Spreading depression (SD) has been demonstrated following focal ischemia, and 
the additional workload imposed by SD on a tissue already compromised by a 
marked reduction in blood flow may contribute to the evolution of irreversible 
damage in the ischemic penumbra. SD was elicited in one group of rats by 
injecting KCl directly into a frontal craniectomy and the wave of depolarization 
was recorded in two craniectomies 3 and 6 mm posterior to the first one. In a 
second group, the middle cerebral artery was occluded using the monofilament 
technique and a recording electrode was placed 5 mm lateral to the midline and 
0.2 mm posterior to bregma. To determine the metabolic response in the penumbral 
region of the cortex ipsilateral to the occlusion, brains from both groups were 
frozen in situ when the deflection of the SD was maximal. The spatial metabolic 
response of SD in the ischemic cortex was compared to that in the non-ischemic 
cortex. Coronal sections of the brains were lyophilized, pieces of the 
dorsolateral cortex were dissected and weighed, and analyzed for ATP, 
P-creatine, inorganic phosphate (Pi), glucose, glycogen and lactate at varying 
distances anterior and posterior to the recording electrode. ATP and P-creatine 
levels were significantly decreased at the wavefront in both groups and the 
levels recovered after passage of the wavefront in the normal brain, but not in 
the ischemic brain. Glucose and glycogen levels were significantly decreased and 
lactate levels significantly increased in the tissue after the passage of the 
wavefront. While the changes in the glucose-related metabolites persisted during 
recovery even in anterior portions of the cortex in both groups in the aftermath 
of the SD, the magnitude of the changes was greater in the penumbra than in the 
normal cortex. SD appears to impose an equivalent increase in energy demands in 
control and ischemic brain, but the ability of the penumbra to recover from the 
insult is compromised. Thus, increasing the energy imbalance in the penumbra 
after multiple SDs may hasten the deterioration of the energy status of the 
tissue and eventually contribute to terminal depolarization and cell death, 
particularly in the penumbra.