Induced spreading depressions in energy-compromised neocortical tissue: calcium transients and histopathological correlates.

Mechanisms causing gradual recruitment of damaged cells in the penumbra zone around the core of a focal ischaemic lesion may encompass irregularly occurring depolarization waves of the spreading depression (SD) type, each leading to transient loading of cells with calcium. It has been speculated that, when elicited in an underperfused or otherwise energy-compromised tissue, such depolarization waves lead to cell damage. We assessed under what conditions the calcium transients during KCl-induced SDs are prolonged, and explored if marked prolongation of the transients leads to brain damage. Cerebral blood flow (CBF) was reduced by marked hypocapnia. Tissue oxygenation was reduced by arterial hypoxia, without or with unilateral carotid artery occlusion, or by occlusion of the carotid arteries in normoxic, anaesthetized rats. In all animals the DC potential and extracellular calcium concentration (Ca2+e) were measured before and during a series of SDs. The animals were recovered for histopathological assessment. Hypoxia alone (Pao2, 32.5 +/- 3.8 mmHg) increased mean and total depolarization times, but repeated SDs elicited over 1.7 (+/-0.4) h failed to induce cell damage. Unilateral carotid artery occlusion further prolonged the SD waves but, in spite of total depolarization times of up to 40 min during 2 h, only two out of seven animals showed damage, localized to caudoputamen and parietal cortex, as well as to the subiculum, CA1 and CA3 sectors of the hippocampus. Bilateral carotid artery occlusion was associated with the most pronounced prolongation of the DC potential shifts and Ca2+ transients, with total depolarization times of up to 70 min. In spite of this, only four out of 13 animals showed brain damage and in two of these the damage was contralateral. The results justify modification of the hypothesis stating that SD-like depolarizations in the perifocal penumbra zone per se is what leads to gradual recruitment of such tissues in the infarction process. It is suggested that additional factors are required, such as a larger reduction in CBF, or the proximity of cells at risk to necrotic tissue.