Activation of either the ETA or the ETB receptors is involved in the development of electrographic seizures followed intrahippocampal infusion of the endothelin-1 in immature rats
Abstrakt
The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome.
Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-dayold rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40 pmol/μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70 nmol/μl) or ETB receptors (BQ788; 70 nmol/1 μl).
Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40 pmol/1 μl). Regional cerebral blood flow(rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively.
Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volumeof the appropriate vehicle (10mMPBS or 0.01%DMSO- PBS solution; pH 7.4).
The extent of hippocampal lesion was determined using FluoroJade B staining performed 24 h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5 h,whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels.
Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors...