OBJECTIVES: The aim of this study was to evaluate the effect of cortical spreading depression (CSD) on the metabolic, hemodynamic, electrical and ionic properties during anesthesia as compared with the awake state. METHODS: The mitochondrial NADH redox state, reflected light, direct current (DC) potential, electrocorticography (ECoG), cerebral blood flow (CBF) and volume (CBV), and extracellular K(+) concentrations (K(+)), were measured continuously and simultaneously in real time using two unique monitoring systems that evaluate brain function. Three consecutive CSD waves were initiated using a KCl solution in both awake and anesthetized rats. RESULTS AND DISCUSSION: CSD caused typical amplitude changes: biphasic waves in reflectance, oxidation cycles in NADH, an increase in CBF, CBV and in K(+), a negative shift in DC potential and depression in ECoG. Anesthesia by equithesin decreased significantly the baseline levels of CBF and K(+), showing a reduction in oxygen supply and demand. After anesthesia, CSD significantly decreased K(+) and NADH oxidation cycles, indicating a reduction in oxygen demand and in oxygen balance, respectively. Furthermore, anesthesia reduced CSD wave frequencies by slowing the recovery period, showing a decline in energy production during brain activation, or by changing electrophysiological properties of the tissue. No changes were found in the propagation rate and in the initiation period of CSD, which may indicate that equithesin does not block CSD initiation. In addition, we found that the whole cerebral cortex reacts homogenously to CSD and that equithesin may reduce oxygen demand and energy production, which may have a protective effect on the brain exposed to pathophysiological conditions.