Botaceuticals

Red Sage roots x Neurological benefits

1. INTRODUCTION

Red sage (Salvia miltiorrhiza), also known as Danshen, is a perennial plant from eastern Asia. The health benefits of its roots has been praised for over two millenia, mainly for cardiovascular health (more about red sage & cardiovascular data). However, recent scientific data indicate that red sage and its active constituents (Tanshinones & phenolic acids) can be used in a variety of health applications. Among them, the link between vascular and neurological properties were of peculiar interest. Indeed, it has been determined that tanshinones and phenolic acids have anti-inflammatory properties and vascular protection activity, leading to the assessment of their interest in vascular dementia [1]. The health potential in this context led to futher investigations in neuroprotection and neurodegenerative diseases.

2. NEUROLOGICAL HEALTH & SALVIA MILTIORRHIZA

2.1. Neuroprotective effect of Red Sage

If diterpenoids from Salvia miltiorrhiza roots were identified as potentially neuroprotective in multiple conditions (tanshinone IIA [2-6] & cryptotanshinone [7-11]), Salvianolic acids are the molecules that have been the subject of most of the studies in this context [12-19] and more specifically in ischaemic conditions. It is however difficult to determine if the benefits in vivo are due to the neuroprotective and/or to the vascular positive impact of red sage. Anyway, the results obtained, even in a clinical context [20], seem really promising and invite to more investigations.  Beyond "typical" neuroprotective activity in ischaemic conditions and excitotoxicity models, very interesting data were collected in high glucose context and diabetic neuropathic pain models [21-26]. Finally, another obvious pathological condition where neuroprotection is involved is Alzheimer's disease... 

2.2. Red sage & Alzheimer's Disease

Due to its neuroprotective properties, Danshen was quickly identified as a potential tool in Alzheimer's disease early stages [27-28]. Experiments performed on in vitro and in vivo models, confirmed the positive impact of tanshinone IIA [29-31] and Cryptotanshinone [31-32]. Moreover, in the case of cryptotanshinone, a stimulation of the non-amyloïdogenic pathway as been identified [33-34]. In other words cryptotanshinone is stimulating the activity of alpha-secretase through PI3K activantion and hence limits the production of Aβ (the "key player" in Alzheimer's disease). In parallel, Salvianolic acids and more specifically Salvianolic acid B, has been highlighted as an inhibitor of β-secretase, leading to a diminution of Aβ production [35-37]. This activity identified in vitro, seems to have positive impact in vivo too [38]. 

2.3. Red sage & Anxiety

More surprisingly, the neurological benefits of red sage and its constituent doesn't stop at neuroprotection. The evaluation of the effect of Salvianolic acids in chronic stress and depression models highlighted some beneficial effect [39-42], probably associated with the inflammation regulation. This is proof that red sage has probably not yet revealed all its properties in a neurological context.
3. CONCLUSION

Health benefits combining vascular anti-inflammatory activity, global neuroprotection and modulation of Aβ poduction, is a powerful synergy that invites to investigate futher the interest of Salvia miltiorrhiza roots as "adjuvant" in a neurodegenerative context.  However, it should be noticed that some active constituent like cryptotanshinone are also acetylcholinesterase inhibitors [43-44]. Therefore, a synergistic activity (drug interaction) with drugs like galanthamine (an acetylcholinesterase inhibitor typically used in the early stage of Alzheimer's disease) can't be excluded. Other potential drugs interactions can be assumed and should be taken in consideration in a clinical context. 
Red sage roots is a fascinating medicinal plant with promising health benefits in the cardiovascular and the neurological area. In both cases, inflammation pathway regulation seems to be critical, opening up opportunities in other therapeutic areas like dermatology (erythema, psoriasis, etc.) and rheumatology (see futher articles).
REFERENCES

[1] Habtemariam S (2020) - "Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer's and Vascular Dementia Drugs." Int J Mol Sci. 2018 Feb 3;19(2). pii: E458. doi: 10.3390/ijms19020458. Review.
[2] Cheng W, Xiang W, Wang S, Xu K (2019) - "Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion." Am J Transl Res. 2019 May 15;11(5):3140-3149. eCollection 2019.
[3] Tang N, Chang J, Zeng Y, Zheng J (2019) - "Tanshinone IIA protects hypoxia-induced injury by preventing microRNA-28 up-regulation in PC-12 cells." Eur J Pharmacol. 2019 Jul 5;854:265-271. doi: 10.1016/j.ejphar.2019.04.030. Epub 2019 Apr 17.
[4] Zhou L, Zhang J, Wang C, Sun Q (2017) - “Tanshinone inhibits neuronal cell apoptosis and inflammatory response in cerebral infarction rat model.” Int J Immunopathol Pharmacol. 2017 Jun;30(2):123-129. doi: 10.1177/0394632017703274. Epub 2017 Apr 12.
[5] Zhu Y, Tang Q, Wang G, Han R (2017) - “Tanshinone IIA Protects Hippocampal Neuronal Cells from Reactive Oxygen Species Through Changes in Autophagy and Activation of Phosphatidylinositol 3-Kinase, Protein Kinas B, and Mechanistic Target of Rapamycin Pathways.” Curr Neurovasc Res. 2017;14(2):132-140. doi: 10.2174/1567202614666170306105315.
[6] Cai M, Guo Y, Wang S, Wei H, Sun S, Zhao G, Dong H (2017) - “Tanshinone IIA Elicits Neuroprotective Effect Through Activating the Nuclear Factor Erythroid 2-Related Factor-Dependent Antioxidant Response.” Rejuvenation Res. 2017 Aug;20(4):286-297. doi: 10.1089/rej.2016.1912. Epub 2017 Mar 23.
[7] Park OK, Choi JH, Park JH, Kim IH, Yan BC, Ahn JH, Kwon SH, Lee JC, Kim YS, Kim M, Kang IJ, Kim JD, Lee YL, Won MH (2012) - “Comparison of neuroprotective effects of five major lipophilic diterpenoids from Danshen extract against experimentally induced transient cerebral ischemic damage.” Fitoterapia. 2012 Dec;83(8):1666-74. doi: 10.1016/j.fitote.2012.09.020. Epub 2012 Sep 28.
[8] Mahesh R, Jung HW, Kim GW, Kim YS, Park YK (2012) – “Cryptotanshinone from Salviae miltiorrhizae radix inhibits sodium-nitroprusside-induced apoptosis in neuro-2a cells.” Phytother Res. 2012 Aug;26(8):1211-9. doi: 10.1002/ptr.3705. Epub 2012 Jan 6.
[9] Zhu W, Qiu W, Lu A (2017) – “Cryptotanshinone exhibits therapeutical effects on cerebral stroke through the PI3K/AKT‑eNOS signaling pathway.” Mol Med Rep. 2017 Dec;16(6):9361-9366. doi: 10.3892/mmr.2017.7824. Epub 2017 Oct 19
[10] Park OK, Choi JH, Park JH, Kim IH, Yan BC, Ahn JH, Kwon SH, Lee JC, Kim YS, Kim M, Kang IJ, Kim JD, Lee YL, Won MH (2012) – “Comparison of neuroprotective effects of five major lipophilic diterpenoids from Danshen extract against experimentally induced transient cerebral ischemic damage.” Fitoterapia. 2012 Dec;83(8):1666-74. doi: 10.1016/j.fitote.2012.09.020. Epub 2012 Sep 28.
[11] Zhang F, Zheng W, Pi R, Mei Z, Bao Y, Gao J, Tang W, Chen S, Liu P (2009) - “Cryptotanshinone protects primary rat cortical neurons from glutamate-induced neurotoxicity via the activation of the phosphatidylinositol 3-kinase/Akt signaling pathway.” Exp Brain Res. 2009 Feb;193(1):109-18. doi: 10.1007/s00221-008-1600-9. Epub 2008 Oct 21.
[12] Song J, Zhang W, Wang J, Yang H, Zhou Q, Wang H, Li L, Du G (2019) – “Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury.” Acta Pharm Sin B. 2019 May;9(3):505-515. doi: 10.1016/j.apsb.2019.01.010. Epub 2019 Jan 24.
[13] Yu X, Guan Q, Wang Y, Shen H, Zhai L, Lu X, Jin Y (2019) – “Anticonvulsant and anti-apoptosis effects of salvianolic acid B on pentylenetetrazole-kindled rats via AKT/CREB/BDNF signaling.” Epilepsy Res. 2019 Aug;154:90-96. doi: 10.1016/j.eplepsyres.2019.05.007. Epub 2019 May 13.
[14] Zhang X, Wu Q, Lu Y, Wan J, Dai H, Zhou X, Lv S, Chen X, Zhang X, Hang C, Wang J (2018) – “Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways.” Free Radic Biol Med. 2018 Aug 20;124:504-516. doi: 10.1016/j.freeradbiomed.2018.06.035. Epub 2018 Jun 30.
[15] Gu X, Zheng C, Zheng Q, Chen S, Li W, Shang Z, Zhang H (2017) – “Salvianolic acid A attenuates early brain injury after subarachnoid hemorrhage in rats by regulating ERK/P38/Nrf2 signaling.” Am J Transl Res. 2017 Dec 15;9(12):5643-5652. eCollection 2017.
[16] Wang SB, Pang XB, Zhao Y, Wang YH, Zhang L, Yang XY, Fang LH, Du GH (2012) – “Protection of salvianolic acid A on rat brain from ischemic damage via soluble epoxide hydrolase inhibition.” J Asian Nat Prod Res. 2012;14(11):1084-92. doi: 10.1080/10286020.2012.723200. Epub 2012 Oct 29.
[17] Wang Y, Jiang YF, Huang QF, Ge GL, Cui W (2010) – “Neuroprotective effects of salvianolic acid B against oxygen-glucose deprivation/reperfusion damage in primary rat cortical neurons.” Chin Med J (Engl). 2010 Dec;123(24):3612-9.
[18] Jiang M, Wang XY, Zhou WY, Li J, Wang J, Guo LP (2011) – “Cerebral protection of salvianolic acid A by the inhibition of granulocyte adherence.” Am J Chin Med. 2011;39(1):111-20.
[19] Chen T, Liu W, Chao X, Zhang L, Qu Y, Huo J, Fei Z (2011) – “Salvianolic acid B attenuates brain damage and inflammation after traumatic brain injury in mice.” Brain Res Bull. 2011 Feb 1;84(2):163-8. doi: 10.1016/j.brainresbull.2010.11.015. Epub 2010 Dec 4.
[20] Peng JW, Liu Y, Meng G, Zhang JY, Yu LF (2018) – “Effects of salvianolic acid on cerebral perfusion in patients after acute stroke: A single-center randomized controlled trial.” Exp Ther Med. 2018 Sep;16(3):2600-2614. doi: 10.3892/etm.2018.6444. Epub 2018 Jul 16.
[21] Feng FB, Qiu HY (2018) – “Neuroprotective effect of tanshinone IIA against neuropathic pain in diabetic rats through the Nrf2/ARE and NF-κB signaling pathways.” Kaohsiung J Med Sci. 2018 Aug;34(8):428-437. doi: 10.1016/j.kjms.2018.03.005. Epub 2018 Apr 27.
[22] Liu Y, Wang L, Li X, Lv C, Feng D, Luo Z (2010) – “Tanshinone IIA improves impaired nerve functions in experimental diabetic rats.” Biochem Biophys Res Commun. 2010 Aug 13;399(1):49-54. doi: 10.1016/j.bbrc.2010.07.037. Epub 2010 Jul 15.
[23] Yu X, Zhang L, Yang X, Huang H, Huang Z, Shi L, Zhang H, Du G (2012) – “Salvianolic acid A protects the peripheral nerve function in diabetic rats through regulation of the AMPK-PGC1α-Sirt3 axis.” Molecules. 2012 Sep 20;17(9):11216-28.
[24] Wang QQ, Zhai C, Wahafu A, Zhu YT, Liu YH, Sun LQ (2019) – “Salvianolic acid B inhibits the development of diabetic peripheral neuropathy by suppressing autophagy and apoptosis.” J Pharm Pharmacol. 2019 Mar;71(3):417-428. doi: 10.1111/jphp.13044. Epub 2018 Dec 7.
[25] Yang MC, You FL, Wang Z, Liu XN, Wang YF (2016) – “Salvianolic acid B improves the disruption of high glucose-mediated brain microvascular endothelial cells via the ROS/HIF-1α/VEGF and miR-200b/VEGF signaling pathways.“ Neurosci Lett. 2016 Sep 6;630:233-240. doi: 10.1016/j.neulet.2016.08.005. Epub 2016 Aug 3.
[26] Yang XY, Sun L, Xu P, Gong LL, Qiang GF, Zhang L, Du GH (2011) – “Effects of salvianolic scid A on plantar microcirculation and peripheral nerve function in diabetic rats.” Eur J Pharmacol. 2011 Aug 31;665(1-3):40-6. doi: 10.1016/j.ejphar.2011.03.054. Epub 2011 Apr 15.
[27] Zhang XZ, Qian SS, Zhang YJ, Wang RQ (2016) – “Salvia miltiorrhiza: A source for anti-Alzheimer's disease drugs.” Pharm Biol. 2016;54(1):18-24. doi: 10.3109/13880209.2015.1027408. Epub 2015 Apr 10.
[28] Chong CM, Su H1, Lu JJ, Wang Y (2019) – “The effects of bioactive components from the rhizome of Salvia miltiorrhiza (Danshen) on the characteristics of Alzheimer's disease.” Chin Med. 2019 May 21;14:19. doi: 10.1186/s13020-019-0242-0. eCollection 2019.
[29] Yang W, Zhang J, Shi L, Ji S, Yang X, Zhai W, Zong H, Qian Y (2019) - "Protective effects of tanshinone IIA on SH-SY5Y cells against oAβ1-42-induced apoptosis due to prevention of endoplasmic reticulum stress." Int J Biochem Cell Biol. 2019 Feb;107:82-91. doi: 10.1016/j.biocel.2018.12.011. Epub 2018 Dec 19.
[30] He Y, Ruganzu JB, Lin C, Ding B, Zheng Q, Wu X, Ma R, Liu Q, Wang Y, Jin H, Qian Y, Peng X, Ji S, Zhang L, Yang W, Lei X (2019) - "Tanshinone IIA ameliorates cognitive deficits by inhibiting endoplasmic reticulum stress-induced apoptosis in APP/PS1 transgenic mice." Neurochem Int. 2019 Nov 26;133:104610. doi: 10.1016/j.neuint.2019.104610.
[31] Maione F, Piccolo M, De Vita S, Chini MG, Cristiano C, De Caro C, Lippiello P, Miniaci MC, Santamaria R, Irace C, De Feo V, Calignano A, Mascolo N, Bifulco G (2018) – “Down regulation of pro-inflammatory pathways by tanshinone IIA and cryptotanshinone in a non-genetic mouse model of Alzheimer's disease.” Pharmacol Res. 2018 Mar;129:482-490. doi: 10.1016/j.phrs.2017.11.018. Epub 2017 Nov 20
[32] Mei Z, Yan P, Situ B, Mou Y, Liu P (2012) – “Cryptotanshinione inhibits β-amyloid aggregation and protects damage from β-amyloid in SH-SY5Y cells.” Neurochem Res. 2012 Mar;37(3):622-8. doi: 10.1007/s11064-011-0652-6. Epub 2011 Nov 19.
[33] Durairajan SS, Liu LF, Lu JH, Koo I, Maruyama K, Chung SK, Huang JD, Li M (2011) – “Stimulation of non-amyloidogenic processing of amyloid-β protein precursor by cryptotanshinone involves activation and translocation of ADAM10 and PKC-α.” J Alzheimers Dis. 2011;25(2):245-62. doi: 10.3233/JAD-2011-102085.
[34] Mei Z, Situ B, Tan X, Zheng S, Zhang F, Yan P, Liu P (2010) – “Cryptotanshinione upregulates alpha-secretase by activation PI3K pathway in cortical neurons.” Brain Res. 2010 Aug 12;1348:165-73. doi: 10.1016/j.brainres.2010.05.083. Epub 2010 Jun 2.
[35] Yu T, Paudel P, Seong SH, Kim JA, Jung HA, Choi JS (2018) – “Computational insights into β-site amyloid precursor protein enzyme 1 (BACE1) inhibition by tanshinones and salvianolic acids from Salvia miltiorrhiza via molecular docking simulations.” Comput Biol Chem. 2018 Jun;74:273-285. doi: 10.1016/j.compbiolchem.2018.04.008. Epub 2018 Apr 13.
[36] Durairajan SSK, Chirasani VR, Shetty SG, Iyaswamy A, Malampati S, Song J, Liu L, Huang J, Senapati S, Li M (2017) – “Decrease in the Generation of Amyloid-β Due to Salvianolic Acid B by Modulating BACE1 Activity.” Curr Alzheimer Res. 2017;14(11):1229-1237. doi: 10.2174/1567205014666170417103003.
[37] Tang Y, Huang D, Zhang MH, Zhang WS, Tang YX, Shi ZX, Deng L, Zhou DH, Lu XY (2016) – « Salvianolic Acid B Inhibits Aβ Generation by Modulating BACE1 Activity in SH-SY5Y-APPsw Cells. » Nutrients. 2016 Jun 1;8(6). pii: E333. doi: 10.3390/nu8060333.
[38] Shen L, Han B, Geng Y, Wang J, Wang Z, Wang M (2017) – “Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid.” PLoS One. 2017 Mar 30;12(3):e0174763. doi: 10.1371/journal.pone.0174763. eCollection 2017.
[39] Huang Q, Ye X, Wang L, Pan J.(2019) - "Salvianolic acid B abolished chronic mild stress-induced depression through suppressing oxidative stress and neuro-inflammation via regulating NLRP3 inflammasome activation." J Food Biochem. 2019 Mar;43(3):e12742. doi: 10.1111/jfbc.12742. Epub 2018 Dec 17.
[40] Zhang J, Xie X, Tang M, Zhang J, Zhang B, Zhao Q, Han Y, Yan W, Peng C, You Z (2017) - "Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stress-exposed mice." Brain Behav Immun. 2017 Nov;66:111-124. doi: 10.1016/j.bbi.2017.07.012. Epub 2017 Jul 20.
[41] Zhang JQ, Wu XH, Feng Y, Xie XF, Fan YH, Yan S, Zhao QY, Peng C, You ZL. (2016) - "Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway." Acta Pharmacol Sin. 2016 Sep;37(9):1141-53. doi: 10.1038/aps.2016.63. Epub 2016 Jul 18.
[42] Feng Y, You Z, Yan S, He G, Chen Y, Gou X, Peng C (2012) - "Antidepressant-like effects of salvianolic acid B in the mouse forced swim and tail suspension tests." Life Sci. 2012 Jun 27;90(25-26):1010-4. doi: 10.1016/j.lfs.2012.05.021. Epub 2012 Jun 5.
[43] Wong KK, Ngo JC, Liu S, Lin HQ, Hu C, Shaw PC, Wan DC (2010) – “Interaction study of two diterpenes, cryptotanshinone and dihydrotanshinone, to human acetylcholinesterase and butyrylcholinesterase by molecular docking and kinetic analysis.” Chem Biol Interact. 2010 Sep 6;187(1-3):335-9. doi: 10.1016/j.cbi.2010.03.026. Epub 2010 Mar 27.
[44] Wong KK, Ho MT, Lin HQ, Lau KF, Rudd JA, Chung RC, Fung KP, Shaw PC, Wan DC (2010) – “Cryptotanshinone, an acetylcholinesterase inhibitor from Salvia miltiorrhiza, ameliorates scopolamine-induced amnesia in Morris water maze task.” Planta Med. 2010 Feb;76(3):228-34. doi: 10.1055/s-0029-1186084. Epub 2009 Sep 11.