Abstract
Alzheimer disease (AD) is a common form of dementia associated with loss of memory and disruption of synaptic plasticity. There is a strong correlation between the pathophysiological features of AD and diabetes, including induction of oxidative stress, inflammation, and abnormality in blood vessels. Considering the brain’s limited capacity to repair damage and the potential of stem cell-derived neural cells in the repair of neurodegenerative disease, we investigated the effects of artemisinin and TSP‑1‑human endometrial-derived-derived stem cells (TSP‑1‑hEDSCs) on the cognitive function and synaptic plasticity in AD-diabetes rats. The authors previously showed that artemisinin and TSP‑1‑hEDSCs suppressed oxidative stress and inflammation in AD-diabetes rats. Thrombospondins-1 (TSPs-1) is a glycoprotein that inhibits angiogenesis. AD and diabetes were induced using streptozotocin. Synaptic plasticity and learning and memory function were studied using the Morris water maze and electrophysiological test, respectively. Streptozotocin increased traveled swimming distance and escape latency in the morris water maze test, decreased the percent time spent in the target quadrant, inhibited the long-term potentiation (LTP), and increased the blood glucose levels. Simultaneous or separate administration of artemisinin and TSP‑1‑hEDSCs decreased the blood levels of glucose and improved cognitive tasks and synaptic plasticity by considerably reducing traveled swimming distance and escape latency, increasing the percent time spent in the target quadrant, and retrieval of the LTP; therefore, they could be utilized as an adjunct treatment for AD treatment. These results may be due to a decrease in oxidative stress and inflammation.
Similar content being viewed by others
Data availability
Data is available upon request.
References
Bagheri–Mohammadi S, Alani B, Karimian M, Moradian–Tehrani R, Noureddini M (2019) Intranasal administration of endometrial mesenchymal stem cells as a suitable approach for Parkinson’s disease therapy. Mol Biol Rep 46:4293–4302. https://doi.org/10.1007/s11033-019-04883-8
Cade WT (2008) Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 88:1322–1335. https://doi.org/10.2522/ptj.20080008
Chakari-Khiavi F, Dolati S, Chakari-Khiavi A, Abbaszadeh H, Aghebati-Maleki L, Pourlak T, Mehdizadeh A, Yousefi M (2019) Prospects for the application of mesenchymal stem cells in Alzheimer’s disease treatment. Life Sci 231:116564. https://doi.org/10.1016/j.lfs.2019.116564
Chatterjee S, Mudher A (2018) Alzheimer’s disease and type 2 diabetes: a critical assessment of the shared pathological traits. Front Neurosci 12:383. https://doi.org/10.3389/fnins.2018.00383
Cho SJ, Park MH, Han C, Yoon K, Koh YH (2017) VEGFR2 alteration in Alzheimer’s disease. Sci Rep 7:17713. https://doi.org/10.1038/s41598-017-18042-1
Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433. https://doi.org/10.1016/j.cell.2004.12.020
Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8:79–84. https://doi.org/10.1038/nn1372
Cui YB, Ma SS, Zhang CY, Cao W, Liu M, Li DP, Lv PJ, Xing Q, Qu RN, Yao N, Yang B, Guan FX (2017) Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer’s disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis. Behav Brain Res 320:291–301. https://doi.org/10.1016/j.bbr.2016.12.021
Cvetković-Dožić D, Skender-Gazibara M, Dožić S (2001) Neuropathological hallmarks of Alzheimer’s disease. Arch Oncol 9:195–199
de la Monte SM (2012) Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs 72:49–66. https://doi.org/10.2165/11597760-000000000-00000
Doshmanziari M, Shirian S, Kouchakian MR, Moniri SF, Jangnoo S, Mohammadi N, Zafari F (2021) Mesenchymal stem cells act as stimulators of neurogenesis and synaptic function in a rat model of Alzheimer’s disease. Heliyon 7:e07996. https://doi.org/10.1016/j.heliyon.2021.e07996
Ferreira JF, Luthria DL, Sasaki T, Heyerick A (2010) Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules 15:3135–3170. https://doi.org/10.3390/molecules15053135
Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18. https://doi.org/10.1146/annurev.med.57.121304.131306
Gao WL, Li XH, Dun XP, Jing XK, Yang K, Li YK (2020) Grape seed proanthocyanidin extract ameliorates streptozotocin induced cognitive and synaptic plasticity deficits by inhibiting oxidative stress and preserving AKT and ERK activities. Curr Med Sci 40:434–443. https://doi.org/10.1007/s11596-020-2197-x
Garofalo RS, Rosen OM (1989) Insulin and insulin like growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor β subunits. Mol Cell Biol 9:2806–2817. https://doi.org/10.1128/mcb.9.7.2806-2817.1989
Ge Y, Dong Z, Bagot RC, Howland JG, Phillips AG, Wong TP, Wang YT (2010) Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci USA 107(38):16697–16702. https://doi.org/10.1073/pnas.1008200107
Ginguay A, Regazzetti A, Laprevote O, Moinard C, De Bandt JP, Cynober L, Billard JM, Allinquant B, Dutar P (2019) Citrulline prevents age-related LTP decline in old rats. Sci Rep 9:20138. https://doi.org/10.1038/s41598-019-56598-2
Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87:6624–6628. https://doi.org/10.1073/pnas.87.17.6624
Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, Sakai RR, Kelly SJ, Wilson MA, Mott DD, Reagan LP (2015) Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes 64(11):3927–3936. https://doi.org/10.2337/db15-0596
Helal EGE, Abou- Aouf N, Khattab AM, Zoair MA (2014) Anti-diabetic effect of artemisia annua (kaysom) in alloxan-induced diabetic rats. Egypt J Hosp Med 57:422–430. https://doi.org/10.12816/0008476
Hofstetter CP, Schwartz EJ, Hess D, Widenfalk J, Manira AEl, Prockop DJ, Olson L (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 99(4):2199–2204. https://doi.org/10.1073/pnas.042678299
Hoyer S (2002) The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm (Vienna) 109:991–1002. https://doi.org/10.1007/s007020200082
Jeon SG, Lee HJ, Park H, Han KM, Hoe HS (2020) The VEGF inhibitor vatalanib regulates AD pathology in 5xFAD mice. Mol Brain 13:131. https://doi.org/10.1186/s13041-020-00673-7
Kamal A, Biessels GJ, Ramakers GMJ, Gispen WH (2005) The effect of short duration streptozotocin-induced diabetes mellitus on the late phase and threshold of long-term potentiation induction in the rat. Brain Res 1053:126–130. https://doi.org/10.1016/j.brainres.2005.06.036
Kaur S, Martin-Manso G, Pendrak ML, Garfield SH, Isenberg JS, Roberts DD (2010) Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47. J Biol Chem 285(50):38923–38932. https://doi.org/10.1074/jbc.M110.172304
Khanmohammadi M, Khanjani S, Bakhtyari MS, Zarnani AH, Edalatkhah H, Akhondi MM, Mirzadegan E, Kamali K, Alimoghadam K, Kazemnejad S (2012) Proliferation and chondrogenic differentiation potential of menstrual blood- and bone marrow-derived stem cells in two-dimensional culture. Int J Hematol 95(5):484–493. https://doi.org/10.1007/s12185-012-1067-0
Kumar A (2011) Long-term potentiation at CA3–CA1 hippocampal synapses with special emphasis on aging, disease, and stress. Front Aging Neurosci 3(7):1–20. https://doi.org/10.3389/fnagi.2011.00007
Lee CC, Huang CC, Hsu KS (2011) Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 61(4):867–879. https://doi.org/10.1016/j.neuropharm.2011.06.003
Lee IS, Jung K, Kim IS, Lee H, Kim M, Yun S, Hwang K, Shin JE, Park KI (2015) Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegener 10:38. https://doi.org/10.1186/s13024-015-0035-6
Li H, Yahaya BH, Ng WH, Yusoff NM, Lin J (2019) Conditioned medium of human menstrual blood-derived endometrial stem cells protects against MPP+-Induced cytotoxicity in vitro. Front Mol Neurosci 12:1–15. https://doi.org/10.3389/fnmol.2019.00080
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signaling pathway in Alzheimer’s disease and diabetes. J Pathol 225:54–62. https://doi.org/10.1002/path.2912
Liu Y, Niu R, Yang F, Yan Y, Liang S, Sun Y, Shen P, Lin J (2018) Biological characteristics of human menstrual blood-derived endometrial stem cells. J Cell Mol Med 22:1627–1639. https://doi.org/10.1111/jcmm.13437
Lobo V, Patil A, Phatak A, Chandra N (2010) Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev 4:118–126. https://doi.org/10.4103/0973-7847.70902
Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84(1):87–136. https://doi.org/10.1152/physrev.00014.2003
Moreira-Silva D, Carrettiero DC, Oliveira ASA, Rodrigues S, dos Santos-Lopes J, Canas PM, Cunha RA, Almeida MC, Ferreira TL (2018) Anandamide effects in a streptozotocin-induced Alzheimer’s disease-like sporadic dementia in rats. Front Neurosci 12:653. https://doi.org/10.3389/fnins.2018.00653
Navaei-Nigjeh M, Amoabedini G, Noroozi A, Azami M, Asmani MN, Ebrahimi-Barough S, Saberi H, Ai A, Ai J (2014) Enhancing neuronal growth from human endometrial stem cells derived neuron-like cells in three-dimensional fibrin gel for nerve tissue engineering. J Biomed Mater Res A 102(8):2533–2543. https://doi.org/10.1002/jbm.a.34921
Olerud J, Mokhtari D, Johansson M, Christoffersson G, Lawler J, Welsh N, Carlsson PO (2011) Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function. Diabetes 60(7):1946–1954. https://doi.org/10.2337/db10-0277
Park CR, Seeley RJ, Craft S, Woods SC (2000) Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 68(4):509–514. https://doi.org/10.1016/s0031-9384(99)00220-6
Patel AN, Park E, Kuzman M, Benetti F, Silva FJ, Allickson JG (2008) Multipotent menstrual blood stromal stem cells: isolation, characterization, and differentiation. Cell Transpl 17:303–311. https://doi.org/10.3727/096368908784153922
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, New York
Poorgholam P, Yaghmaei P, Hajebrahimi Z (2018) Thymoquinone recovers learning function in a rat model of Alzheimer’s disease. Avicenna J Phytomed 8(3):188–197
Poorgholam P, Yaghmaei P, Noureddini M, Hajebrahimi Z (2021) Effects of artemisinin and TSP–1–human endometrial–derived stem cells on a streptozocin–induced model of Alzheimer’s disease and diabetes in Wistar rats. Acta Neurobiol Exp (Wars) 81(2):141–150. https://doi.org/10.21307/ane-2021-013
Postnikova TY, Diespirov GP, Amakhin DV, Vylekzhanina EN, Soboleva EB, Zaitsev AV (2021) Impairments of long-term synaptic plasticity in the Hippocampus of Young rats during the latent phase of the Lithium-pilocarpine model of temporal lobe Epilepsy. Int J Mol Sci 22(24):13355. https://doi.org/10.3390/ijms222413355
Ryu JK, Cho T, Choi HB, Wang YT, McLarnon JG (2009) Microglial VEGF receptor response is an integral chemotactic component in Alzheimer’s disease pathology. J Neurosci 29:3–13. https://doi.org/10.1523/JNEUROSCI.2888-08.2009
Shalaby MA, Nounou HA, Deif MM (2019) The potential value of capsaicin in modulating cognitive functions in a rat model of streptozotocin-induced Alzheimer’s disease. Egypt J Neurol Psychiat Neurosurg 55:48. https://doi.org/10.1186/s41983-019-0094-7
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. https://doi.org/10.1038/nm1782
Staff NP, Jones DT, Singer W (2019) Mesenchymal stromal cell therapies for neurodegenerative diseases. Mayo Clin Proc 94:892–905. https://doi.org/10.1016/j.mayocp.2019.01.001
Su K, Edwards SL, Tan KS, White JF, Kandel S, Ramshaw JAM, Gargett CE, Werkmeister JA (2014) Induction of endometrial mesenchymal stem cells into tissue-forming cells suitable for fascial repair. Acta Biomater 10(12):5012–5020. https://doi.org/10.1016/j.actbio.2014.08.031
Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta–analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941. https://doi.org/10.1016/j.biopsych.2010.06.012
Sweatt JD (2016) Neural plasticity & behavior - sixty years of conceptual advances. J Neurochem 139:79–199. https://doi.org/10.1111/jnc.13580
Tian X, Liu Y, Ren G, Yin L, Liang X, Geng T, Dang H, An R (2016) Resveratrol limits diabetes-associated cognitive decline in rats by preventing oxidative stress and inflammation and modulating hippocampal structural synaptic plasticity. Brain Res 1650:1–9. https://doi.org/10.1016/j.brainres.2016.08.032
Tönnies E, Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis 57:1105–1121. https://doi.org/10.3233/JAD-161088
Vagnucci AH Jr, Li WW (2003) Alzheimer’s disease and angiogenesis. Lancet 361(9357):605–608. https://doi.org/10.1016/S0140-6736(03)12521-4
Verdi J, Tan A, Shoae-Hassani A, Seifalian AM (2014) Endometrial stem cells in regenerative medicine. J Biol Eng 8:20. https://doi.org/10.1186/1754-1611-8-20
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539. https://doi.org/10.1038/416535a
Wolff EF, Gao XB, Yao KV, Andrews ZB, Du H, Elsworth JD, Taylor HS (2011) Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model. J Cell Mol Med 15:747–755. https://doi.org/10.1111/j.1582-4934.2010.01068.x
Wolff EF, Mutlu L, Massasa EE, Elsworth JD, Eugene Redmond D, Taylor HS (2015) Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson’s disease. J Cell Mol Med 19(1):249–256. https://doi.org/10.1111/jcmm.12433
Yagishita H, Nishimura Y, Noguchi A, Shikano Y, Ikegaya Y, Sasaki T (2020) Urethane anesthesia suppresses hippocampal subthreshold activity and neuronal synchronization. Brain Res 1749:147137. https://doi.org/10.1016/j.brainres.2020.147137
Yang W, Ma J, Liu Z, Lu Y, Hu B, Yu H (2014) Effect of naringenin on brain insulin signaling and cognitive functions in ICV–STZ induced dementia model of rats. Neurol Sci 35:741–751. https://doi.org/10.1007/s10072-013-1594-3
Yang Y, Wu Y, Zhang S, Song W (2013) High glucose promotes Aβ production by inhibiting APP degradation. PLoS ONE 8(7):e69824. https://doi.org/10.1371/journal.pone.0069824
Zhao Y, Chen X, Wu Y, Wang Y, Li Y, Xiang C (2018) Transplantation of human menstrual blood–derived mesenchymal stem cells alleviates Alzheimer’s disease–like pathology in APP/PS1 transgenic mice. Front Mol Neurosci 11:140. https://doi.org/10.3389/fnmol.2018.00140
Acknowledgements
This is PP Ph.D.’s results under the supervision of PY and MN and the advice of ZH. Partial financial support was received from Islamic Azad University, Science and Research Branch, for conducting this study.
Funding
This is PP Ph.D.’s results under the supervision of PY and MN, and the advice of ZH. Partial financial support was received from Islamic Azad University, Science and Research Branch, for conducting this study.
Author information
Authors and Affiliations
Contributions
P.Y., Z.H., M.N.; Contributed to conception and design. P.P.; Contributed to all experimental work, data and statistical analysis, and interpretation of data. P.Y., Z.H., M.N.; Were responsible for overall supervision. Z.H.; Drafted the manuscript, which was revised by P.Y., and M.N. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Islamic Azad University, Science and Research Branch, Tehran, Iran (IR.IAU.SRB.REC.1398).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Poorgholam, P., Yaghmaei, P., Noureddini, M. et al. Artemisin and human endometrial-derived stem cells improve cognitive function and synaptic plasticity in a rat model of Alzheimer disease and diabetes. Metab Brain Dis 38, 1925–1936 (2023). https://doi.org/10.1007/s11011-023-01200-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-023-01200-y