Abstracts

NO is a potent vasodilator involved in the regulation of local cerebral blood flow (LCBF) in physiological and pathological situations. The mechanisms coupling the neuronal activity to the vascular response during seizures have to be clarified. The role of NO in the cerebrovascular response to generalized or focal seizures has been shown, but the origin of NO (endothelial or neuronal) remains to be elucidated. We investigated LCBF in limbic areas in response to partial seizures in mice lacking the neuronal (nNOS-/-) or endothelial isoform of NO synthase (eNOS-/-). nNOS-/- mice, eNOS-/- mice and their paired wild type controls, nWT- and eWT mice (Jackson Laboratory) received a unilateral injection of kainate (KA, 50 nl;1nmol) or saline within the right dorsal hippocampus under equithesin anesthesia. Four monopolar electrodes were implanted over the frontal and parietal cortices for EEG recordings. LCBF was measured upon awakening from anesthesia during partial seizures (4-6h after KA injection) using the quantitative autoradiographic ¹⁴C-iodoantipyrine method. LCBF was quantified in 14 limbic areas ipsi- and contralaterally to the injection site. In nWT- and eWT mice, KA seizures led to ipsilateral 23-52% LCBF increases restricted to the hippocampus. Contralaterally, seizures induced LCBF decreases (27-41%) in all hippocampal areas, cingulate and parietal cortices, and amygdala of eWT mice, and in CA3, subiculum, perirhinal and entorhinal cortices of nWT mice, compared to saline-injected animals. In seizing nNOS-/- mice, hippocampal LCBF displayed ipsilateral 31-88% increases but no contralateral change, compared to saline-injected nNOS-/- mice. Conversely, a significant 27-47% contralateral decrease was recorded in the other limbic areas of nNOS-/- treated with KA, compared to saline. In eNOS-/- mice, seizures induced no ipsi- or contralateral change in LCBF within the hippocampus. However, KA seizures induced significant 22-46% contralateral LCBF decreases in limbic cortices and amygdala of eNOS-/- mice. The absence of LCBF increases in the ipsilateral hippocampus of eNOS-/- mice during seizures emphasizes the role of NO of endothelial origin in the vascular response within the epileptic focus. Contralaterally, the LCBF decreases during seizures in limbic cortices in both eNOS and nNOS-/- mice demonstrate the involvement of both isoforms of NOS in seizure-induced vascular changes within areas distant from the focus. Thus, NO appears to play a role in the redistribution of LCBF between the focus and the other brain regions during partial seizures. The specific involvement of endothelial and/or neuronal NO appears to depend on the structure. (Supported by Institut National de la Recherche et de la Sante Medicale (U398) and NATO grant n[deg] 960716)