Heme oxygenase inhibition reduces neuronal activation evoked by bicuculline in newborn pigs

Carbon monoxide (CO) is a product of heme degradation by heme oxygenase (HO) that is highly expressed in the brain. The present study addresses the hypothesis that CO can be involved in brain neuronal function. The effects of the HO inhibitor, tin protoporphyrin (SnPP), on brain electrical activity and pial arteriolar diameter were examined using quantitative electroencephalography (EEG) and cranial window techniques in the bicuculline model of sustained generalized seizures in newborn pigs. SnPP (3 mg/kg i.v.) inhibits brain HO as indicated by blocking cerebral vasodilation to heme and decreasing CO concentration in cortical periarachnoid cerebrospinal fluid. The quantitative spectral analysis of digitalized scalp EEG recordings was performed to determine the EEG amplitude and spectral power within a 1-15-Hz frequency range. SnPP did not affect basal brain EEG parameters. Bicuculline (3 mg/kg i.v.) immediately (in <1 min) evoked bursts of brain electrical activity characterized by four- to seven-fold increases in EEG amplitude and power in all analyzed frequency bands that occurred simultaneously with cerebral vasodilation. Increased EEG activity and cerebral vasodilation were sustained for a 2h period. SnPP inhibited cerebral vasodilation but did not affect the EEG amplitude evoked by bicuculline. However, 20-40% reductions of the power in 7.5 Hz (theta), 10 and 12.5 Hz (alpha), and a 15-Hz (beta) bands, the major evoked EEG spectral components, were observed for the duration of seizures in SnPP-treated animals. These findings suggest that endogenous CO can have proconvulsant action and affect neuronal activation during seizures.