Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain

Abstract

One of the prominent features of Alzheimer's disease is the excessive accumulation of the protein amyloid beta (Aβ) in certain areas of the brain leading to neurodegeneration. Aβ is cytotoxic and disrupts several cytoprotective pathways. Recent literature has demonstrated that certain cytochrome P450 (CYP) products are neuroprotective, including epoxide metabolites of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs). The action of Aβ with respect to regionally produced EETs in the brain has yet to be defined. Epoxygenases metabolize AA into 4 regioisomers of EETs (14,15 -, 11,12-, 8,9- and 5,6-EET). EETs are rapidly degraded into dihydroxyeicosatrienoic acids (DiHETEs) by soluble epoxide hydrolase (sEH). To determine the effect of Aβ on the epoxygenase activity in different regions of the brain, microsomes were prepared from the cerebrum and cerebellum of adult Sprague-Dawley rats and incubated with 1 and 10 μM Aβ for 30 minutes after which epoxygenase activity assay was performed. Mass spectrometry indicated that incubation with Aβ reduced 14,15-EET production by 30% as compared to vehicle in the cerebrum, but not in the cerebellum. When we separated the cerebrum into cortex and hippocampus, significant decrease in the production of total EETs and DiHETEs were seen in presence of Aβ (81% and 74%) in the cortex. Moreover, 11, 12-EET production was decreased to ∼70% of vehicle in both cortex and hippocampus. Epoxygenase activity in the cultured astrocytes and neurons also showed reduction in total EET and DiHETE production (to 80% and ∼70% of vehicle respectively) in presence of Aβ. Altogether, our data suggest that Aβ reduces epoxygenase activity differentially in a region-specific and cell-specific manner. The reduction of cytoprotective EETs by Aβ in the cerebrum may make it more prone to degeneration than the cerebellum. Further understanding of these interactions will improve our ability to protect against the pathology of Alzheimer's disease.

Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication

“…This cytosolic enzyme regulates the levels of the epoxy fatty acids, which are bioactive lipid metabolites with anti-inflammatory properties (Iliff and Alkayed, 2009; Inceoglu et al, 2007). The anti-inflammatory effects of epoxy fatty acids and sEHIs have been demonstrated in other models of neuroinflammation, including a mouse model of scrapie (Poli et al , 2013), a mouse model of neurodegeneration following cardiac arrest (Wang et al, 2013), and an in vitro model of amyloid peptide-induced neurotoxicity (Sarkar et al , 2011). We have previously shown that epoxy fatty acids and sEHIs protect against seizures induced by PTZ, and this anticonvulsant activity seems to be mediated, in part, by augmentation of GABAergic signaling (Inceoglu et al, 2013).…”

14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

“…The 14,15-EET is enriched in the brain cortex and exerts neuroprotective effect on neuronal cells in ischemia and reperfusion [2][3][4][5][6]. Numerous studies demonstrate that the decline in mitochondrial biogenesis and suppression of mitochondrial function are involved in the essential pathological processes of the neuronal injury induced by ischemia and reperfusion [19][20][21][22][23].…”

“…It has been reported that 14,15-EET is enriched in the brain cortex and exerts neuroprotective effect on neuronal cells in ischemia and reperfusion. For instance, administration of 14,15-EET lessens infarct size in global cerebral ischemia, inhibits astrocyte apoptosis under oxygen-glucose deprivation (OGD) and reduces neurodeficit score after middle cerebral artery occlusion (MCAO) [2][3][4][5][6]. However, the potential neuroprotective effect and underlying mechanism of 14,15-EET against apoptosis in cortical neurons under the condition of ischemia and reperfusion remain to be elucidated.…”

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

“…A CYP450 inhibitor, miconazole, decreased cell viability in co-cultured astrocytes and dopaminergic neurons (Terashvili, et al, 2012). β-amyloid also reduced EET synthesis in hippocampal astrocytes and neurons (Sarkar, et al, 2011), thus, supporting the levels of EETs by inhibiting sEH holds great promise by improving mitochondrial function in this pathological condition. More recently molecular mechanisms of this action have been revealed in human embryonic kidney 293 (HEK293)/Tau cells activated by hydrogen peroxide (Yao, et al, 2016).…”