Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia

Weichun Yang, Ziyi Shen, Sixian Wen, Wei Wang, Minyu Hu

Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight. There was a control group containing rats fed a standard laboratory rodent chow diet (CD); a hypercholesterolemic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil - this is also called a CCT diet) group; a positive group (CCT + F) fed CCT, supplemented with 10 mg·kg·bw- 1·d- 1 fluvastatin sodium by gastric perfusion; and lycopene groups at five dose levels (CCT + LYCO) fed with CCT and supplied lycopene at doses of 5, 25, 45, 65, and 85 mg·kg·bw- 1·d- 1. The levels of TC, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), oxidized low density lipoprotein (ox-LDL), low-density lipoprotein receptor (LDLR), nerve growth factor (NGF), glutamic acid (Glu), Gamma aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), N-methyl-D-aspartate (NMDA1R), GABAA, 5-HT1, D1, and apoptosis-related proteins Caspase3, bax, and bcl-2 were measured after the experiment. Nissl staining was adopted to observe the morphological changes in neurons. At the end of the experiment, the levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain as well as the content of Glu, DA, NMDA, and D1 in the brain of rats in the CCT group were higher than those in the control group (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABAA, 5-HT1, and neuron quantities in the hippocampal CA1 and CA3 areas were lower than those in the control group (P<0.05). Compared to the CCT group, levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain, as well as the content of Glu, DA and the expression of pro-apoptotic Caspase3 in the brain decreased in the rats with lycopene (25 mg to 85 mg) added to the diet (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABAA, and 5-HT1 as well as the expression of anti-apoptotic bcl-2 and the neuron quantity in hippocampal CA1 and CA3 areas increased (P<0.05); further, the hippocampal cells were closely arranged. Lycopene dose was negatively correlated with the levels of TC, TG, and LDL-C in the serum and brain as well as levels of IL-1, TNF-α, ox-LDL, Glu/GABA, NMDA1R, and Caspase3 (P<0.05); it was positively correlated with the levels of LDLR, NGF, 5-HT, 5-HT1, GABAA, bcl-2, and the neuron quantity in hippocampal CA1 and CA3 areas (P<0.05). Lycopene exerts anti-injury effects in the brain as-induced by hyperlipidemia. It can inhibit the elevation of serum TC, TG, and LDL-C in rats with hyperlipidemia while indirectly affecting the levels of TC, TG, and LDL-C in the brain, leading to a reduction in ox-LDL, IL-1, and TNF-α in the brain. This inhibits the release of Glu, which weakens nerve toxicity and downregulates pro-apoptotic Caspase3. Lycopene also plays an anti-injury role by promoting the release of the inhibitory neurotransmitter GABA and 5-HT, which enhances the protective effect, and by upregulating the anti-apoptotic bcl-2.