Role of nitric oxide and serotonin in modulation of cortical spreading depression-evoked neurogenic vasculare inflammation

Abstract

Cortical spreading depression (CSD) is a possible physiological phenomenon underlying aura phase of migraine. However, definite relationship between CSD and the generation of headache as well as changes in cerebrovascular flow is not well understood. This study was conducted to investigate the role of nitric oxide (NO) and serotonin (5-HT) in pathophysiologic mechanism of cerebrovascular changes induced by CSD. Adult male Wistar rats were divided into two main groups, including the control group and the CSD group. CSD was induced by topical application of solid KCI 3 mg on the parietal brain surface where solid NaCI was served as a control. The rats from each group were further divided into three sub-groups (5 rats each) receiving normal saline (NSS), L-NAME and naratriptan-treated group. L-NAME and naratriptan were used as NOS inhibitor and 5-HT 1B receptor agonist, respectively. Regional cerebral blood flow (rCBF) and pial arteriolar diameter were chosen as outcome measures. The rCBF was monitored by the laser Doppler flowmetry (LDF) and pial arteriolar diameter was measured by the fluorescent microscopic technique. The results showed that KCI application induced the repeated pattern of hyperemic cycles. The fluorescent microscope showed the vasodilation-vasoconstriction cycles which its temporal pattern correlated well with the signal from LDF. Administration of L-NAME could minimize the amplitude of hyperemic peaks as well as the maximal vasodilation of hyperemic cycles. The minimizing effect of L-NAME on cerebral hyperemia depended on its dosage. Our findings suggest that CSD evokes cerebral hyperemia via activating NO pathway. On the other hand, administration of naratriptan at the dose of 0.1 mg/kg BW did not decrease cerebral hyperemia evoked by CSD. The data suggest that activation of this class of vascular receptor may play a minor role in this process. Based on these findings, we conclude that the stimulation of nNOS activity may play a major role in CSD-evoked cerebral hyperemia. This information may further clarify the physiologic mechanism underlying the changes in CBF observe during migraine attack.