Protective Effects of the Soluble Epoxide Hydrolase Inhibitor 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea in a Rat Model of Permanent Middle Cerebral Artery Occlusion

Abstract

Acute ischemic stroke is a serious disease that endangers human health. In our efforts to develop an effective therapy, we previously showed that the potent, highly selective inhibitor of soluble epoxide hydrolase called 1-trifuoromethoxyphenyl-3-(1propionylpiperidin-4-yl) urea (TPPU) protects the brain against focal ischemia in rats. Here we explored the mechanism of TPPU action by assessing whether it could preserve blood-brain barrier integrity and reduce apoptosis in the brain during permanent middle cerebral artery occlusion in male Sprague-Dawley rats. TPPU administration at the onset of stroke and once daily thereafter led to smaller infarct volume and brain edema as well as milder neurological deficits. TPPU significantly inhibited the activity of soluble epoxide hydrolase and matrix metalloproteases 2 and 9, reducing 14,15-DHET levels, while increasing expression of tight junction proteins. TPPU decreased numbers of apoptotic cells by down-regulating the pro-apoptotic proteins BAX and Caspase-3, while upregulating the anti-apoptotic protein BCL-2. Our results suggest that TPPU can protect the blood-brain barrier and reduce the apoptosis of brain tissue caused by ischemia.

Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine

“…Furthermore, treatment with TPPU does not improve daily neurologic deficit scores above those observed in piglets administered vehicle after CA. Despite efficacy in rodent models of global [ 16 , 17 ] and focal hypoxic brain injury [ 15 , 27 , 28 ], short-term therapy with an sEH inhibitor is not neuroprotective after CA in this pediatric swine model.…”

“…There are several considerations for the lack of neuroprotection in this study. We used a TPPU dose of 1 mg/kg based on our own and others’ experiences with a rodent model of focal ischemic brain injury [ 15 , 28 ]. To our knowledge, TPPU has not been used in swine injury models, and the pharmacokinetics may differ from that of rodents and cynomolgus monkeys, in which the half-life is approximately 10 h [ 29 ] and 30 h [ 30 ], respectively.…”

“…Moreover, the potency of different sEH inhibitors for sEH can differ markedly among species [ 30 , 33 ]. Furthermore, discrepant outcomes have been reported with both higher- and lower-than-optimal TPPU doses in studies examining dose escalation [ 28 , 34 – 36 ].…”

“…However, it is possible that earlier administration after CA is necessary for neuroprotection, especially since molecular pathways of cell death are activated within 15 min of injury in this swine model [ 37 ]. One study in mice demonstrated neuroprotection when an sEH inhibitor was administered within 5 min of ROSC [ 16 ], and other stroke models have suggested a greater benefit when sEH inhibitor is administered earlier, such as before injury [ 13 , 27 , 38 ], at the onset of ischemia [ 28 ], or at the time of reperfusion [ 15 ]. Another explanation for the apparent species differences in the neuroprotective efficacy of TPPU could be that neuronal responses and cell death mechanisms are differential and nuanced in rodents and pigs [ 39 ] or depend upon developmental stage.…”

“…It is also possible that the 24-h duration of TPPU therapy in this study was insufficient. Other studies have demonstrated neuroprotection with daily dosing of sEH inhibitors for 3 days after MCAO [ 28 , 41 ]. Moreover, we have previously shown that neuronal cell death peaks at 24 h in striatum [ 42 ] but is progressive over 4 days [ 20 ].…”