Complementary Therapies in Medicine 44 (2019) 68–82 Contents lists available at ScienceDirect Complementary Therapies in Medicine journal homepage: www.elsevier.com/locate/ctim Neuropharmacological and cognitive effects of Bacopa monnieri (L.) Wettst – A review on its mechanistic aspects T ⁎ Nimisha Pulikkal Sukumaran, Augustine Amalraj, Sreeraj Gopi R&D Centre, Aurea Biolabs (P) Ltd, Kolenchery, Cochin 682 311, Kerala, India ARTICLE INFO ABSTRACT Keywords: Bacopa monnieri (L.) – (BM) is a perennial, creeping herb which is widely used in traditional ayurvedic medicine Brahmi as a neural tonic to improve intelligence and memory. Research into the biological effects of this plant has Bacopa monnieri burgeoned in recent years, promising its neuroprotective and memory boosting ability among others. In this Bacosides context, an extensive literature survey allows an insight into the participation of numerous signaling pathways Cognitive health and oxidative mechanism involved in the mitigation of oxidative stress, along with other indirect mechanisms Neuroprotection modulated by bioactive molecules of BM to improve the cognitive action by their synergistic potential and Memory booster cellular multiplicity mechanism. This multi-faceted review describes the novel mechanisms that underlie the unfounded but long flaunted promises of BM and thereby direct a way to harness this acquired knowledge to develop innovative approaches to manipulate its intracellular pathways. 1. Introduction hypercholesterolemic effect,29 anti-emetic30 and antiulcer31 activities. Preliminary animal studies of BM whole plant or alcohol extracts have Bacopa monnieri (L.) – (BM) (Common names: Brahmi, Bacopa, reported cognition-enhancing effects, including a decrease in walking Waterhyssop), renowned as a nootropic plant; belonging to the family errors,32 enhanced learning ability, increased memory retrieval and Scrophulariaceae, is a well-known ayurvedic medicinal plant used in prevented dendritic atrophy following hypoxic exposure in rats.33 India, as a neural tonic to improve intelligence and memory, increase Beneficial effects of the plant may be attributed to its vast range of – brain function and promote longevity.1 3 Being mainly of complex closely related saponins, which differs slightly in structure. Some of the formulations rather than a single bioactive compound, ayurvedic earlier work in this regard, reported the effects of BM on cognitive system of medicine contains several individual components that have a function.34,35 Hence, its effects on cognitive performance, holds a great synergic interaction among phytochemicals, that mutually enhance promise for the amelioration of age-related cognitive decline as well as their efficacy and allows them to act on multiple targets to control cognitive enhancement in the young.33 A controlled study has been complex molecular recognition sites.4 Encouragingly, recently there is a done by Roodenrys et al.36 with various memory functions and the le- growing support for the ‘black-box’ approach – a whole-system ap- vels of anxiety measured, demonstrated the significance of BM on the proach considering the entire compounds rather than individual active retention of new information. Later, Peth-Nui et al.37 verified the effect compounds, for the reason that they can contribute to the synergistic of BM on boosted attention and cognitive processing skill together with action of various molecules to achieve a physiological or pharmacolo- improved working memory and cholinergic function. gical effect.5 Several in vitro and in vivo studies investigating the pharmacological Of the most noticeable therapeutic influences of BM, researchers properties of BM have been published and have especially highlighted generally pointed at the neuroprotection against dementia,6 amnesia,7 its neuroprotective ability which is attributed to its antioxidative, anti- memory dysfunction,8,9 Parkinson's disease (PD),10 Alzheimer's disease apoptotic and anti-inflammatory properties. Herein, not just blue-sky (AD),11 epileptic seizures12 and schizophrenia.13 Nevertheless, BM is thinking, but to decipher the molecular pathways that are already being reported to possess sedative,14 antimicrobial,15 anti-inflammatory,16 used to guide systematic procedures and algorithms for neurochemical/ calcium antagonistic,17 anticonvulsant,18 anti-aging,19 cognitive en- biological properties of BM, suggesting its protection against neurotoxic – hancive,20 22 antinociceptive,23 broncho-vasodilatory,24 anticancer,25 and memory enhancing ability are revised. Moreover, in this review, we hepatoprotective,26 anti-allergic,27 antidepressant,28 anti- evaluate the ways in which BM contributes to cognitive health beyond ⁎ Corresponding author. E-mail address: [email protected] (S. Gopi). https://doi.org/10.1016/j.ctim.2019.03.016 Received 2 February 2019; Received in revised form 23 March 2019; Accepted 25 March 2019 Available online 30 March 2019 0965-2299/ © 2019 Elsevier Ltd. All rights reserved. N.P. Sukumaran, et al. Complementary Therapies in Medicine 44 (2019) 68–82 Fig. 1. Chemical structure of Bacoside A. the known mechanisms of its action and to explore the molecular L-arabinofuranosy(1→2)]-Ob-D-glucopyranosyl)oxy] jujubogenin by crosstalk between these mechanisms and other related pathways in cell chemical and spectral analyses. Along with another bacogenin A4, survival, neuroprotection, and cognitive enhancing capabilities that are which was identified as ebelin lactone pseudojujubogenin and a minor critical to its underlying molecular mechanism to formulate therapeutic saponin bacoside A1 was isolated and characterized as 3-O-[a-L-arabi- 42 43 interventions. nofuranoyl(1→3)-β-L-arabinopyranosyl] jujubogenin. Garay et al. isolated three dammarane-type triterpenoid saponins: bacopasaponins fi 2. Active constituents of BM A, B and C, which was identi ed as 3-O-a-L-arabinopyranosyl-20-O-a-L- arabinopyranosyl-jujubogenin, 3-O-[a-L-arabinofuranosyl (I→2) a-L- β → The characteristic bioactive constituents of BM responsible for its arabinopyranosyl]pseudojujubogenin and 3-O-[ -D-glucopyranosyl(1 → cognitive effects are saponins called bacosides.38 The active ingredients 3){a-L-arabinofuranosyl(1 2)}a-Larabinopyranosyl]. Along with a specifically bacosides A (Fig. 1) and B (Fig. 2) are believed to underlie dammarane-type pseudojujubogenin glycoside, bacopasaponin D was fi α → β the memory-enhancing effects of BM.33 Bacosides, comprise a family of also isolated and de ned as 3-O-[ -Larabinofuranosyl (I 2) -D-glu- 12 known analogs, is a dammarane type of triterpenoid saponin with copiranosyl] pseudojujubogenin. Four cucurbitacins, bacobitacin A, B, jujubogenin, or pseudo-jujubogenin moieties (glycone units). The most C and D and a known cytotoxic, cucurbitacin E, together with three studied constituent bacoside A (3-(a-L-arabinopyranosyl)-O-b-D-gluco- known phenylethanoid glycosides viz. monnieraside I, III and plantio- 44 pyranoside-10,20-dihydroxy-16-keto-dammar-24-ene) is a mixture of side B were isolated from aerial parts of BM. A triterpene bacosine four triglycosidic saponins, namely bacoside A3, bacopaside II, baco- (3alpha)-3-Hydroxylup-20(29)-en-27-oic acid), was also isolated and fi 45,46 pasaponin C and the jujubogenin isomer of bacosaponin C (bacopaside identi ed from aerial parts of BM. – X),39 whereas bacoside B consists of bacopaside N1, bacopaside N2, Recently, novel saponins called bacopasides I XII have been iden- fi 39 ff bacopaside IV, and bacopaside V.40 ti ed by Le et al., in a study to clarify the anti-dementia e ects of BM. Levorotatory bacoside A, a mixture of compounds co-occurs usually Other medicinally important chemical entities include alkaloids with dextrorotatory bacoside B.41 Rastogi et al.42 demonstrated tri- (brahmine and herpestine), saponins (D-mannitol and hersaponin), terpenoid saponin, bacoside A3 (3-b-[O-b-Dglucopyranosyl (1–3)-O-[a- monnierin, betulic acid, stigmastarol, beta-sitosterol, wogonin, Fig. 2. Chemical structure of Bacoside B. 69 N.P. Sukumaran, et al. Table 1 Major active constituents of BM. Compound IUPAC name Biological activity Molecular formula References Bacoside A3 3-β-[(O-β-D-glucopyranosyl(1→3)-O-(α-L-arabinofuranosyl(1→2)]-O-β-D-glucopyranosyl) oxy)jujubogenin Anti-depression activity, Hepatoprotective C47H76O18 26,28,47 Bacopaside II 3-O-[α-L-arabinofuranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl] pseudojujubogenin Anti-depression activity, Hepatoprotective C47H76O18 26,28,47 Bascopasaponin C 3-O-[β-D-glucopyranosyl-(1→3)-[α-L-arabinofuranosyl-(1→2)]-α-L-arabinopyranosyl] pseudojujubogenin Anti-depression activity, Hepatoprotective C46H74O17 26,28,47 Bacopaside X 3-O-[β-D-glucopyranosyl-(1→3)-[α-L-arabinofuranosyl-(1→2)]-α-L-arabinopyranosyl] jujubogenin Hepatoprotective C46H74O17 26,47 Bacopaside N2 3-O-[β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl] pseudojujubogenin Cognitive enhancive, antinociceptive C42H68O14 22,23,47 Bacopaside N1 3-O-[β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl] jujubogenin Cognitive enhancive, anticonvulsant C42H68O14 18,20,47 Bacopaside IV 3-O-[α-L-arabinofuranosyl-(1→2)-[6-O-sulfo-β-D-glucopyranosyl-(1→3)]-α-L-arabinopyranosyl] pseudojujubogenin Cognitive enhancive, anti-aging C46H74O20S 19,22,47 Bacopaside V 3-O-b-D-glucopyranosyl-(1→3)-a-Larabinofuranosyl pseudojujubogenin Cognitive enhancive, anticancer C41H66O13 25,48 70 by Babita etinduced al. motor skill abnormalities onneurotoxicant mouse model studied MPTP was studied (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)