Post‐ischaemic treatment with the cyclooxygenase‐2 inhibitor nimesulide reduces blood–brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats

Abstract

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/ kg) on prostaglandin E 2 (PGE 2 ) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post-ischaemic treatment with nimesulide markedly reduced the increase in PGE 2 levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…Focal cerebral ischemia was done by tMCAO using the intraluminal filament method as previously described by our group (Candelario‐Jalil, Gonzalez‐Falcon, Garcia‐Cabrera, Leon, & Fiebich, 2007; Frankowski et al., 2015; Hawkins et al., 2014). Briefly, non‐fasted rats were anesthetized with isoflurane (4% for induction and 2% for maintenance) in medical‐grade oxygen.…”

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

“…Cox-2-deficient mice are protected against brain ischemia (2), and inhibition of COX-2 provides beneficial effects against ischemic damage and neuronal death (3)(4)(5)(6), suggesting a detrimental effect of COX-2 in stroke. In contrast, in neurodegenerative diseases, COX-2 inhibitors are not protective in mouse models of Alzheimer disease (7) and did not show benefits in clinical trials in Alzheimer disease patients (8) or in patients with mild cognitive impairment (9).…”

TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress

“…These data suggest that hypoxic stress triggers alterations to cytoskeletal structure that contribute to BBB disruption and that calcium influx through TRPC channels contributes to these events. cation channels; endothelial cell; stroke; blood-brain barrier; calcium; transient receptor potential C channels BREAKDOWN of the blood-brain barrier (BBB) contributes to edema formation, infarct size, and brain damage following ischemic stroke (3,10,36,39). There are many factors contributing to BBB disruption in ischemia, including generation of oxygen radicals (24, 56, 58), nitric oxide (22, 42), production of vascular endothelial growth factor (67, 69), and changes in intracellular calcium (5,26,35).…”

“…BREAKDOWN of the blood-brain barrier (BBB) contributes to edema formation, infarct size, and brain damage following ischemic stroke (3,10,36,39). There are many factors contributing to BBB disruption in ischemia, including generation of oxygen radicals (24,56,58), nitric oxide (22,42), production of vascular endothelial growth factor (67,69), and changes in intracellular calcium (5,26,35).…”