A Comparative Study of Neuroprotective Effect of Single and Combined Blockade of AT1 Receptor and PARP-1 in Focal Cerebral Ischaemia in Rat

Abstract

Cerebral ischaemia results in enhanced expression of type 1 angiotensin receptor and oxidative stress. Free radicals due to oxidative stress lead to excessive DNA damage causing overactivation of poly (ADP-ribose) polymerase-1 resulting in neuronal death. Activation of both type 1 angiotensin receptors and poly (ADP-ribose) polymerase-1 following cerebral ischaemia takes place simultaneously, but until now, no study has explored the effect of combined blockade of both angiotensin type 1 angiotensin receptor and poly (ADP-ribose) polymerase-1 in cerebral ischaemia. Our purpose was to compare the effect of single and combined treatment with angiotensin type 1 angiotensin receptor blocker, candesartan, and the poly (ADP-ribose) polymerase-1 inhibitor, 1, 5 isoquinolinediol, on brain damage and oxidative stress in transient focal cerebral ischaemia in rats. Transient focal cerebral ischaemia was induced in Sprague-Dawley rats by an intraluminal technique for two-hours following 48 h of reperfusion. Candesartan (0·05 mg/kg) was administered just after initiation of ischaemia followed by a repeat administration at 24 h while 1, 5 isoquinolinediol (0·1 mg/kg) was given one-hour after of ischaemia. After 24 h of reperfusion, neurological deficit was evaluated in the different treatment groups. After 48 h of reperfusion, the rats were sacrificed and the brain was isolated. Ischaemic brain damage by 2,3,5 triphenyl tetrazolium chloride staining, oxidative stress markers, and levels of reactive oxygen species were determined biochemically. Single treatment with candesartan and 1, 5 isoquinolinediol significantly reduced neurological deficit, infarct, and oedema volume as compared to ischaemic control and different vehicle groups for each of the drugs. However, treatment with candesartan + 1, 5 isoquinolinediol offered greater reduction in neurological deficit, cerebral infarct volume, and oedema as compared to single-drug treatments. Furthermore, treatment with candesartan + 1, 5 isoquinolinediol significantly decreased oxidative stress as compared to single treatments with each drug. The study suggests that blockade of either type 1 angiotensin receptor or poly (ADP-ribose) polymerase-1 alone provides neuroprotection, but the better result was achieved when both type 1 angiotensin receptor and poly (ADP-ribose) polymerase-1 were blocked together by the combined use of their pharmacological inhibitor in transient cerebral ischaemia in rat.