DL-3-n-butylphthalide enhances synaptic plasticity in mouse model of brain impairments

  • Qian Ding Department of Anesthesiology, Xi’an International Medical Center Hospital, Northwest University, Xi’an, Shaanxi, China
  • Qian Yu Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi, China
  • Lei Tao Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi, China
  • Yifei Guo Clinical Experimental Center, Xi’an International Medical Center Hospital, Northwest University, Xi’an, Shaanxi, China
  • Juan Zhao Department of Anesthesiology, Xi’an International Medical Center Hospital, Northwest University, Xi’an, Shaanxi, China
  • Jun Yu Clinical Experimental Center, Xi’an International Medical Center Hospital, Northwest University, Xi’an, Shaanxi, China
Keywords: synaptic plasticity, L-3-n-butylphthalide, glutamate, Alzheimer’s disease, learning and memory ability


Synaptic impairment results in cognitive dysfunction of Alzheimer’s disease (AD). As a plant extract, it is found that DL-3-n-butylphthalide (L-NBP) rescues abnormal cognitive behaviors in AD animals. However, the regulatory effects of L-NBP on synaptic plasticity remains unclear. APP/PS1 mice at 12 months old received oral L-NBP treatment for 12 weeks. A water maze test assessed cognitive performances. In vitro patch-clamp recordings and in vivo field potential recordings were performed to evaluate synaptic plasticity. The protein expression of AMPA receptor subunits (GluR1 and GluR2) and NMDA receptor subunits (NR1, NR2A, and NR2B) was examined by Western blot. In addition, glutaminase activity and glutamate level in the hippocampus were measured by colorimetry to evaluate presynaptic glutamate release. L-NBP treatment could significantly improve learning and memory ability, upregulate NR2A and NR2B protein expressions, increase glutaminase activity and glutamate level in the hippocampus, and attenuate synaptic impairment transmission in the AD mice. L-NPB plays a beneficial role in AD mice by regulating NMDA receptor subunits’ expression and regulating presynaptic glutamate release.


Download data is not yet available.


Takeuchi T, Duszkiewicz AJ, Morris RGM. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc B Biol Sci 2014; 369(1633): 20130288. doi: 10.1098/rstb.2013.0288

Shankar GM, Walsh DM. Alzheimer’s disease: synaptic dysfunction and Aβ. Mol Neurodegener 2009; 4(1): 48. doi: 10.1186/1750-1326-4-48

Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 2007; 68(18): 1501–8. doi: 10.1212/01.wnl.0000260698.46517.8f

Pozueta J, Lefort R, Shelanski ML. Synaptic changes in Alzheimer’s disease and its models. Neuroscience 2013; 251: 51–65. doi: 10.1016/j.neuroscience.2012.05.050

Cavanagh C, Wong TP. Preventing synaptic deficits in Alzheimer’s disease by inhibiting tumor necrosis factor alpha signaling. IBRO Rep 2018; 4: 18–21. doi: 10.1016/j.ibror.2018.01.003

Sheng C, Xu P, Zhou K, Deng D, Zhang C, Wang Z. Icariin Attenuates Synaptic and Cognitive Deficits in an A β1-42-Induced Rat Model of Alzheimer’s disease. BioMed Res Int 2017; 2017: 12. doi: 10.1155/2017/7464872

Xu ZP, Li L, Bao J, Wang ZH, Zeng J, Liu EJ, et al. Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer’s model. PLoS One 2014; 9(9):e108645. doi: 10.1371/journal.pone.0108645

Bereczki E, Branca RM, Francis PT, Pereira JB, Baek J-H, Hortobágyi T, et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 2018; 141(2): 582–95. doi: 10.1093/brain/awx352

Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 2014; 76: 27–50. doi: 10.1016/j.neuropharm.2013.07.004

Peng Y, Hu Y, Xu S, Li P, Li J, Lu L, et al. L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer’s transgenic mice. J Alzheimers Dis 2012; 29: 379–91. doi: 10.3233/JAD-2011-111577

Peng Y, Sun J, Hon S, Nylander AN, Xia W, Feng Y, et al. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease. J Neurosci 2010; 30(24): 8180–9. doi: 10.1523/JNEUROSCI.0340-10.2010

Xu J, Wang Y, Li N, Xu L, Yang H, Yang Z. l-3-n-butylphthalide improves cognitive deficits in rats with chronic cerebral ischemia. Neuropharmacology 2012; 62(7): 2424–9. doi: 10.1016/j.neuropharm.2012.02.014

Li PP, Wang WP, Liu ZH, Xu SF, Lu WW, Wang L, et al. Potassium 2-(1-hydroxypentyl)-benzoate promotes long-term potentiation in Abeta1-42-injected rats and APP/PS1 transgenic mice. Acta Pharmacol Sin 2014; 35(7): 869–78. doi: 10.1038/aps.2014.29

Zhang Y, Huang L-J, Shi S, Xu S-F, Wang X-L, Peng Y. L-3-n-butylphthalide rescues hippocampal synaptic failure and attenuates neuropathology in aged APP/PS1 mouse model of Alzheimer’s disease. CNS Neurosci Ther 2016; 22(12): 979–87. doi: 10.1111/cns.12594

Peng Y, Xing C, Xu S, Lemere CA, Chen G, Liu B, et al. L-3-n-butylphthalide improves cognitive impairment induced by intracerebroventricular infusion of amyloid-beta peptide in rats. Eur J Pharmacol 2009; 621(1–3): 38–45. doi: 10.1016/j.ejphar.2009.08.036

Song S, Wang X, Sava V, Weeber EJ, Sanchez-Ramos J. In vivo administration of granulocyte colony-stimulating factor restores long-term depression in hippocampal slices prepared from transgenic APP/PS1 mice. J Neurosci Res 2014; 92(8): 975–80. doi: 10.1002/jnr.23378

Gengler S, Hamilton A, Holscher C. Synaptic plasticity in the hippocampus of a APP/PS1 mouse model of Alzheimer’s disease is impaired in old but not young mice. PLoS One 2010; 5(3):e9764. doi: 10.1371/journal.pone.0009764

Li J, Zhang S, Zhang L, Wang R, Wang M. Effects of L-3-n-butylphthalide on cognitive dysfunction and NR2B expression in hippocampus of streptozotocin (STZ)-induced diabetic rats. Cell Biochem Biophys 2015; 71(1): 315–22. doi: 10.1007/s12013-014-0200-5

Rao VR, Finkbeiner S. NMDA and AMPA receptors: old channels, new tricks. Trends Neurosci 2007; 30(6): 284–91. doi: 10.1016/j.tins.2007.03.012

Luscher C, Malenka RC. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol 2012; 4(6): a005710. doi: 10.1101/cshperspect.a005710

Tozzi A, Sclip A, Tantucci M, de Iure A, Ghiglieri V, Costa C, et al. Region- and age-dependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer’s disease. Neurobiol Aging 2015; 36(1): 123–33. doi: 10.1016/j.neurobiolaging.2014.07.002

Belayev L, Lu Y, Bazan NG. Chapter 35 – brain ischemia and reperfusion: cellular and molecular mechanisms in stroke injury A2 – Brady, Scott T. In: Siegel GJ, Albers RW, Price DL, eds. Basic neurochemistry (Eighth Edition). New York: Academic Press; 2012, pp. 621–42.

Miller SL, Yeh HH. Chapter 3 – neurotransmitters and neurotransmission in the developing and adult nervous system A2 – Conn, P. Michael. In: Michael P, ed. Conn’s translational neuroscience. San Diego, CA: Academic Press; 2017, pp. 49–84.

Banerjee A, Borgmann-Winter KE, Ray R, Hahn CG. Chapter 8 – the PSD: a microdomain for converging molecular abnormalities in schizophrenia. In: Abel T, Nickl-Jockschat T, eds. The neurobiology of schizophrenia. San Diego, CA: Academic Press; 2016, pp. 125–47.

Bi H, Sze C-I. N-methyl-d-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease. J Neurol Sci 2002; 200(1): 11–18. doi: 10.1016/S0022-510X(02)00087-4

Wakabayashi K, Narisawa-Saito M, Iwakura Y, Arai T, Ikeda K, Takahashi H, et al. Phenotypic down-regulation of glutamate receptor subunit GluR1 in Alzheimer’s disease☆. Neurobiol Aging 1999; 20(3): 287–95.

Huang H-J, Liang K-C, Ke H-C, Chang Y-Y, Hsieh-Li HM. Long-term social isolation exacerbates the impairment of spatial working memory in APP/PS1 transgenic mice. Brain Res 2011; 1371: 150–60. doi: 10.1016/j.brainres.2010.11.043

Dickey CA, Loring JF, Montgomery J, Gordon MN, Eastman PS, Morgan D. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci 2003; 23(12): 5219–26.

Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol 2002; 64(1): 355–405. doi: 10.1146/annurev.physiol.64.092501.114547

Fayed N, Modrego PJ, Rojas-Salinas G, Aguilar K. Brain glutamate levels are decreased in Alzheimer’s disease: a magnetic resonance spectroscopy study. Am J Alzheimers Dis Other Demen 2011; 26(6): 450–6. doi: 10.1177/1533317511421780

Antuono PG, Jones JL, Wang Y, Li SJ. Decreased glutamate + glutamine in Alzheimer’s disease detected in vivo with (1) H-MRS at 0.5 T. Neurology 2001; 56(6): 737–42. doi: 10.1212/WNL.56.6.737

Burbaeva G, Boksha IS, Tereshkina EB, Savushkina OK, Prokhorova TA, Vorobyeva EA. Glutamate and GABA-metabolizing enzymes in postmortem cerebellum in Alzheimer’s disease: phosphate-activated glutaminase and glutamic acid decarboxylase. Cerebellum 2014; 13(5): 607–15. doi: 10.1007/s12311-014-0573-4

Akiyama H, McGeer PL, Itagaki S, McGeer EG, Kaneko T. Loss of glutaminase-positive cortical neurons in Alzheimer’s disease. Neurochem Res 1989; 14(4): 353–8. doi: 10.1007/BF01000038

González-Domínguez R, García-Barrera T, Vitorica J, Gómez-Ariza JL. Region-specific metabolic alterations in the brain of the APP/PS1 transgenic mice of Alzheimer’s disease. Biochim Biophys Acta 2014; 1842(12, Part A): 2395–402. doi: 10.1016/j.bbadis.2014.09.014

How to Cite
DingQ., YuQ., TaoL., GuoY., ZhaoJ., & YuJ. (2022). DL-3-n-butylphthalide enhances synaptic plasticity in mouse model of brain impairments. STEMedicine, 3(1), e113. https://doi.org/10.37175/stemedicine.v3i1.113
Research articles