Abstract
Rationale
Early diagnosis of diabetic cognitive impairment (DCI) and investigation of effective medicines are significant to prevent or delay the occurrence of irreversible dementia.
Objectives
In this study, proteomics was applied to investigate the changes of hippocampal proteins after administration of Panax quinquefolius-Acorus gramineus (PQ-AG) to DCI rats, with a view to discover the differentially expressed proteins of PQ-AG action and elucidated the potential biological relationships.
Methods
The model and PQ-AG group rats were injected intraperitoneally with streptozotocin, and the PQ-AG group rats were continuously administered with PQ-AG. Social interaction and Morris water maze were performed to evaluate the behavior of rats on the 17th week after the model was established, and DCI rats were screened out from the model group by a screening approach. The hippocampal protein differences were investigated with proteomics in DCI and PQ-AG-treated rats.
Results
The learning and memory abilities and contact duration of DCI rats were improved after 16 weeks of PQ-AG administration. Altogether, 9 and 17 differentially expressed proteins were observed in control versus DCI rats and in DCI versus PQ-AG-treated rats, respectively. Three proteins were confirmed with western blotting analyses. These proteins were mainly involved in the pathways of JAK-STAT, apoptosis, PI3K/AKT, fork-head box protein O3, fructose, and mannose metabolism.
Conclusions
This suggested that PQ-AG ameliorated cognitive impairment of diabetic rats by influencing the above pathways and providing an experimental basis for the mechanism of DCI and PQ-AG.
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Data Availability
The authors confirm that the data supporting the findings of this study are available within the article [and/or its supplementary materials].
References
Acikgoz B, Dalkiran B, Dayi A (2022) An overview of the currency and usefulness of behavioral tests used from past to present to assess anxiety, social behavior and depression in rats and mice. Behav Process 200:104670. https://doi.org/10.1016/j.beproc.2022.104670
Araujo MS, Paulo OLDOH, Scott C, Paranzini CS, Codognoto VM, Dell’Aqua CDPF, Papa FO, Souza FFD (2022) Insights into the influence of canine breed on proteomics of the spermatozoa and seminal plasma. J Proteomics 257:104508. https://doi.org/10.1016/j.jprot.2022.104508
Arbour N, Vanderluit JL, Le Grand JN, Jahani-Asl A, Ruzhynsky VA, Cheung EC, Kelly MA, MacKenzie AE, Park DS, Opferman JT, Slack RS (2008) Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage. J Neurosci 28:6068–6078. https://doi.org/10.1242/jcs.205666
Arikawa K, Williams DS (1993) Acetylated alpha-tubulin in the connecting cilium of developing rat photoreceptors. Invest Ophthalmol Vis Sci 34:2145–2149
Bae J, Leo CP, Hsu SY, Hsueh AJ (2000) MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 275:25255–25261. https://doi.org/10.1074/jbc.M909826199
Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14:591–604. https://doi.org/10.1038/s41574-018-0048-7
Boyle LL, Lyness JM, Duberstein PR, Karuza J, King DA, Messing S, Tu X (2010) Trait neuroticism, depression, and cognitive function in older primary care patients. Am J Geriatr Psychiatry 18:305–312. https://doi.org/10.1097/JGP.0b013e3181c2941b
Chandrasekaran K, Choi J, Arvas MI, Salimian M, Singh S, Xu S, Gullapalli RP, Kristian T, Russell JW (2020) Nicotinamide mononucleotide administration prevents experimental diabetes-induced cognitive impairment and loss of hippocampal neurons. Int J Mol Sci 21:3756. https://doi.org/10.3390/ijms21113756
Chen J, Zhan LB, Lu XG, Xiao C, Sun NJ (2017) The alteration of ZiBuPiYin recipe on proteomic profiling of forebrain postsynaptic density of db/db mice with diabetes-associated cognitive decline. J Alzheimers Dis 56:471–489. https://doi.org/10.3233/JAD-160691
Ci LY, Liu DS, Yang JQ, Liu YZ, Li CL, Zhang X, Ma CM, Hu RT (2018) Expression of long non-coding RNA and mRNA in the hippocampus of mice with type 2 diabetes. Mol Med Rep 18:4960–4968. https://doi.org/10.3892/mmr.2018.9504
DeRossi C, Bode L, Eklund EA, Zhang F, Davis JA, Westphal V, Wang L, Borowsky AD, Freeze HH (2006) Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality. J Biol Chem 281:5916–5927. https://doi.org/10.1074/jbc.M511982200
Dong L, Hyde AJ, Zhang AL, Xue CC, May BH (2019) Chinese herbal medicine for mild cognitive impairment using Montreal Cognitive Assessment: a systematic review. J Altern Complement Med 25:578–592. https://doi.org/10.1089/acm.2018.0346
Gao NX, Liu HQ, Li SQ, Tu X, Tian S, Liu J, Li GY, Ma YX (2019) Volatile oil from Acorus gramineus ameliorates the injury neurons in the hippocampus of amyloid Beta 1–42 injected mice. Anat Rec (Hoboken) 302:2261–2270. https://doi.org/10.1002/ar.24236
Geng JL, Wang LP, Zhang LY, Qin C, Song YY, Ma YY, Chen YJ, Chen SD, Wang YT, Zhang ZJ, Yang GY (2018) Blood-brain barrier disruption induced cognitive impairment is associated with increase of inflammatory cytokine. Front Aging Neurosci 10:129. https://doi.org/10.3389/fnagi.2018.00129
Gonzalez PS, O’Prey J, Cardaci S, Barthet VJA, Sakamaki JI, Beaumatin F, Roseweir A, Gay DM, Mackay G, Malviya G, Kania E, Ritchie S, Baudot AD, Zunino B, Mrowinska A, Nixon C, Ennis D, Hoyle A, Millan D, McNeish IA, Sansom OJ, Edwards J, Ryan KM (2018) Mannose impairs tumour growth and enhances chemotherapy. Nature 563:719–723. https://doi.org/10.1038/s41586-018-0729-3
Han X, Shao W, Liu Z, Fan S, Yu J, Chen J, Qiao R, Zhou J, Xie P (2015) iTRAQ-based quantitative analysis of hippocampal postsynaptic density-associated proteins in a rat chronic mild stress model of depression. Neuroscience 298:220–292. https://doi.org/10.1016/j.neuroscience.2015.04.006
Hinder LM, Giri AV, McLean LL, Pennathur S, Feldman EL (2013) Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes. J Endocrinol 216:1–11. https://doi.org/10.1530/JOE-12-0356
Huang AD, Zhang MY, Li TJ, Qin X (2018a) Serum proteomic analysis by tandem mass tags (TMT) based quantitative proteomics in gastric cancer patients. Clin Lab 64:855–866. https://doi.org/10.7754/Clin.Lab.2018.171129
Huang X, Duan XK, Li J, Niu JJ, Yuan SQ, Wang XY, Lambert N, Li X, Xu JQ, Gong Z, Yan SQ, Xie LX, Xie JP (2018b) The synergistic effect of exogenous glutamine and rifampicin against mycobacterium persisters. Front Microbiol 9:1625. https://doi.org/10.3389/fmicb.2018.01625
Huerta MG (2006) Adiponectin and leptin: potential tools in the differential diagnosis of pediatric diabetes? Rev Endocr Metab Disord 7:187–196. https://doi.org/10.1007/s11154-006-9017-x
Hyde AJ, May BH, Dong L, Feng M, Liu SN, Guo XF, Zhang AL, Lu CJ, Xue CC (2017) Herbal medicine for management of the behavioural and psychological symptoms of dementia (BPSD): a systematic review and meta-analysis. J Psychopharmacol 31:169–183. https://doi.org/10.1177/0269881116675515
Jaroudi W, Garami J, Garrido S, Hornberger M, Keri S, Moustafa AA (2017) Factors underlying cognitive decline in old age and Alzheimer’s disease: the role of the hippocampus. Rev Neurosci 28:705–714. https://doi.org/10.1515/revneuro-2016-0086
Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J, Woodgett JR (2011) Assessment of social interaction behaviors. J Vis Exp 48:2473. https://doi.org/10.3791/2473
Kassab S, Begley P, Church SJ, Rotariu SM, Riffard CC, Dowsey AW, Phillips AM, Zeef LAH, Grayson B, Neill JC, Cooper GJS, Unwin RD, Gardiner NJ (2019) Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation. Mol Metab 28:107–119. https://doi.org/10.1016/j.molmet.2019.08.003
Kim TH, Kang JW (2020) Herbal medicine for vascular dementia: an overview of systematic reviews. Curr Vasc Pharmacol 18:349–409. https://doi.org/10.2174/1570161117666190618164443
Kim JH, Sim SH, Ha HJ, Ko JJ, Lee K, Bae J (2009) MCL-1ES, a novel variant of MCL-1, associates with MCL-1L and induces mitochondrial cell death. FEBS letters 583:2758–2764. https://doi.org/10.1016/j.febslet.2009.08.006
Kimura M, Waki I, Chujo T, Kikuchi T, Hiyama C, Yamazaki K, Tanaka O (1981) Effects of hypoglycemic components in ginseng radix on blood insulin level in alloxan diabetic mice and on insulin release from perfused rat pancreas. J Pharmaco biodyn 4(6):410–417. https://doi.org/10.1248/bpb1978.4.410
Klok MD, Jakobsdottir S, Drent ML (2007) The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev 8:21–34. https://doi.org/10.1111/j.1467-789X.2006.00270.x
Kumar N, Kavita S (2017) The Cdk5-Mcl-1 axis promotes mitochondrial dysfunction and neurodegeneration in a model of Alzheimer’s disease. J Cell Sci 130:3023–3039. https://doi.org/10.1242/jcs.205666
Li H, Luo Y, Xu Y, Yang L, Hu CL, Chen Q, Yang Y, Ma J, Zhang JH, Xia H, Li YK, Yang JQ (2018) Meloxicam improves cognitive impairment of diabetic rats through COX2-PGE2-EPs-cAMP/pPKA pathway. Mol Pharm 15:4121–4131. https://doi.org/10.1021/acs.molpharmaceut.8b00532
Li JJ, Liu YR, Liu BB, Li F, Hu JY, Wang Q, Li MM, Lou SJ (2019) Mechanisms of aerobic exercise upregulating the expression of hippocampal synaptic plasticity-associated proteins in diabetic rats. Neural Plast 2019:7920540. https://doi.org/10.1155/2019/7920540
Liu SN, Zheng ML, Li YX, He L, Chen T (2020) The protective effect of Geniposide on diabetic cognitive impairment through BTK/TLR4/NF-κB pathway. Psychopharmacology (Berl) 237:465–477. https://doi.org/10.1007/s00213-019-05379-w
Mancuso C, Santangelo R (2017) Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol 107:362–372. https://doi.org/10.1016/j.fct.2017.07.019
Matsuo N, Tanda K, Nakanishi K, Yamasaki N, Toyama K, Takao K, Takeshima H, Miyakawa T (2009) Comprehensive behavioral phenotyping of ryanodine receptor type 3 (RyR3) knockout mice: decreased social contact duration in two social interaction tests. Front Behav Neurosci 3:3. https://doi.org/10.3389/neuro.08.003.2009
Moriya Y, Itoh M, Okuda S, Yoshizawa AC, Kanehisa M (2007) KAAS: an automatic genome annotation and pathway reconstruction server. Nucleic Acids Res 35:W182-185. https://doi.org/10.1093/nar/gkm321
Munshi M, Grande L, Hayes M, Ayres D, Suhl E, Capelson R, Lin SS, Milberg W, Weinger K (2006) Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care 29:1794–1799. https://doi.org/10.2337/dc06-0506
Nasonkin IO, Merbs SL, Lazo K, Oliver VF, Brooks M, Patel K, Enke RA, Nellissery J, Jamrich M, Le YZ, Bharti K, Fariss RN, Rachel RA, Zack DJ, Boulan EJR, Swaroop A (2013) Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis. Development 140:1330–1341. https://doi.org/10.1242/dev.086603
Ochi R, Fujita N, Takaishi K, Oshima T, Nguyen ST, Nishijo H, Urakawa S (2022) Voluntary exercise reverses social behavior deficits and the increases in the densities of cholecystokinin-positive neurons in specific corticolimbic regions of diabetic OLETF rats. Behav Brain Res 428:113886. https://doi.org/10.1016/j.bbr.2022.113886
Omidi G, Karimi SA, Kamran AR, Monsef A, Shahidi S, Komaki A (2019) Effect of coenzyme Q10 supplementation on diabetes induced memory deficits in rats. Metab Brain Dis 34:833–840. https://doi.org/10.1007/s11011-019-00402-7
Ossoukhova A, Owen L, Savage K, Meyer M, Ibarra A, Roller M, Pipingas A, Wesnes K, Scholey A (2015) Improved working memory performance following administration of a single dose of American ginseng (Panaxquinquefolius L.) to healthy middle-age adults. Hum Psychopharmacol 30:108–122. https://doi.org/10.1002/hup.2463
Pires G, Drummond E (2021) It takes more than tau to tangle: using proteomics to determine how phosphorylated tau mediates toxicity in neurodegenerative diseases. Neural Regen Res 16:2211–2212. https://doi.org/10.4103/1673-5374.310680
Qu YD, Wang WQ, Chen TR, Yang YM, Zhang YZ, Wang D (2021) The neuroprotection of deproteinized calf blood extractives injection against Alzheimer’s disease via regulation of Nrf-2 signaling. Aging (Albany NY) 13: 11150–11169 https://doi.org/10.18632/aging.202776
Samaras K, Lutgers HL, Kochan NA, Crawford JD, Campbell LV, Wen W, Slavin MJ, Baune BT, Lipnicki DM, Brodaty H, Trollor JN, Sachdev PS (2014) The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study. Age (Dordr) 36:977–993. https://doi.org/10.1007/s11357-013-9613-0
Savage S, Kehr J, Olson L, Mattsson A (2011) Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation. Neuroscience 195:60–69. https://doi.org/10.1016/j.neuroscience.2011.08.027
Sen S, Querques MA, Chakrabarti S (2013) North American Ginseng (Panax quinquefolius) prevents hyperglycemia and associated pancreatic abnormalities in diabetes. J Med Food 16:587–592. https://doi.org/10.1089/jmf.2012.0192
Shin K, Guo H, Cha Y, Ban YH, Seo DW, Choi YJ, Kim TS, Lee SP, Kim JC, Choi EK, Yon JM, Kim YB (2016) Cereboost™, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection. Regul Toxicol Pharmacol 78:53–58. https://doi.org/10.1016/j.yrtph.2016.04.006
Steven LG, Klaus P, Jean-Luc H, Kenneth CA (2004) Mcl-1 regulation and its role in multiple myeloma. Cell Cycle 3:1259–1262. https://doi.org/10.4161/cc.3.10.1196
Umegaki H (2014) Type 2 diabetes as a risk factor for cognitive impairment: current insights. Clin Interv Aging 9:1011–1019. https://doi.org/10.2147/CIA.S48926
Vuksan V, Xu ZZ, Jovanovski E, Jenkins AL, Zdravkovic UB, Sievenpiper JL, Stavro PM, Zurbau A, Duvnjak L, Li MZC (2019) Efficacy and safety of American ginseng (Panax quinquefolius L.) extract on glycemic control and cardiovascular risk factors in individuals with type 2 diabetes: a double-blind, randomized, cross-over clinical trial. Eur J Nutr 58:1237–1245. https://doi.org/10.1007/s00394-018-1642-0
Wang H, Sun XX, Zhang N, Ji ZY, Ma ZQ, Fu Q, Qu R, Ma SP (2017) Ferulic acid attenuates diabetes-induced cognitive impairment in rats via regulation of PTP1B and insulin signaling pathway. Physiol Behav 182:93–100. https://doi.org/10.1016/j.physbeh.2017.10.001
Wang DX, Zhao Y, Yang Y, Xie HL (2021a) Safety assessment of multiple repeated percutaneous punctures for the collection of cerebrospinal fluid in rats. Braz J Med Biol Res 54:e10032. https://doi.org/10.1590/1414-431X202010032
Wang HL, Guo M, Wei HD, Chen YH (2021b) Targeting MCL-1 in cancer: current status and perspectives. J Hematol Oncol 14:67. https://doi.org/10.1186/s13045-021-01079-1
Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Eldik LJV (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88. https://doi.org/10.3389/fgene.2014.00088
Weinstein G, Maillard P, Himali JJ, Beiser AS, Au R, Wolf PA, Seshadri S, DeCarli C (2015) Glucose indices are associated with cognitive and structural brain measures in young adults. Neurology 84:2329–2337. https://doi.org/10.1212/WNL.0000000000001655
Wu Y, Yu Y, Szabo A, Han M, Huang X-F (2014) Central inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat diet. PloS One 9:e92618. https://doi.org/10.1371/journal.pone.0092618
Xie HL, Wang DX, Zhang WJ, Yan XJ, Zhao Y (2019) Comparative pharmacokinetic studies of four ginsenosides in rat plasma by UPLC-MS/MS after oral administration of panax quinquefolius-Acorus gramineus and Panax quinquefolius extracts. J Anal Methods Chem 2019:4972816. https://doi.org/10.1155/2019/4972816
Xiong Y, Shen L, Liu KJ, Tso P, Xiong YQ, Wang GJ, Woods SC, Liu M (2010) Antiobesity and antihyperglycemic effects of ginsenoside Rb1 in rats. Diabetes 59:2505–2512. https://doi.org/10.2337/db10-0315
Xu YZ, Tong QC (2017) Central leptin action on euglycemia restoration in type 1 diabetes: restraining responses normally induced by fasting? Int J Biochem Cell Biol 88:198–203. https://doi.org/10.1016/j.biocel.2016.09.027
Yang JW, Wang XR, Zhang M, Xiao LY, Zhu W, Ji CS, Liu CZ (2018) Acupuncture as a multifunctional neuroprotective therapy ameliorates cognitive impairment in a rat model of vascular dementia: a quantitative iTRAQ proteomics study. CNS Neurosci Ther 24:1264–1274. https://doi.org/10.1111/cns.13063
Yang Y, Wang DX, Zhao Y, Wang Y, Bi YY, Bi TT (2021) Metabolomics study of cerebrospinal fluid from diabetic rats with cognitive impairment simultaneously treated with Panax quinquefolius and Acorus gramineus. Biomed Chromatogr 35:e5041. https://doi.org/10.1002/bmc.5041
Yi YQ, Fang R, Ge JW, Cheng SW, Wang GZ, Liu L (2018) Analysis on medication rules for treatment of dementia by ancient physicians based on data mining methods. Zhongguo Zhong Yao Za Zhi 43: 3376–3381 https://doi.org/10.19540/j.cnki.cjcmm.20180419.004
Zhang LY, Virgous C, Si HW (2017) Ginseng and obesity: observations and understanding in cultured cells, animals and humans. J Nutr Biochem 44:1–10. https://doi.org/10.1016/j.jnutbio.2016.11.010
Zhao Y, Huan S, Yang Y, Gao WY, Wang J (2022a) Hippocampal proteins discovery of diabetes-induced central neuropathy based on proteomics. Neuroreport 33:354–362. https://doi.org/10.1097/WNR.0000000000001790
Zhao Y, Yang Y, Wang DX, Wang J, Gao WY (2022b) Cerebrospinal fluid amino acid metabolite signatures of diabetic cognitive dysfunction based on targeted mass spectrometry. J Alzheimers Dis 86:1655–1665. https://doi.org/10.3233/JAD-215725
Zhou Y, Li XL, Xie HL, Cao DN, Nie BB, Zhao Y, Sun ZR (2018) Voxel-based morphology analysis of STZ-induced type 1 diabetes mellitus rats with and without cognitive impairment. Neurosci Lett 684:210–217. https://doi.org/10.1016/j.neulet.2018.08.017
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This work was supported by the National Natural Science Foundation of China (Grant No. 81673871).
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Ying Zhao conceived and supervised the study. Shuai Huan, Yang Yang, Dongxue Wang, Xiu Zhang, and Yujia Zheng designed and performed experiments. Shuai Huan wrote the manuscript and created the figures and the tables. Ying Zhao made manuscript revisions. All the authors discussed the results and have approved the manuscript for publishing.
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Huan, S., Yang, Y., Wang, D. et al. Hippocampal proteins discovery of Panax quinquefolius and Acorus gramineus ameliorating cognitive impairment in diabetic rats. Psychopharmacology 240, 1759–1773 (2023). https://doi.org/10.1007/s00213-023-06393-9
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DOI: https://doi.org/10.1007/s00213-023-06393-9