Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model

Abstract

Recently, a number of non-beneficial effects of chronic treatment with paracetamol (APAP) have been reported in several systems, including circulatory system. In this study, the effects of acute (1 hour) and chronic (30 days) APAP treatments on cerebral microvessels in a cortical spreading depression (CSD) migraine animal model were investigated. Rats were divided into control, CSD only, and APAP treatment with or without CSD groups. A single dose (200 mg/kg body weight) or once-daily APAP treatment over 30 days was intraperitoneally injected into the acute and chronic APAP treated groups, respectively. CSD was induced by topical application of potassium chloride on the parietal cortex. Ultrastructural alterations and the expressions of cell adhesion molecules (ICAM-1 and VCAM-1) of the cerebral microvessels were monitored in all experimental groups. The results demonstrated that the induction of CSD caused ultrastructural alterations of the cerebral endothelial cells, as indicated by increases in microvillous and pinocytic formations and swelling of the astrocytic foot plates. The expression of ICAM-1 was significantly elevated in the CSD groups as compared with the control groups. Pretreatment with APAP 1 hour prior to CSD activation attenuated the alterations induced by CSD. However, chronic APAP treatment resulted in an enhancement of the ultrastructural alterations and the expressions of cell adhesion molecules in the cerebral microvessels that were induced by CSD. Interestingly, the rats that received chronic APAP treatment alone exhibited higher degrees of ultrastructural alterations and ICAM-1 expression than those in the control group. Based on these results, we suggest that short-term treatment with APAP has no effect on cerebral microvessels and that chronic APAP treatment can alter cerebral microvasculature, especially when combined with CSD activation.

Keywords: Blood brain barrier; Cell adhesion molecule; Cerebral microvessel; Cortical spreading depression; Intercellular adhesion molecule-1; Long-term treatment; Migraine; Paracetamol; Ultrastructure; Vascular cell adhesion molecule-1.