Nonenzymatic derived lipid peroxide, 8-iso-PGF_2α, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model

Abstract

We studied whether 8-iso-PGF2alpha, nonenzymatic arachidonyl peroxide, participated in the pathogenesis of delayed vasospasm using a canine subarachnoid hemorrhage (SAH) model. Fourteen adult mongrel dogs were divided into two groups, two-hemorrhage SAH group (n = 8) and control group (n = 6). The contents of 8-iso-PGF2alpha in CSF, the basilar artery segment, and subarachnoid clot were measured by enzyme immunoassay kit. The CSF 8-iso-PGF2alpha content on Day 7 in the SAH group was 67.9+/-29.9 pg ml(-1) (n = 8), which was significantly higher than 27.1+/-13.8 (n = 8) on Day 0 in the SAH group, and 33.2+/-14.4 pg ml(-1) (n = 5) on Day 7 in the control group. The 8-iso-PGF2alpha content in the basilar artery segment with spasm on Day 7 in the SAH group was 13.5+/-1.9 pg mg(-1) wet weight (n = 8), significantly higher than 8.7+/-1.9 (n = 6) in the control group. The 8-iso-PGF2alpha content in subarachnoid clot was 1.7+/-1.4 ng g(-1) wet weight (n = 8). Significant elevation of the 8-iso-PGF2alpha contents in the CSF and the basilar artery segment occurred on Day 7 in the SAH group. The subarachnoid clot enclosed the basilar artery on Day 7, contained a considerable amount of 8-iso-PGF2alpha. These results suggested that 8-iso-PGF2alpha could play a crucial role in the pathogenesis of the delayed cerebral vasospasm.

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

“…It is likely that the release of vasoconstrictor mediators by clotting blood plays a major role in triggering the fall in CBF after SAH. This conclusion is further supported by previous findings that the levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), PAF (18), and 5-HT (6,43) in CSF all increase after SAH. In addition, this view is consistent with the evidence that cerebral vasospasm after SAH is attenuated by inhibitors of endothelin synthesis or receptors (10, 12), 5-HT receptor antagonists (6), and inhibitors of downstream second messengers of cerebral vasoconstriction, including Ras, Rho, MAPK, and PKC (25,26,33,52).…”

“…Superoxide radicals at low concentration have been reported to constrict vessels in several vascular beds in part by decreasing the levels of nitric oxide (NO) (13,42), and there is a recent report that supports a similar mechanism in cerebral arteries (55). Free radicals also increase the production of lipid peroxides and isoprostanes (20,44) that are potent constrictors of cerebral arteries (19).…”

“…The levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), platelet-activating factor (PAF) (17) and serotonin (5-HT) (6,43) in CSF all increase after SAH, and the response of cerebral arteries to most of these constrictors is enhanced. Cerebral vasospasm after SAH has been reported to be attenuated by inhibitors of endothelin synthesis or receptors (10,12), by 5-HT receptor antagonists (6), and by inhibitors of the downstream effectors of these vasoconstrictors, including Ras, Rho, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) (25,26,33,52).…”

Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats

“…We previously showed that 8-ISO level, which is a sensitive indicator of tissue lipid peroxidation (LPO) concentration (Wood et al, 2003), increased in lungs, in agreement with other data (Razavi et al, 2005). In the present study, the increase in tissue 8-ISO levels after carrageenan injection correlates with other experimental studies (Basu et al, 2001;Chung et al, 2011;Sakamoto et al, 2002). Agonist administration decreased 8-ISO levels in paw tissue, prompting us to think that stimulation of 5-HT 7 receptors protected paw tissue by reducing oxidative stress.…”

The Redox Activity of Hemoglobins: From Physiologic Functions to Pathologic Mechanisms

“…Like the contamination of the kidney with Mb, the CSF is contaminated with Hb. With a reduced antioxidant capacity, oxidative damage occurs that may lead to the formation of IsoPs in the CSF (235). Also, like that of rhabdomyolysis, we have shown by HPLC that the respiratory hemoprotein in the CSF is modified such that a percentage of the protein is in the heme-to-protein cross-linked form, demonstrating that Hb undergoes redox cycling in the CSF (Fig.…”