha
LS
Zhang
Rong
R
Han
Bo
B
Gao
Xiao-qian
XQ
Liu
Zheng-hong
ZH
Qin
D000527:Alprostadil / Q000627:therapeutic use*; D000818:Animals; D018692:Antimanic Agents / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004338:Drug Combinations; D018020:Lithium Compounds / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D014665:Vasodilator Agents / Q000627:therapeutic use
D018692:Antimanic Agents; D004338:Drug Combinations; D018020:Lithium Compounds; D018696:Neuroprotective Agents; D014665:Vasodilator Agents; D000527:Alprostadil
Mol Neurobiol. 2003 Feb;27(1):33-72
12668901
Vasa. 2004 Aug;33(3):119-24
15461062
Stroke. 1999 Nov;30(11):2464-70; discussion 2470-1
10548685
Biochim Biophys Acta. 2002 Sep 2;1592(1):51-62
12191768
Stroke. 2004 Sep;35(9):2195-9
15243143
Brain Res. 2008 May 7;1208:217-24
18395193
Acta Pharmacol Sin. 2009 Aug;30(8):1071-80
19617892
Exp Neurol. 2007 Dec;208(2):247-56
17931626
J Pharmacol Sci. 2005 Dec;99(4):307-21
16340157
Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S250-4
14677087
J Neurosci. 1999 May 15;19(10):4023-33
10234031
Brain Res. 2006 Aug 2;1102(1):154-62
16797496
J Cereb Blood Flow Metab. 2003 Jun;23(6):718-27
12796720
Blood Rev. 1987 Jun;1(2):141-5
3332095
EMBO J. 1999 Nov 1;18(21):6027-36
10545114
Expert Rev Mol Med. 2004 Oct 18;6(21):1-18
15488156
Brain Res. 1999 Aug 7;837(1-2):38-45
10433986
Brain Res. 2007 Dec 12;1184:270-6
18028886
Exp Neurol. 2004 Jun;187(2):478-86
15144874
J Gastrointest Surg. 2005 Jul-Aug;9(6):758-68
15985230
Bipolar Disord. 2002 Apr;4(2):129-36
12071510
J Biol Chem. 2003 Jun 6;278(23):20915-24
12665508
J Biol Chem. 1996 Jul 26;271(30):17724-32
8663604
Stroke. 1989 Jan;20(1):84-91
2643202
Acta Pharmacol Sin. 2008 Oct;29(10):1141-9
18817617
Brain Res Bull. 2000 Sep 15;53(2):141-6
11044589
Trends Biochem Sci. 2001 Aug;26(8):504-10
11504627
J Cereb Blood Flow Metab. 1981;1(1):53-60
7328138
Neurosci Lett. 2003 Sep 18;348(3):185-9
12932824
Brain Res Mol Brain Res. 1996 Dec;42(2):236-44
9013779
Psychopharmacology (Berl). 2001 Oct;158(1):100-6
11685390
Autophagy. 2010 May;6(4):482-94
20400854
Ann N Y Acad Sci. 2005 Aug;1053:74-83
16179510
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6210-5
12732732
J Biol Chem. 1999 Mar 5;274(10):6039-42
10037682
J Biol Chem. 2000 Aug 18;275(33):25665-71
10806214
Ann Neurol. 2000 Jun;47(6):782-91
10852544