Bexarotene Exerts Protective Effects Through Modulation of the Cerebral Vascular Smooth Muscle Cell Phenotypic Transformation by Regulating PPARγ/FLAP/LTB4 After Subarachnoid Hemorrhage in Rats

Vascular smooth muscle cells (VSMCs) play an important role after a subarachnoid hemorrhage (SAH). The changes in VSMCs following bexarotene treatment after SAH are unknown. In the present study, neurological impairment, decreased cerebral cortical blood flow and transformation of cerebral VSMCs from a contractile to a synthetic phenotype were observed after SAH. Bexarotene reduced neurological impairment, improved cerebral cortical blood flow, inhibited VSMC phenotypic transformation and suppressed the expression of 5-lipoxygenase-activating protein (FLAP) and leukotriene B4 (LTB4), which was partly reversed by GW9662, an inhibitor of peroxisome proliferator-activated receptor gamma (PPARγ). Mechanistically, sh-PPARγ-mediated phenotypic transformation of VSMCs was partially suppressed by MK886, an antagonist of FLAP. Therefore, we conclude that bexarotene reduced neurological impairment, improved cerebral cortical blood flow and inhibited the VSMC phenotypic transformation after SAH, which was achieved by activating PPARγ-mediated inhibition of FLAP/LTB4 in VSMCs

Effect of serotonin depletion on cortical spreading depression evoked cerebrovascular changes

Background: The cortical spreading depression (CSD) is a phenomenon associated with several pathological conditions including migraine. It can induce alterations in both neural and vascular compartments. Serotonin (5-HT) depletion is known as a condition involved in migraine pathophysiology. The hyper-excitability of the cortical neurons to the CSD activation in the low 5-HT state has been previously reported. However, the cerebrovascular responses to CSD activation in this condition have never been studied yet. Objectives: Determine the effect of 5-HT depletion on the cerebrovascular responses to CSD activation. Methods: Wistar rats (weighing 250-300 grams) were divided into three groups: control, CSD, and low 5-HT with CSD group (five rats per group). To induce the low 5-HT state, the para-chlorophenylalanine was injected intraperitoneally into the rats three days before the experiment. CSD was induced by the application of solid KCl (3 mg) on the parietal cortex. NaCl instead of KCl was applied to the control group. Cerebral cortical blood flow was monitored using Laser Doppler flowmetry. The ultrastructure of cerebral microvessels was examined using electron microscopy to determine the cerebral microcirculatory responses to CSD. Results: Depletion of serotonin induced a significant increase in the peak amplitude of CSD-evoked cerebral hyperaemia. This condition also enhanced the development of CSD-induced endothelial pinocytosis and microvillus formation in cerebrocortical microvessels. Conclusion: 5-HT was an important neurotransmitter involved in the control of cerebrovascular responses to CSD activation. The hypersensitivity of the cerebrovascular responses observed in the 5-HT depleted state may explain the relationship between headache and 5-HT depletion.

Isoflurane-induced Cerebral Hyperemia Is Partially Mediated by Nitric Oxide and Epoxyeicosatrienoic Acids in Mice In Vivo

Background Despite intense investigation, the mechanism of isoflurane-induced cerebral hyperemia is unclear. The current study was designed to determine the contributions of neuronal nitric oxide synthase, prostaglandins, and epoxyeicosatrienoic acids to isoflurane-induced cerebral hyperemia. Methods Regional cerebral cortical blood flow was measured with laser Doppler flowmetry during stepwise increases of isoflurane from 0.0 to 1.2, 1.8, and 2.4 vol% end-tidal concentration in alpha-chloralose-urethane-anesthetized, C57BL/6 mice before and 45 min after administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI, 40 mg/kg, intraperitoneal), the cyclooxygenase inhibitor indomethacin (INDO, 10 mg/kg, intravenous), and the cytochrome P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 20 mg/kg, intravenous). Results Isoflurane increased regional cerebral cortical blood flow by 9 +/- 3, 46 +/- 21, and 101 +/- 26% (SD) at 1.2, 1.8, and 2.4 vol%, respectively. The increases in regional cerebral cortical blood flow were significantly (*P < 0.05) smaller after 7-NI (5 +/- 6, 29 +/- 19*, 68 +/- 15%*) or PPOH (4 +/- 8, 27 +/- 17*, 67 +/- 30%*), but not after administration of INDO (4 +/- 4, 33 +/- 18 [NS], 107 +/- 35% [NS]). The effect of combined treatment with 7-NI, PPOH, and INDO was not additive and was equal to that of either 7-NI or PPOH alone (5 +/- 5, 30 +/- 12*, 76 +/- 24%*). Chronic treatment of mice for 5 days with 7-NI (2 x 40 mg/kg, intraperitoneal) produced similar decreases in regional cerebral cortical blood flow as those seen with acute administration. Neither PPOH nor INDO conferred a significant additional block of the hyperemia in these animals. Conclusions Nitric oxide and epoxyeicosatrienoic acids contribute to isoflurane-induced hyperemia. However, only approximately one third of the cerebral hyperemic response to isoflurane is mediated by autacoids. The remaining part of this response appears to be mediated by a direct action of isoflurane on smooth muscle by some yet-unknown mechanism.