Abstract
Non-alcoholic fatty liver disease (NAFLD) has been reported to induce cognitive impairments of hippocampus and may influence central nervous system. In the present study, we investigated whether carnosic acid (CA) ameliorates dopaminergic neuron injury in a rat model of NAFLD. In order to induce NAFLD, rats were fed with high-fat diet (HFD) for 10 weeks. We found that continued CA administration reduced lipid accumulation marked by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, and an increase in high-density lipoprotein cholesterol (HDL-C) level in the serum. H&E staining revealed that feeding CA reduced lipid droplets accumulation, and alleviated oxidative stress by increasing in superoxide dismutase (SOD) level and decreasing in malondialdehyde (MDA) level in the liver. In addition, by measuring several parameters of gait analysis, we demonstrated that CA treatment ameliorated behavioral impairments, as evidenced by decreased duration and maximum variation, accompanied by increased average speed and cadence. Furthermore, CA treated-animals displayed an increase in the contents of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacelic acid (DOPAC) and elevated the expressions of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) as well as the TH protein in the striatum. Together, these findings suggest that CA may be an effective agent in protecting rats from NAFLD-induced dopaminergic neuron injury.
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Abbreviations
- CA:
-
carnosic acid
- NAFLD:
-
non-alcoholic fatty liver disease
- HFD:
-
high-fat diet
- ALT:
-
alanine aminotransferase
- AST:
-
aspartate aminotransferase
- TG:
-
serum triglyceride
- TC:
-
total cholesterol
- LDL-C:
-
low-density lipoprotein cholesterol
- HDL-C:
-
high-density lipoprotein cholesterol
- SOD:
-
superoxide dismutase
- MDA:
-
malondialdehyde
- TH:
-
tyrosine hydroxylase
- DA:
-
dopamine
- DOPAC:
-
3,4-dihydroxyphenylacelic acid
- SN:
-
substantia nigra
- MAO:
-
monoamine oxidase
References
Bayer-Carter JL et al (2011) Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment. Arch Neurol 68:743–752. doi:10.1001/archneurol.2011.125
Benitez SU, Carneiro EM, de Oliveira AL (2015) Synaptic input changes to spinal cord motoneurons correlate with motor control impairments in a type 1 diabetes mellitus model. Brain Behav 5:e00372. doi:10.1002/brb3.372
Chen JH, Ou HP, Lin CY, Lin FJ, Wu CR, Chang SW, Tsai CW (2012) Carnosic acid prevents 6-hydroxydopamine-induced cell death in SH-SY5Y cells via mediation of glutathione synthesis. Chem Res Toxicol 25:1893–1901. doi:10.1021/tx300171u
Choi JY, Jang EH, Park CS, Kang JH (2005) Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med 38:806–816. doi:10.1016/j.freeradbiomed.2004.12.008
Chuang CS, Su HL, Cheng FC, Hsu SH, Chuang CF, Liu CS (2010) Quantitative evaluation of motor function before and after engraftment of dopaminergic neurons in a rat model of Parkinson’s disease. J Biomed Sci 17:9. doi:10.1186/1423-0127-17-9
Ding CC et al (2016) New insights into salvianolic acid A action: Regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats. Sci Rep 6:28734. doi:10.1038/srep28734
Gao X, Chen H, Fung TT, Logroscino G, Schwarzschild MA, Hu FB, Ascherio A (2007) Prospective study of dietary pattern and risk of Parkinson disease. Am J Clin Nutr 86:1486–1494
Ghareeb DA, Hafez HS, Hussien HM, Kabapy NF (2011) Non-alcoholic fatty liver induces insulin resistance and metabolic disorders with development of brain damage and dysfunction. Metab Brain Dis 26:253–267. doi:10.1007/s11011-011-9261-y
Greenlund LJ, Deckwerth TL, Johnson EM Jr (1995) Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14:303–315. doi:10.1016/0896-6273(95)90287-2
Greenwood CE, Winocur G (2005) High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging 26(Suppl 1):42–45. doi:10.1016/j.neurobiolaging.2005.08.017
Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348. doi:10.1038/334345a0
Jordan MJ, Lax V, Rota MC, Loran S, Sotomayor JA (2012) Relevance of carnosic acid, carnosol, and rosmarinic acid concentrations in the in vitro antioxidant and antimicrobial activities of Rosmarinus officinalis (L.) methanolic extracts. J Agric Food Chem 60:9603–9608. doi:10.1021/jf302881t
Kelley GL, Allan G, Azhar S (2004) High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation. Endocrinology 145:548–555. doi:10.1210/en.2003-1167
Kim DG et al (2016) Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 13:1. doi:10.1186/s12974-015-0467-5
Kujoth GC et al (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484. doi:10.1126/science.1112125
Labouesse MA, Stadlbauer U, Langhans W, Meyer U (2013) Chronic high fat diet consumption impairs sensorimotor gating in mice. Psychoneuroendocrinology 38:2562–2574. doi:10.1016/j.psyneuen.2013.06.003
Lang AE (2007) The progression of Parkinson disease: a hypothesis. Neurology 68:948–952. doi:10.1212/01.wnl.0000257110.91041.5d
Lemos JC, Friend DM, Kaplan AR, Shin JH, Rubinstein M, Kravitz AV, Alvarez VA (2016) Enhanced GABA transmission drives bradykinesia following loss of dopamine D2 receptor signaling. Neuron 90:824–838. doi:10.1016/j.neuron.2016.04.040
Li Y, South T, Han M, Chen J, Wang R, Huang XF (2009) High-fat diet decreases tyrosine hydroxylase mRNA expression irrespective of obesity susceptibility in mice. Brain Res 1268:181–189. doi:10.1016/j.brainres.2009.02.075
Ma D, Shuler JM, Raider KD, Rogers RS, Wheatley JL, Geiger PC, Stanford JA (2015) Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats. Brain Res 1613:49–58. doi:10.1016/j.brainres.2015.03.053
Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16:843–857. doi:10.1016/S0899-9007(00)00449-4
Meredith GE, Sonsalla PK, Chesselet MF (2008) Animal models of Parkinson’s disease progression. Acta Neuropathol 115:385–398. doi:10.1007/s00401-008-0350-x
Michely J et al (2015) Dopaminergic modulation of motor network dynamics in Parkinson’s disease. Brain 138:664–678. doi:10.1093/brain/awu381
Morris JK, Bomhoff GL, Stanford JA, Geiger PC (2010) Neurodegeneration in an animal model of Parkinson’s disease is exacerbated by a high-fat diet. Am J Physiol Regul Integr Comp Physiol 299:R1082–1090. doi:10.1152/ajpregu.00449.2010
Nagatsua T, Sawadab M (2009) L-dopa therapy for Parkinson’s disease: past, present, and future. Parkinsonism Relat Disord 15(Suppl 1):S3–8. doi:10.1016/s1353-8020(09)70004-5
Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 37:1202–1219. doi:10.1053/jhep.2003.50193
Niedernhofer LJ, Daniels JS, Rouzer CA, Greene RE, Marnett LJ (2003) Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem 278:31426–31433. doi:10.1074/jbc.M212549200
Olanow CW, Kordower JH (2009) Modeling Parkinson’s disease. Ann Neurol 66:432–436. doi:10.1002/ana.21832
Park MY, Mun ST (2013) Dietary carnosic acid suppresses hepatic steatosis formation via regulation of hepatic fatty acid metabolism in high-fat diet-fed mice. Nutr Res Pract 7:294–301. doi:10.4162/nrp.2013.7.4.294
Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE (2006) Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 43:413–427. doi:10.1097/01.mpg.0000239995.58388.56
Petiwala SM, Berhe S, Li G, Puthenveetil AG, Rahman O, Nonn L, Johnson JJ (2014) Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth. PLoS One 9, e89772. doi:10.1371/journal.pone.0089772
Raskovic A, Milanovic I, Pavlovic N, Cebovic T, Vukmirovic S, Mikov M (2014) Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potentia. BMC Complement Altern Med 14:225. doi:10.1186/1472-6882-14-225
Ross AP, Bruggeman EC, Kasumu AW, Mielke JG, Parent MB (2012) Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats. Physiol Behav 106:133–141. doi:10.1016/j.physbeh.2012.01.008
Saal KA et al (2015) AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson’s disease in vitro and in vivo. Neurobiol Dis 73:150–162. doi:10.1016/j.nbd.2014.09.013
Shan W et al (2015) Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis 6, e1833. doi:10.1038/cddis.2015.196
Simopoulos AP (2013) Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients 5:2901–2923. doi:10.3390/nu5082901
Tsika E et al (2014) Conditional expression of Parkinson’s disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiol Dis 71:345–358. doi:10.1016/j.nbd.2014.08.027
Ur Rasheed MS, Tripathi MK, Mishra AK, Shukla S, Singh MP (2016) Resveratrol protects from toxin-induced Parkinsonism: plethora of proofs hitherto petty translational value. Mol Neurobiol 53:2751–2760. doi:10.1007/s12035-015-9124-3
Videla LA et al (2004) Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci (Lond) 106:261–268. doi:10.1042/cs20030285
Yan H et al (2014) Sirtuin 1-mediated inhibition of p66shc expression alleviates liver ischemia/reperfusion injury. Crit Care Med 42:e373–381. doi:10.1097/ccm.0000000000000246
Zeng W et al (2015) Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease. Sci Rep 5:16013. doi:10.1038/srep16013
Acknowledgements
This work was supported by grants from Education Department of Liaoning Province (L2015161) and the Chinese National Natural Science Foundation (No. 81473266).
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Xu, T., Zhou, J., Zhu, J. et al. Carnosic acid protects non-alcoholic fatty liver-induced dopaminergic neuron injury in rats. Metab Brain Dis 32, 483–491 (2017). https://doi.org/10.1007/s11011-016-9941-8
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DOI: https://doi.org/10.1007/s11011-016-9941-8