Hyperlipidemia exacerbates cerebral injury through oxidative stress, inflammation and neuronal apoptosis in MCAO/reperfusion rats

Abstract

Recent studies showed that hyperglycemia enhanced brain damage when subjected to transient cerebral ischemic stroke. However, the etiologic link between them has been less known. In the present study, based on an experimental rat's model of hyperlipidemia combined with cerebral ischemia-reperfusion injury (I/R), we herein showed that hyperlipidemia induced by high-fat diet (HFD) resulted in considerable increase in serum triglycerides, cholesterol and low-density lipoprotein cholesterol, and remarkable decrease in serum high-density lipoprotein cholesterol, which associated with an exacerbation on neurological deficit, cerebral infarct and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells in the ischemic hemisphere of cerebral I/R rats treated with HFD diet. The data showed that serum superoxide dismutase activity and glutathione peroxides content were significantly decreased, while malondialdehyde level was obviously increased by hyperlipidemia or cerebral I/R alone, especially by coexistence of hyperlipidemia and cerebral I/R; meantime, hyperlipidemia also enhanced cerebral I/R-induced protein expression of cytochrome P450 2E1 (CYP2E1) and the levels of pro-inflammatory factors tumor necrosis factor-α and IL-6 in the ischemic hemispheres. Furthermore, the combined action of hyperlipidemia and cerebral I/R resulted in a protein increase expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 compared to hyperlipidemia or cerebral I/R alone. Meanwhile, this study also showed that hyperlipidemia significantly enhanced cerebral I/R-induced transfer of cytochrome c from mitochondria to cytosolic and the protein expressions of Apaf-1 and caspase-3, but also decreased cerebral I/R-induced bcl-2 protein expression. The results reveal that hyperlipidemia exacerbates cerebral I/R-induced injury through the synergistic effect on CYP2E1 induction, which further induces reactive oxygen species formation, oxidative stress, inflammation and neuronal apoptosis by coexistence of hyperlipidemia and cerebral I/R.

Serum Pro-Oxidant-Antioxidant Balance, Advanced Oxidized Protein Products (AOPP) and Protein Carbonyl in Patients With Stroke

“…In this situation which is defined as hypoxia, the brain cells loss their normal functionalities and metabolism (37)(38)(39). The presence of abundant polyunsaturated fatty acids (40) and lower levels of antioxidant enzymes such as catalase and glutathione peroxidase in brain cells, makes them vulnerable and sensitive to free radicals.…”

Obesity and stroke: Can we translate from rodents to patients?

“…57 Worse stroke outcome has also been confirmed in diet-induced models in which animals become obese due to being fed a high-fat diet. These detrimental effects of a high-fat diet have been observed in rat, 58,61,65,73,82,93 mouse 60,64,66,88 and gerbil 62,63,94 models of diet-induced obesity. A variety of models of cerebral ischaemia have also been used in these studies, including transient and permanent occlusion of the middle cerebral artery, common carotid artery ligation and exposure to a low-oxygen environment.…”

Pathophysiological implications of neurovascular P450 in brain disorders

“…Hyperlipidemia was also linked to brain CYP modifications. It has been shown that induction of CYP2E1 in the brain occurs in hyperlipidemia subjects, or after associated ischemia-reperfusion (IR) injury [92]. Furthermore, CYP2E1 induction can contribute to the production of tissue-damaging radicals, inflammatory response, and neuronal apoptosis.…”

“…Furthermore, CYP2E1 induction can contribute to the production of tissue-damaging radicals, inflammatory response, and neuronal apoptosis. Therefore, the occurrence of hyperlipidemia in patients with cerebral ischemia presents a higher threat to neuronal degeneration, because of CYP2E1 expression [92]. …”