Pharmacologic investigations on the role of Sirt-1 in neuroprotective mechanism of postconditioning in mice.
BACKGROUND
Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effects of iPoCo. However, the neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of Sirtinol, a selective class III histone deacetylase (HDAC) inhibitor in the neuroprotective mechanism of iPoCo in mice.


METHODS
Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce I-R-induced cerebral injury in Swiss albino mice. iPoCo involving three episodes of 10-s carotid artery occlusion and reperfusion instituted immediately after BCAO just before prolonged reperfusion of 24 h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam-walking test, and neurologic severity score (NSS) were used to assess motor incoordination. Acetylcholine esterase levels, brain thiobarbituric acid reactive species (TBARS), and glutathione level were also estimated.


RESULTS
BCAO for 12 min followed by reperfusion for 24 h produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (↑acetylcholine esterase, ↓glutathione, and ↑TBARS). iPoCo, involving three episodes of 10-s carotid artery occlusion with intermittent reperfusion of 10 s applied just after ischemic insult of 12 min produced a significant decrease in cerebral infarct size and NSS along with the reversal of I-R-induced impairment of memory and motor coordination. iPoCo-induced neuroprotective effects were significantly abolished by pretreatment with selective SIRT 1 (class III HDAC) blocker Sirtinol (10 mg/kg intraperitoneal).


CONCLUSIONS
It may be concluded that the neuroprotective effect of iPoCo probably involves activation of SIRT 1 (class III HDAC) enzyme.
CNS Research Lab, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Harpreet
H
Kaur
CNS and CVS Research Lab, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Amit
A
Kumar
Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Amteshwar S
AS
Jaggi
Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India. Electronic address: nirmal_puru@rediffmail.com.
Nirmal
N
Singh
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002544:Cerebral Infarction / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D057775:Ischemic Postconditioning; D008297:Male; D051379:Mice; D009284:Naphthols / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*
D001549:Benzamides; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D009284:Naphthols; C439060:sirtinol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Cerebral ischemia; Histone deacetylase; Ischemia–reperfusion injury; Ischemic postconditioning; Sirtinol