The effect of serotonin depletion on the cortical spreading depression induced alteraion of blood brain barrier

Abstract

Serotonin (5-HT) depletion is one of the important pathogenesis involved in migraine pathophysiology. This neurotransmitter is involved in both neural and vascular controls. Previous studies in the cortical spreading depression (CSD) migraine animal model demonstrated that depletion of serotonin could induce the hyper-excitability of cortical neurons. Since the tight association between the neuron and the blood brain barrier (BBB), the alteration of the BBB integrity in 5-HT depleted state can be expected. However, the alteration of BBB induced by 5-HT depletion and the mechanism underlying of this event have never been studied. In order to clarify this point, this study aims to investigate the effect of 5-HT depletion on the CSD induced alteration of the BBB integrity and the expression of neuropeptides SP and CGRP in the trigeminal ganglion in 5-HT depleted state. Wistar rats were divided into four groups: control, CSD, 5-HT depletion, and 5-HT depletion with CSD group. 5-HT was depleted by intraperitoneal injection with parachlorophenylalanine (PCPA) 3 days before the experiment. The CSD was induced by KCl application on the cortical surface. The results from this study demonstrated that the induction of CSD in the 5-HT depletion can significantly increase the number of endothelial pinocytic vesicles and microvilli compared with those observed the control and CSD group. The degree of astrocytic foot plate swelling in 5-HT depletion with CSD group was more severe than that in the CSD group. The analysis of tight junction demonstrated that alignment of tight junction between the endothelial cells in the 5-HT depleted with CSD group demonstrate the increased of the BBB permeability compared with those observed in the CSD group. The results from the ultrstructural study are in line with the result from protein analysis by western blotting. The expression of occludin, ZO-1, and ZO-2, which are the important tight junction proteins, are all decreased in the 5-HT depleted with CSD group. In addition, we have found that the depletion of serotonin could induce an significant increment of CGRP and SP expression in TG as compared with those observed in rats with a normal level of 5-HT. Altogether, it can be concluded that CSD activation in the serotonin depletion can result in both the increment of the BBB permeability and the expression of vasoactive neuropeptide (CGRP and SP) in TG. These abnormalities of the BBB observed in 5HT depletion from this study might be one explanation for the close association between migraine and cerebrovascular disease.