Effect of middle cerebral artery occlusion on the passage of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier in therat

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown t o be a potent neuroprotective agent in global and focal ischemia. We demons trated that PACAP could cross the blood-brain barrier (BBB) by a saturable transport system, and a systemic administration of PACAP reduced the infarc t induced by unilateral middle cerebral artery occlusion (MCAO). Therefore, we studied whether this transport system is affected by MCAO in the rat. T he entry of PACAP38 into the brain was compared in five groups: control, 4, 6, 24, and 48 h after MCAO. [I-125]PACAP38 was injected intravenously and serum and various brain regions were collected 3 min later. The rate of ent ry into the brain of PACAPS8 was also determined. We showed that PACAP ente red the rat brain via a rapid transport system when the BBB is intact. Afte r transient (2 h) unilateral MCAO, all regions of the brain, showed a selec tive increase in the passage of PACAP38 across the BBB after 4 h after the occlusion, which was not related to any generalized change in the permeabil ity of the BBB, as measured with albumin. A significant decrease in the amo unt of PACAP38 entering the brain was observed in the 6- and 24-h groups, b ut it returned to the baseline level in the 48-h group. These results sugge st that focal cerebral ischemia can selectively modify the passage of PACAP S8 across the BBB, in both damaged and undamaged sides of the brain, and th at these changes in influx are not solely due to the disruption of BBB. The se findings imply the necessity of adjusting the dose of intravenously admi nistered PACAP38 in order to maximize its therapeutic effect on the brain d amage resulting from focal ischemia (C) 2000 Elsevier Science BN. All right s reserved.