Local cerebral glucose utilization and cytoskeletal proteolysis as indices of evolving focal ischemic injury in core and penumbra.
To ascertain the tempo of progression to irreversible injury in focal ischemia, we subjected halothane-anesthetized Sprague-Dawley rats to photochemically induced distal middle cerebral artery occlusion (dMCAO) combined with permanent ipsilateral and 1 h contralateral common carotid artery occlusions. Head temperature was maintained at 36 degrees C. At times centered at either 1.5 or 3 h post-dMCAO, the rate of local glucose metabolism (lCMRgl) was measured by 2-deoxyglucose autoradiography, and cytoskeletal proteolysis was assessed regionally by an immunoblotting procedure to detect spectrin breakdown products. At 1.5 h (n = 5), the cortical ischemic core was already severely hypometabolic (lCMRgl 15.5 +/- 10.8 mumol 100 g-1 min-1, mean +/- SD), whereas the cortical penumbral zone was hypermetabolic (69.0 +/- 9.7). (The lumped constant was verified to be unchanged by methylglucose studies). Neutral red pH studies at this time point showed that both the core and penumbral zones were equally acidotic. By 3 h post-dMCAO (n = 6), lCMRgl in the penumbral zone had fallen to low levels (15.4 +/- 2.2 mumol 100 g-1 min-1) equal to those of the ischemic core (16.7 +/- 4.5). Correspondingly, spectrin breakdown in the ischemic core was advanced at both 2 and 3.5 h post-dMCAO (36 +/- 18% and 33 +/- 18% of total spectrin, respectively), whereas in the penumbral zone spectrin breakdown was less extensive and more highly variable at both times (22 +/- 23% and 29 +/- 16%). We conclude that irreversible deterioration of the ischemic core, as evidenced by the onset of local cytoskeletal proteolysis, begins within 2 h of middle cerebral artery occlusion. In the ischemic penumbra, the transition from glucose hyper- to hypometabolism occurs by 3.5 h and is associated with a milder and more variable degree of spectrin breakdown.
Yao
H
H
Department of Neurology, University of Miami School of Medicine, FL 33101, USA.
Ginsberg
M D
MD
Eveleth
D D
DD
LaManna
J C
JC
Watson
B D
BD
Alonso
O F
OF
Loor
J Y
JY
Foreman
J H
JH
Busto
R
R
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000378:metabolism
D003598:Cytoskeletal Proteins; D013049:Spectrin; D002154:Calpain; D005947:Glucose