The Molecular Mechanism of Scutellaria baicalensis Georgi Stems and
Leaves Flavonoids in Promoting Neurogenesis and Improving Memory
Impairment by the PI3K-AKT-CREB Signaling Pathway in Rats

Qian-Qian      Liu; Sheng-Kai      Ding; Hui       Zhang; Ya-Zhen      Shang

doi:10.2174/1386207324666210506152320

Abstract

Aim: The aim of this study was to investigate the effect and molecular mechanism of Scutellaria baicalensis Georgi stems and leaves flavonoids (SSF) in promoting neurogenesis and improving memory impairment induced by the PI3K-AKT-CREB signaling pathway.

Methods: Alzheimer's disease (AD) was induced in the male Wistar rats by intracerebroventricular injection of amyloid beta peptide 25-35 (Aβ_25-35) in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1(RHTGF-β1) (composited Aβ). The Morris water maze was used to screen the successful establishment of the memory impairment model of rats. The screened successful model rats were randomly divided into a model group and three groups of three different doses of the drug (SSF). Rats in the drug group were treated with 35, 70, and 140 mg/kg of SSF for 43 days. The Eight-arm maze was used to measure the spatial learning and memory abilities of the rat, including working memory errors (WME) and reference memory errors (RME). Immunohistochemistry was used to detect the expression of BrdU, an indicator of neuronal proliferation, in the hippocampal gyrus of rats. The mRNA and protein expressions of TRKB, PI3K, AKT, P-AKT, and IGF2 in the PI3K-AKT-CREB signaling pathway in the hippocampus and cerebral cortex of the rats were determined by quantitative real-time PCR (qPCR) and Western blotting methods.

Results: Compared to the sham group, the spatial memory ability of rats with composited Aβ was decreased, the number of WME and RME (P < 0.01) was increased, the expression of BrdU protein (P < 0.01) in the hippocampal gyrus was reduced, the mRNA and protein expression levels of TRKB, AKT, and IGF2 (P < 0.01, P < 0.05) in the hippocampus and cerebral cortex were lowered, and the mRNA expression level of PI3K (P < 0.01) in the cerebral cortex and the protein expression level of PI3K (P < 0.01) in the hippocampus were augmented. However, compared to the model group, the three-doses of SSF improved memory disorder induced by composited Aβ, reduced the number of WME and RME, increased the expression of BrdU protein in the hippocampal gyrus, and differently regulated the mRNA and protein expressions in composited Aβ rats.

Conclusion: SSF improved memory impairment and neurogenesis disorder induced by composited Aβ in rats by activating the PI3K-AKT-CREB signaling pathway and up-regulating the mRNA and protein expressions of TRKB, PI3K, AKT, CREB, and IGF2.

Keywords: Scutellaria baicalensis Georgi stems and leaves flavonoids, Alzheimer's disease, neurogenesis, PI3K-AKT-CREB signaling pathway, memory impairment, molecular mechanism.

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[1] 
He, L.Y.; He, X.H.; Pang, G.F.; Liang, Q.H.; Yang, Z.; Hu, C.Y. Pathogenesis and treatment of Alzheimer’s disease. Chinese J. Geriatric Care,  2017, 15(5), 12-14.
[http://dx.doi.org/10.3969/j.issn.1672-4860.2017.05.002] 
[2] 
Liu, Z.; Wei, C.X. The pathogenesis of Alzheimer’s disease. World Latest Med. Inf.,  2019, 19(8), 176-177. https://doi.org /CNKI:SUN:WMIA.0.2019-08-080
[3] 
Unger, M.S.; Marschallinger, J.J.; Kaindl, J.; Höfling, C.; Rossner, S.; Heneka, M.T.; Vander, L.A.; Linden, A. Early changes in hippocampal neurogenesis in transgenic mouse models for Alzheimer’s disease. Mol. Neurobiol.,  2016, 53(8), 5796-5806.
[http://dx.doi.org/10.1007/s12035-016-0018-9] [PMID:  27544234] 
[4] 
Zhang, W.; Song, J.K.; Yan, R.; Li, L.; Xiao, Z.Y.; Zhou, W.X.; Wang, Z.Z.; Xiao, W.; Du, G.H. Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling. Acta Pharmacol. Sin.,  2018, 39(8), 1259-1272.
[http://dx.doi.org/10.1038/aps.2017.149] [PMID:  29542683] 
[5] 
Taupin, P. BrdU immunohistochemistry for studying adult neurogenesis: Paradigms, pitfalls, limitations, and validation. Brain Res. Rev.,  2017, 53(1), 198-214.
[http://dx.doi.org/10.1016/j.brainresrev.2006.08.00] [PMID:  17020783] 
[6] 
Li, B.S.; Ma, W.; Howard, J.; Zheng, Y.L.; Satoru, T.; Zhang, L. Cyclin dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J. Biol. Chem.,  2003, 278(37), 35702-35709.
[http://dx.doi.org/10.1074/jbc.M302004200.] [PMID:  12824184] 
[7] 
Li, M.; Dai, F.R.; Du, X.P.; Yang, Q.D.; Zhang, X.W.; Chen, Y.X. Infusion of BDNF into the nucleus accumbens of aged rats improves cognition and structural synaptic plasticity through PI3K-ILK-Akt signaling. Behav. Brain Res.,  2012, 231(1), 146-153.
[http://dx.doi.org/10.1016/j.bbr.2012.03.010] [PMID:  22446058] 
[8] 
Fang, F.; Yan, Y.; Feng, Z.H.; Liu, X.Q.; Wen, M.; Huang, H. Study of Alzheimer’s disease model induced multiple factors. Chongqing Med.,  2007, 36(2), 146-151.
[http://dx.doi.org/10.3969/j.issn.1671-8348.2007.02.025] 
[9] 
Guo, K.; Wu, X.G.; Miao, H.; Cheng, J.J.; Cui, Y.D.; Shang, Y.Z. Regulation and mechanism of Scutellaria barbata flavonoids on apoptosis of cortical neurons and cytochondriome induced by composite Aβ. Chinese J. Hospital Pharm.,  2015, 35(22), 1994-1999.
[http://dx.doi.org/10.13286/j.cnki.chinhosppharmacyj.2015.22.04] 
[10] 
Wu, X.G.; Wang, S.S.; Miao, H.; Cheng, J.J.; Zhang, S.F.; Shang, Y.Z. Scutellaria barbata flavonoids alleviate memory deficits and neuronal injuries induced by composited Aβ in rats. Behav. Brain Funct.,  2016, 12(1), 33.
[http://dx.doi.org/10.1186/s12993-016-0118-8] [PMID:  27931218] 
[11] 
Cheng, J.J.; Miao, H.; Shang, Y.Z.; Ma, S.; Gao, Y. Inhibition of flavonoids from Scutellaria Stem and leaf against information of PHF and regulation of protein phosphatase inokadaic acid induced brain injury in rats. Med. Plant,  2018, 9(6), 76-81. https://doi.org/CNKI:SUN:MDPT.0.2018-06-022
[12] 
Wang, Y.M.; Liu, Y.P.; Cao, K.; Shang, Y.Z. Effects of flavonoids in stem and leaves of Scutellaria baicalensis Georgi on ischemic memory disorders and neuroinflammation in rats. Chinese J.
Pharmacol. Toxicol.,  2011, 25(2), 135-140.
[http://dx.doi.org/10.3867/j.issn.1000-3002.2011.02.002] 
[13] 
Zhang, S.F.; Dong, Y.C.; Zhang, X.F.; Wu, X.G.; Cheng, J.J.; Guan, L.H.; Shang, Y.Z. Flavonoids from Scutellaria attenuate okadaic acid-induced neuronal damage in rats. Brain Inj.,  2015, 29(11), 1376-1382.
[http://dx.doi.org/10.3109/02699052.2015.1042053] [PMID:  26083050] 
[14] 
Wu, X.G.; Chen, J.J.; Zhang, H.; Shang, Y.Z. Establishment of a valuable mimic of alzheimer’s disease in rat animal model by intracerebroventricular injection of composited amyloid beta protein. J. Vis. Exp.,  2018, 8(6), 24-25.
[http://dx.doi.org/10.3791/56157] [PMID:  30102270] 
[15] 
Tian, H.L.; Ding, N.; Guo, M.W.; Wang, S.; Wang, Z.D.; Liu, H.; Yang, J.Y.; Li, Y.J.; Ren, J.G.; Jiang, J.; Li, Z.G. Analysis of learning and memory ability in an alzheimer’s disease mouse model using the morris water maze. J. Vis. Exp.,  2019, 29, 152.
[http://dx.doi.org/10.3791/60055] [PMID:  31736488] 
[16] 
Naoki, U.; Kotaro, T.; Yuri, S.; Ai, N.; Hiroshi, O.; Takuya, W.; Taro, S. Cholinergic involvement and synaptic dynamin 1 expression in Yokukansan-mediated improvement of spatial memory in a rat model of early Alzheimer’s disease. Phyto. Res.,  2013, 27(7), 966-972.
[http://dx.doi.org/10.1002/ptr.4818] [PMID:  22888033] 
[17] 
Wang, W.D.; Wang, H.D.; Wang, B.; Jiang, W.; Zhang, Z.J.; Wang, J.C. Evaluated the sensitivity and reliability of the method to display the level of neurogenesis in adult rat brain tissue. J. Clinical Rehabilitative Tissue Engg Res.,  2002, 6(013), 1902-1902.
[http://dx.doi.org/10.3321/j.issn:1673-8225.2002.13.022] 
[18] 
Dong, F.X.; Liu, Y.P.; Xu, T.J. The effect of RO25-6981 on neurogenesis after cerebral ischemia reperfusion. Jiangsu Med. J.,  2012, 38(006), 648-650. https://doi.org/CNKI:SUN:YIYA.0.2012-06-010
[19] 
Aimone, J.B.; Li, Y.; Lee, S.W.; Clemenson, G.D.; Deng, W.; Gage, F.H. Regulation and function of adultneurogenesis: from genes to cognition. Physiol. Rev.,  2014, 94, 991-1026.
[http://dx.doi.org/10.3791/56157] [PMID:  30102270] 
[20] 
Seib, D.R.; Martin-Villalba, A. Neurogenesis in the Normal Ageing Hippocampu: A Mini-Review. Gerontology,  2015, 61(4), 327-335.
[http://dx.doi.org/10.1159/000368575] [PMID:  25471300] 
[21] 
Schaeffer, E.L.; Gattaz, W.F. Chronic inhibition of brain phospholipase A2 in adult rats impairs the survival of newborn mature neurons in the hippocampus. J. Neural Transm.,  2015, 122(5), 619-628.
[http://dx.doi.org/10.1007/s00702-014-1305-0] [PMID:  25160937] 
[22] 
Hall, B.J.; Cauley, M.; Burke, D.A.; Kiany, A.; Slotkin, T.A.; Levin, E.D. Cognitive and behavioral impairments evoked by lowlevel
exposure to tobacco smoke components: comparison with
nicotine alone. J. Society Toxicol.,  2016, 151(2), 236-244.
[http://dx.doi.org/10.1093/toxsci/kfw042] [PMID: 26919958] 
[23] 
Zhao, M.; Wang, T.L.; Li, W.Z. Effects of therapeutic hypercapnia on spatial memory after focal cerebral ischemia/reperfusion in rat. Beijing Med. J.,  2019, 41(4), 287-291. https://doi.org/CNKI:SUN:BJYX.0.2019-04-009
[24] 
Heikki, T. The role of BDNF in Alzheimer’s disease. Neurobiol. Dis.,  2017, 97, 114-118.
[http://dx.doi.org/10.1016/j.nbd.2016.05.008.] [PMID:  27185594] 
[25] 
Meng, C.M.; He, Z.Y.; Xing, D. Low-level laser therapy rescues dendrite atrophy via up-regulating BDNF expression: implications for Alzheimer’s disease. J.
Society Neuroscience,  2013, 33(33), 13505-13517.
[http://dx.doi.org/10.1523/JNEUROSCI.0918-13.2013] [PMID:  23946409] 
[26] 
Chen, Z.; Simmons, M.S.; Perry, R.T.; Wiener, H.W.; Harrel, L.E.; Go, R.C. Genetic Association of Neurotrophic Tyrosine Kinase Receptor Type 2 (NTRK2) with Alzheimer’s Disease. Am. J. Medical Genetics Part B Neuropsychiatric Genetics,  2010, 147(3), 363-369.
[http://dx.doi.org/10.1002/ajmg.b.30607] [PMID:  17918233] 
[27] 
Suire, S.; Coadwell, J.; Ferguson, G.J.; Davidson, K.; Hawkins, P.; Stephens, L. p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma. Curr. Biol.,  2005, 15(6), 566.
[http://dx.doi.org/10.1016/j.cub.2005.02.020] [PMID:  15797027] 
[28] 
Martelli, A.M.; Faenza, I.; Billi, A.M.; Manzoli, L.; Evangelist, C.; Fala, F.; Cocco, L. Intranuclear 3¢-phosphoinositide metabolism and AKT signaling: New mechanisms for tumorigenesis and protection against apoptosis? Cell. Signal.,  2006, 18(8), 1101-1107.
[http://dx.doi.org/10.1016/j.cellsig.2006.01.011] [PMID:  16516442] 
[29] 
Kensuke, S.; Kate, K.; Karl, O. CREB: a multifaceted regulator of neuronal plasticity and protection. J. Neurochem.,  2011, 116, 1-9.
[http://dx.doi.org/10.1111/j.1471-4159.2010.07080.] [PMID:  21044077] 
[30] 
Chen, X.; Hu, J.Y.; Chen, Q.H.; Liang, L.C.; Wang, L.Y.; Liang, Z.W.; Wang, Y.; Cai, M. Metabolic disorder mechanisms of cognitive dysfunction in AD: brain insulin resistance and impairment of the PI3K/Akt signaling pathway. Chem. Life,  2020, 40(02), 269-276.
[http://dx.doi.org/10.13488/j.smhx.20190201] 
[31] 
Li, Y.; Shi, Y.; Li, W.; Xiao, H.H.; Deng, Y.; Li, W.Y.; Chen, J.C.; Yang, J.X. Kaixin Powder Regulates PI3K/Akt/GSK3β Signaling Pathway to Promote Intracranial Nerve Regeneration in AD Model mice. Pharmacol. Clinics Chinese Materia Medica,  2020, 36(05), 73-78.
[http://dx.doi.org/10.13412/j.cnki.zyyl.2020.05.002] 
[32] 
Sandberg, A.C.; Engberg, C.; Lake, M.V.; Holst, H.; Sara, V.R. Expression of insulin-like growth factor I and insulin-like growth factor II genes in the human fetal and adult brain and in glioma. Neurosci. Lett.,  1988, 93(1), 114-119.
[http://dx.doi.org/10.1016/0304-3940(88)90022-5] [PMID:  3211366] 
[33] 
Alberini, C.M.; Chen, D.Y. Memory enhancement: consolidation, reconsolidation and insulin-like growth factor 2. Trends Neurosci.,  2012, 35(5), 274-283.
[http://dx.doi.org/10.1016/j.tins.2011.12.007] [PMID:  22341662] 
[34] 
Zhang, H.; Ding, S.K.; Liu, Q.Q.; Ye, Y.Y.; Xu, Q.; Shang, Y.Z. Ca2+-Camk- CREB mediates the effect of flavonoids from Scutellaria baicalensis stems and leaves on the decrease of neurogenesis-induced by composited aβ in rats. Int. J. Medic. Plants Natural Products,  2019, 5(4), 18-28.
[http://dx.doi.org/10.20431/2454-7999.0504004 ] 
[35] 
Chen, D.Y.; Stem, S.A.; Garcia-Osta, A.; Saunier-Rebori, B.; Pollonini, G.; Bambah-Mukku, D.; Blitzer, R.D.; Alberini, C.M. A critical role for IGF-II in memory consolidation and enhancement. Nature,  2011, 469(7331), 491-497.
[http://dx.doi.org/10.1038/nature09667] [PMID:  21270887] 
[36] 
Shimizu, T.; Sugihara, E.; Yamaguchi-Iwai, S.; Tamaki, S.; Koyama, Y.; Kamel, W.; Ueki, A.; Ishikawa, T.; Chiyoda, T.; Osuka, S. IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress. Cancer Res.,  2014, 74(22), 6531-6541.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-091] [PMID:  25273088] 
[37] 
Bracko, O.; Singer, T.; Aigner, S.; Knobloch, M.; Winner, B.; Ray, J.; Suh, H.; Couillard-Despres, S.; Aigner, L.; Gage, F.H.; Jessberger, S. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J. Nature Neurosci.,  2012, 32(10), 3376-3387.
[http://dx.doi.org/10.1523/JNEUROSCI.4248-11.201] [PMID:  22399759] 
[38] 
Mellott, T.J.; Pender, S.M.; Burke, R.M.; Langley, E.A.; Blusztajn, J.K. IGF2 ameliorates amyloidosis, increases cholinergic marker expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer’s Disease model mice. PLoS One,  2014, 9(4)e94287
[http://dx.doi.org/10.1371/journal.pone.0094287] [PMID:  24732467] 
[39] 
Qiu, Q.; Hu, Z.H.; Xu, H.D.; Xing, H.Y.; Sun, H.F.; Zhang, N.; Lei, X. Effect of naringenin on oxidative stress and tau protein phosphorylation of Aβ25-35-induced PC12 cell injury. Chinese J.
Exp. Traditional Med. Formulae,  2020, 26(21), 92-99.
[http://dx.doi.org/10.13422/j.cnki.syfjx.20202140] 
[40] 
Lai, W.F.; Hong, H.M.; Zhang, X.Q.; Xie, X.L.; Ying, X.; Xu, L.W.; Hong, G.Z. Inhibitive effect of salidro-side on nerve cell apoptosis in MACO rat through an activation of PI3K/Akt/Nrf2 pathway. China J. Trad. Chinese Medic. Pharm.,  2016, 31(5), 1883-1886. https://doi.org/CNKI:SUN:BXYY.0.2016-05-076
[41] 
Ali, T.; Kim, T.; Rehman, S.U.; Khan, M.S.; Amin, F.U.; Khan, M.; Ikram, M.; Kim, M.O. Natural dietary supplementation of anthocyanins via PI3K/Akt/Nrf2/HO-1 pathways mitigate oxidative stress, neurodegeneration, and memory impairment in a mouse model of Alzheimer’s disease. Mol. Neurobiol.,  2018, 55(7), 6076-6093.
[http://dx.doi.org/10.1007/s12035-017-0798-6] [PMID:  29170981] 

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DOI https://dx.doi.org/10.2174/1386207324666210506152320	Print ISSN 1386-2073
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The Molecular Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids in Promoting Neurogenesis and Improving Memory Impairment by the PI3K-AKT-CREB Signaling Pathway in Rats

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