What Are the Side Effects of Bacopa Monnieri Extract?

Bacopa monnieri (L.) Wettst. is a plant belonging to the Scrophulariaceae family and the Bacopa genus, also known as white-flowered pigweed. It is primarily distributed in tropical and subtropical regions, commonly found near water bodies, wetlands, and sandy beaches. In China, it is mainly distributed in Taiwan, Fujian, Guangdong, and Yunnan provinces. This plant has a sweet and bland taste, with a cold nature. The entire plant is used medicinally and possesses properties of clearing heat, cooling the blood, detoxifying, and reducing swelling [1].

In India, this plant has been used as a traditional medicine for thousands of years and is an important medicinal plant in the Ayurvedic system. Its standardized extract formulations are already available in India for the treatment of cognitive memory impairment, Alzheimer's disease, epilepsy, and depression [2]. Currently, there are few reports on this plant in China. A literature review found three review articles on the chemical composition and pharmacological activities of Pseudocentaurea[3-5], but the summaries of chemical composition and pharmacological activities are not comprehensive. Therefore, this study provides a more detailed and comprehensive review of the chemical composition and pharmacological activities of this plant, laying a scientific foundation for further research and development of this plant.

1 Chemical Constituents

1.1 Triterpenoids

Since the 1960s, research has revealed that false purslane contains a significant amount of triterpenoids. Currently, the triterpenoids isolated from this plant are primarily triterpenes, with most existing in the form of glycosides. To date, four main types of aglycone mother nucleus structures have been identified: dammarane, cucurbitane, lupeane, and ursane.

1.1.1 Dammarane

Dammarane-type triterpenoids are the most common component in the false purslane plant. These compounds primarily exist in the form of glycosides, with their aglycone structures mainly consisting of jujubogenin (1–17) and pseudojujubogenin (18–29). The differences among these compounds lie in the types and modes of sugar groups attached to the core structure. To date, a total of 34 dammarane-type triterpenoids have been isolated from the whole plant of Pseudocochlearia japonica, with their structures and names shown in Figure 1 and Table 1.

1.1.2 Cucurbitane-type

In 2007, Bhandari et al. [27]first reported the isolation of four new cucurbitane-type (35, 36, 40, 41) and one known cucurbitane-type (38) triterpenoids from Pseudocaparia. To date, seven cucurbitane-type triterpenoids have been isolated from Pseudocaparia, with their structures and names shown in Figure 2 and Table 2. 1.1.3 Lupane-type and usuan-type Lupane-type and usuan-type triterpenoids belong to the pentacyclic triterpenoid class. The research group previously isolated three compounds of this type (44–46) from Pseudocorydalis pseudocorydalis [22]. Currently, four lupane-type and one usuan-type triterpenoid compounds have been isolated from this plant, with their structures and names shown in Figure 3 and Table 3.

1.2 Flavonoid compounds

Literature review revealed that false purslane also contains flavonoids, primarily flavonoids and chalcones (47–53). The structures and names of the compounds are shown in Figure 4 and Table 4.

1.3 Phenethyl alcohol glycosides

It has been reported that in 2002, Chakravarty et al. [33]isolated a class of phenethyl alcohol glycoside compounds (54–57) from Pseudocentaurea. In 2016, Japanese researchers Ohta et al. [7]isolated two new phenethyl glycoside compounds (58, 59) from the same plant. Currently, seven compounds of this class have been reported, with their structures and names shown in Figure 5 and Table 5.

1.4 Sterol Compounds

Sterol compounds are a class of steroidal compounds derived from the biosynthetic pathway of methylsalicylate. A small amount of these compounds (61–65) have been identified in the plant Pseudocallium. The structures and names of the compounds are shown in Figure 6 and Table 6.

1.5 Other compounds

In addition to the triterpenoids, flavonoids, phenethyl glycosides, and sterols reported above, nine other compounds were isolated from this plant, including aromatic compounds and α,β-unsaturated lactone compounds. The structures and names of these compounds are shown in Figure 7 and Table 7.

2 Pharmacological Activities

2.1 Effects on the Central Nervous System

2.1.1 Enhancement of Cognitive, Learning, and Memory Functions

Numerous experimental studies have demonstrated that Bacopa Monnieri and its extract possess the ability to enhance learning, memory, and cognitive functions. The primary pharmacologically active component is bacoside A, which is a mixture of dammarane-type triterpenoid saponins containing sugar chains [35]. It has been reported that after administering Bacopa Monnieri extract to normal rats for an extended period (4 or 6 weeks), the dendritic length and dendritic branching points of neurons in the amygdala, basolateral amygdala, and hippocampal CA3 regions significantly increased, suggesting that Bacopa Monnieri promotes learning and memory functions in rats [36-38]. Additionally, the standard extract of Bacopa monnieri (CDRI-08) demonstrated significant inhibitory effects on amnesia (memory impairment) induced by scopolamine, 1-(4-chlorophenyl)-biguanide, decabromodiphenyl ether, and low-pressure hypoxia [39-42].

Le et al. [43]investigated the potential molecular mechanisms by which Bacopa Monnieri ethanol extract improves cognitive dysfunction in olfactory bulb (OBX) excised mice. The results showed that OBX mice administered Bacopa Monnieri Extract (50 mg/kg) significantly improved impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. OBX can lead to the phosphorylation of synaptic plasticity-related signaling proteins in the hippocampus of mice [N-methyl-D-aspartate (NMDA) receptor NR1 subunit, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II (αCaMKII) expression]and reduced brain-derived neurotrophic factor (BDNF) mRNA levels, resulting in reduced acetylcholinesterase activity and a decrease in the number of cholinergic neurons in the medial septum, as well as an enlargement of the lateral ventricle. In contrast, administration of CDRI-08 reversed the neurochemical and histological changes induced by OBX, without affecting the downregulation of GluR1 phosphorylation.

Additionally, Pseudoginseng treatment inhibited the in vitro activity of acetylcholinesterase in the brain. Animal studies demonstrated that CDRI-08 increases serum 5-hydroxytryptamine (5-HT) levels, activates 5-HT3A receptors, differentially regulating histone acetylation and protein phosphatases (PP1α and PP2A) in the hippocampus, as well as upregulating the expression levels of BDNF and synaptic proteins (SYT1, SYP, p-αCaMKII, and PSD-95), thereby enhancing hippocampus-dependent contextual memory [44-45].

2.1.2 Antidepressant effects

Studies have shown that Bacopa Monnieri Extract exhibits significant antidepressant-like effects in various depression models. In behavioral despair models, Bacopa Monnieri Extract significantly reduces the immobility time of animals in the forced swimming test (FST) and tail suspension test, possibly due to its active components bacoside A, bacopasaponin C (20), bacopaside I (23), and bacopaside II (24) [46-49]. 

Kumar et al. [50]evaluated the antidepressant activity of Bacopa Monnieri Extract in a chronic mild unpredictable stress (CUMS)-induced animal depression model, and the results demonstrated that Bacopa Monnieri Extract improved depressive symptoms in animals, reversed elevated levels of corticotropin and corticosterone in the serum of depressed rats, and increased the expression of BDNF and neuronal markers in the hippocampus of depressed rats. Its antidepressant effect was comparable to that of imipramine. The research team previously conducted an in-depth study on bacopaside I (23) isolated from Bacopa monnieri, discovering that this compound exhibits antidepressant-like activity, with its mechanism of action potentially related to antioxidant activity and activation of the noradrenergic system [49].

This compound also exhibited antidepressant-like activity in a CUMS-induced depression model, potentially exerting its pharmacological effects by regulating the hypothalamic-pituitary-adrenal axis and the BDNF signaling pathway. Additionally, Rauf et al. [51]investigated the effects of Bacopa monnieri methanol extract on morphine withdrawal-induced depression in mice. The results showed that continuous administration of Bacopa monnieri extract at different doses for 8 days significantly reduced the immobility time in the forced swim test, suggesting that Bacopa monnieri may have potential therapeutic effects on opioid withdrawal-induced depression.

2.1.3 Anti-anxiety effects

Bhattacharya et al. [52]used well-established anxiety models (open field test, elevated plus maze test, and novel environment feeding inhibition test) to investigate the anti-anxiety effects of Bacopa monnieri extract and compared it with the widely used benzodiazepine anxiolytic drug lorazepam. The results showed that rats administered Bacopa Monnieri Extract at doses of 5, 10, and 20 mg/kg via intraperitoneal injection (ip) and lorazepam at 0.5 mg/kg via ip exhibited dose-dependent anxiolytic activity in all experiments. Additionally, the anxiolytic activity of Bacopa Monnieri Extract at high doses was significantly superior to that of lorazepam. Notably, Bacopa Monnieri Extract did not cause any obvious motor impairments at the doses used, whereas lorazepam has side effects associated with dementia, indicating that Bacopa Monnieri Extract can enhance cognitive function while exerting its anxiolytic activity.

2.1.4 Antipsychotic Effects

Studies have shown that reduced levels of presynaptic glutamate markers [vesicular glutamate transporter 1 (VGLUT1), VGLUT2, and VGLUT3]indicate impaired glutamatergic function and cognitive deficits in the brain. Administering 2 mg/kg of phencyclidine (PCP) intraperitoneally to rats for 7 consecutive days induces a schizophrenia model. Piyabhan et al. [53-55]investigated the effects of administering Bacopa monnieri extract after PCP administration or prior to PCP administration on the expression of VGLUT1, VGLUT2, and VGLUT3 in different brain regions. The results showed that administering false valerian after PCP administration or before PCP administration increased the density of VGLUT2 in the prefrontal cortex, and increased the density of VGLUT3 in both the prefrontal cortex and striatum; administering false valerian after PCP administration increased the density of VGLUT1 in the prefrontal cortex, striatum, and hippocampus, further indicating that Bacopa monnieri has cognitive-enhancing effects and neuroprotective properties.

2.1.5 Anti-Parkinsonian Effects

Parkinson's disease (PD) is a common age-related neurodegenerative disorder, with evidence suggesting that oxidative stress, mitochondrial dysfunction, and the neurotoxic agent paraquat are associated with the pathogenesis of PD. Shobana et al. [56]demonstrated that Bacopa Monnieri ethanol extract alleviates neuronal damage in 6-hydroxydopamine-induced Parkinson's disease rats, increases the levels of reduced glutathione (GSH) in brain tissue, significantly improved the activity of glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), with a dose-dependent effect. Similarly, bacoside A has been found to have potential for treating Parkinson's disease [57]. It has been reported that activation of the activity of leucine-rich repeat kinase 2 (LRRK2) due to genetic mutations is considered the primary cause of familial PD, and studies suggest that bacoside A may act as a potential inhibitor of LRRK2 [58].

Nellore et al. [59]administered Bacopa Monnieri Leaf Extract-coated nanoparticles to investigate the effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental zebrafish Parkinson's syndrome. The results showed that GSH, GSH-Px, CAT, SOD, and mitochondrial complex I were significantly enhanced, while malondialdehyde (MDA) levels were markedly reduced. In vitro experimental studies found that Bacopa Monnieri Extract exhibits neuroprotective effects against the toxicity of paraquat-induced PC12 cells and SK-N-SH cell lines, suggesting that Bacopa Monnieri Extract may have potential therapeutic effects for PD [60-61]. Jadiya et al. [62]utilized the strong heritability of Caenorhabditis elegans to explore the anti-Parkinsonian effects of Bacopa Monnieri, The results showed that Bacopa monnieri reduced α-synuclein aggregation, prevented dopaminergic neuronal degeneration, and restored lipid levels in the nematodes, further confirming the potential of Bacopa monnieri as a possible anti-Parkinson's disease drug.

2.1.6 Anticonvulsant and antiepileptic effects

It has been reported that Bacopa Monnieri ethanol extract exhibits significant anticonvulsant activity in various convulsant models (such as pentylenetetrazole, electroconvulsive shock, scopolamine, hypoxia stress, and muscarine-induced models) [63]. The 5-HT2C receptor is a new target for developing anticonvulsant drugs, Krishnakumar et al. [64-66]investigated the effects of Bacopa Monnieri extract on 5-HT2C receptors in brain tissue of epileptic rats induced by muscarine. The results showed that compared with untreated epileptic rats, Bacopa Monnieri extract significantly reversed the downregulation of 5-HT2C receptor expression and increased inositol trisphosphate levels in the cerebral cortex, cerebellum, and hippocampus, as well as increased levels of inositol trisphosphate. NMDA receptors and metabolic glutamate (mGlu) receptors play a key role in memory and cognition. 

Studies have found that Bacopa Monnieri significantly increases the gene expression of NMDA receptors and mGlu receptors (mGluR5 and mGluR8) in epileptic rats, restoring them to levels close to those of the control group [64,67-68].

Studies have shown that bacoside A treatment can significantly upregulate the gene expression of GABA receptor subunits (GABAAα1, GABAAα5, GABAAδ, and GAD) in the cerebellum, hippocampus, cerebral cortex, and striatum of epilepsy-induced rats, and reversing them to levels close to those of the control group [69-72]. Additionally, baccoside A can reduce the activity of acetylcholinesterase and malic dehydrogenase in the muscles of epileptic rats and decrease the levels of adrenaline, noradrenaline, insulin, and triiodothyronine (T3) in the serum, thereby reducing metabolic and excitatory activity in epileptic rats to prevent seizures [73]. Experimental evidence also shows that baccoside A significantly reduces epileptic seizures/convulsions in Caenorhabditis elegans at higher temperatures (26–28 °C) [74]. Vohora et al. [75]found that Bacopa monnieri extract combined with the anticonvulsant phenytoin not only significantly reversed phenytoin-induced cognitive dysfunction but also improved memory acquisition and retention without affecting its anticonvulsant activity.

2.1.7 Improvement of autism

Sandhya et al. [76]evaluated the effects of Pseudocallium on sodium valproate-induced autism. When sodium valproate was administered intraperitoneally to female pregnant rats before pregnancy and to male rat pups postnatally, it induced behavioral changes resembling autism in male rat pups during puberty (30–40 days postnatal) and adulthood (90–110 days postnatal). However, intraperitoneal administration of false purslane to male rat pups at 21 days postnatal for 2 weeks significantly improved their autistic symptoms. Biochemical analysis of rat brains revealed that false purslane reduced the levels of total nitrite, a marker of oxidative stress, and restored cerebellar tissue structure.

2.1.8 Protection of brain mitochondrial function

Studies have shown that pretreatment with Psoralea corylifolia ethanol extract significantly prevents 3-nitropropionic acid (3-NPA)-induced oxidative dysfunction and depletion of glutathione (GSH) and thiols. On one hand, the activity of antioxidant enzymes (such as SOD, GSH-Px, GR, and thioredoxin reductase), Na+, K+-ATPase, and citric acid cycle enzymes in the striatum of the treated group was significantly restored; on the other hand, the activity of electron transport chain enzymes (such as cytochrome c reductase, cytochrome C reductase, succinate-ubiquitin oxidoreductase, and cytochrome C oxidase) and mitochondrial vitality were also significantly enhanced. Therefore, it is inferred that the neuroprotective effects of Pseudostellaria heterophylla may be fully or partially related to the scavenging of free radicals, maintenance of the redox state, and enhancement of antioxidant mechanisms in striatal mitochondria [77]. Additionally, reports indicate that extracts of Pseudocontortum have protective effects against brain mitochondrial dysfunction induced by methylmercury or morphine, with the mechanism potentially related to the protection of brain mitochondrial enzyme activity [78-79].

2.1.9 Alleviating morphine tolerance and withdrawal symptoms

Rauf et al. [80]induced a morphine analgesic tolerance model in mice by administering morphine (20 mg/kg) intraperitoneally twice daily for 5 consecutive days. Acute and chronic administration of Pseudogentiana extract (mainly containing compounds 14, 20, and 24) significantly reduced the expression and development of morphine tolerance in mice. It was also found that Pseudostellaria heterophylla enhanced the analgesic effect of morphine in non-tolerant animals, and no tolerance to Pseudostellaria heterophylla analgesia was observed during the 7-day administration period. 

Furthermore, it was found that the n-butanol extract could alleviate morphine-induced hyperkinesia [81]. Sumathi et al. [82]evaluated the effects of Pseudocontrahelia extract in ethanol on morphine withdrawal in the ileum of guinea pigs in vitro. The results indicated that adding different concentrations of Bacopa monnieri ethanol extract (100–1,000 mg/mL) 15 minutes before morphine exposure reduced naloxone-induced ileal contractions in a dose-dependent manner, suggesting that Bacopa monnieri may be used to alleviate morphine-induced withdrawal symptoms.

2.2 Effects on the Cardiovascular System

It has been reported that Bacopa Monnieri Extract can prevent ischemic-induced brain damage and reduce the area of ischemic cerebral infarction [83]. The research team previously found that bacopaside I (23) exhibits excellent neuroprotective effects against brain ischemia-induced damage, with its protective mechanism potentially related to improving brain energy metabolism and increasing antioxidant levels [84]. Additionally, Bacopa monnieri extract improves myocardial function after ischemia/reperfusion injury by restoring coronary artery blood flow and contractility, thereby reducing infarct size. This may be related to Bacopa monnieri's inhibition of myocardial cell apoptosis and reduction in the expression of Caspase 3 and Bax proteins [85-86].

Kamkaew et al. [87]found that after 8 weeks of administration of Bacopa monnieri extract (ig) to rats, cerebral blood flow increased by 25% without affecting blood pressure. iv Bacopa monnieri extract (20–60 mg/kg) can dose-dependently reduce systolic and diastolic blood pressure without affecting heart rate. Bacoside A3 (14) and bacopaside II (24) exhibit vasodilatory activity and may be the active components responsible for the antihypertensive effects of Bacopa monnieri [88]. Additionally, in vitro and in vivo experiments have shown that Bacopa monnieri extracts also exhibit anti-hypercholesterolemic [89], antiplatelet aggregation [90], thrombolytic [91], and vasculoprotective effects [92].

2.3 Effects on the Digestive System

2.3.1 Anti-ulcer Effects

Studies have shown that methanol extracts of false purslane, administered to rats at doses of 10, 20, and 50 mg/kg twice daily for 5 days, exhibited dose-dependent anti-ulcer effects in models of gastric ulcers induced by ethanol, aspirin, 2-hour cold stress, and 4-hour pyloric ligation. Administration of 20 mg/kg of Pseudocontortum extract to rats for 10 days, twice daily, demonstrated healing effects on gastric ulcers induced by 50% acetic acid. Mechanistic studies indicated that the extract did not affect gastric acid-pepsin secretion, increased mucin secretion, while reducing mucosal cell detachment without affecting cell proliferation [93]. According to reports, a dose of 1,000 μg/mL of Pseudogastrum extract in vitro demonstrated significant anti-Helicobacter pylori activity [94]. Additionally, Dorababu et al. [95]found that the methanol extract of Pseudocallis (50 mg/kg) exhibited anti-ulcer and ulcer healing activity in experimental non-insulin-dependent diabetic rats, with the effect possibly attributed to its influence on mucosal defense factors.

2.3.2 Smooth muscle spasm relief

Dar et al. [96]reported the calcium-antagonistic effects of Bacopa Monnieri ethanol extract. The results showed that the extract inhibited spontaneous contractions in the ileum of guinea pigs and the jejunum of rabbits. At a concentration of 260 μg/mL, Bacopa Monnieri extract significantly attenuated contractions induced by acetylcholine and histamine in the ileum. A certain dose of Bacopa Monnieri extract (100–700 μg/mL) exhibited a dose-dependent inhibitory effect on acetylcholine-induced ileal contractions.

Bacopa Monnieri Extract (100–700 mg/mL) also exhibited inhibitory activity against calcium chloride-induced contractions of rabbit blood vessels and jejunum, indicating that the extract directly interferes with Ca²⁺ influx into cells. However, Bacopa Monnieri Extract had no effect on contractions induced by norepinephrine or caffeine, suggesting that it does not affect intracellular calcium flux. Therefore, it is inferred that the antispasmodic effect of Bacopa Monnieri ethanol extract on smooth muscle is primarily achieved by inhibiting Ca²⁺ influx through membrane potential and receptor-operated calcium channels.

2.3.3 Anti-emetic effect

Recently, Ullah et al. [97-98]investigated the antiemetic activity of Bacopa monnieri methanol and n-butanol extracts in two animal models of vomiting induced by cisplatin (pigeons and skunks). The results showed that both extracts exhibited significant antiemetic effects, and the n-butanol extract exhibited antiemetic activity comparable to that of the 5-HT3 receptor antagonist palonosetron and the antioxidant N-(2-mercaptoacyl)glycine, suggesting that false pennywort may be used alone or in combination with other antiemetic drugs for the treatment of chemotherapy-induced vomiting in humans.

2.3.4 Diarrheagenic effects

Nikhil et al. [99]evaluated the diarrheagenic effects of four fractions of false purslane extract (non-polar fraction, fraction containing 60%–70% bacosides, polar fraction, and fraction containing 40% bacosides). The study showed that the non-polar fraction and the fraction containing 60%–70% bacosides at a dose of 500 mg/kg caused significant diarrhea in rats, while only the non-polar fraction (500 mg/kg) caused diarrhea in mice. When the four different fractions were combined with loperamide, only the non-polar fraction (500 mg/kg) caused non-significant diarrhea in 29% of rats. Studies on small intestinal propulsion rates in mice also indicated that non-polar fractions exhibited the greatest charcoal passage distance, suggesting that the non-polar fractions of Pseudocallium have the strongest laxative effect, while polar fractions have no laxative effect.

2.4 Effects on the respiratory system

Channa et al. [100]demonstrated that various extracts and sub-soluble fractions of false purslane significantly inhibited bronchoconstriction, hypotension, and bradycardia induced by carbachol in anesthetized rats, with better inhibitory efficacy on tracheal pressure. Secondary fractions and the monomer betulinic acid (43) showed greater inhibitory effects on tracheal pressure and heart rate. In vitro, KCl-induced tracheal contraction was also inhibited by crude extracts, petroleum ether fractions, and methanol fractions of false purslane. The CHCl₃/MeOH fraction of Pseudostellaria hypaphenium significantly reduces acetylcholine, potassium chloride, and calcium chloride-induced guinea pig ileal contraction, indicating that it interferes with Ca²⁺ ion flux, suggesting that the bronchodilatory activity of Pseudanthemum indicum is primarily attributed to calcium ion inhibition. Dar et al. [101]speculated that the bronchodilatory effect of Pseudanthemum indicum ethanol extract may be mediated by both β-adrenergic receptor-dependent and independent mechanisms, making it a potential treatment for asthma. Additionally, the ethanol extract of false purslane exerts a relaxing effect on guinea pig tracheal smooth muscle by blocking calcium channel activity [102].

2.5 Effects on the Endocrine System

Kar et al. [103]investigated the effects of false purslane leaf extract (200 mg/kg) on thyroid hormone secretion in male mice, Following ingestion of the extract, thyroid hormone (T4) synthesis increased by 41%, while T3 synthesis remained unaffected, suggesting that the extract may not participate in the T4-to-T3 conversion and could be used to regulate hypothyroidism. Additionally, CDRI-08 has been shown to have anti-fertility effects in male mice, with this effect returning to normal 56 days after discontinuation of the extract, and no significant toxic effects on the liver or kidneys were observed [104-105].

2.6 Antioxidant Activity

In vitro antioxidant activity experiments demonstrated that the methanol extract of false purslane possesses the ability to scavenge nitric oxide free radicals, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, hydroxyl free radicals, and superoxide free radicals, as well as reducing capacity. This may be due to the high content of polyphenols in the methanol extract of Pseudanthias pseudanthias [106-108], and the antioxidant activity of the leaf extract is significantly stronger than that of root or stem extracts [109]. The nitro blue tetrazolium assay indicated that the water-ethanol extract of the whole plant of Bacopa monnieri and its active component bacoside A3 (14) significantly inhibited the release of superoxide radicals from polymorphonuclear cells [110]. Normal rats administered Bacopa Monnieri extract via ig for 14 and 21 days showed a significant increase in SOD, CAT, and GSH-Px activity in the frontal cortex, striatum, and hippocampus tissues, indicating that Bacopa Monnieri's antioxidant activity against oxygen free radicals partially explains its cognitive-enhancing effects [111].

Shinomol et al. [112-114]found that Bacopa monnieri extract completely eliminated 3-NPA-induced oxidative stress reactions in striatal mitochondria in vitro pretreatment experiments and also protected N27 cells from oxidative damage induced by fisetin, 3-NPA, or acrylamide. In vivo experiments further demonstrated that Bacopa Monnieri Extract could eliminate the elevated levels of oxidative stress markers [MDA, reactive oxygen species (ROS), H₂O₂, and protein carbonyl]in mouse brain tissue induced by 3-NPA, increase GSH and thiol levels, restore antioxidant enzyme activity in the striatum, as well as neurotransmitter function and dopamine levels. Additionally, after feeding adolescent mice a diet enriched with Bacopa monnieri leaf powder for four weeks, significant reductions in oxidative stress markers (MDA, ROS, H₂O₂, and protein carbonyl) were observed in the cytoplasm and mitochondria of all brain regions (cortex, cerebellum, hippocampus, striatum), along with increased antioxidant enzyme activity (CAT, GSH-Px, SOD) increased, and GSH and thiol levels were significantly elevated [115].

Chronic smoking can induce the production of unstable free radicals, leading to increased brain membrane permeability and cellular damage. Studies have found that bacoside A can increase the activity of enzymatic antioxidants (SOD, CAT, GSH-Px, and GR) and non-enzymatic antioxidants (GSH, vitamin C, and vitamin E) in the brain, reduce serum creatine kinase (CK) and its three subtypes (CK-MM, MB, and BB) activity, inhibit lipid peroxidation, improve membrane-bound ATPase activity, and maintain ion balance, thereby protecting the brain from smoking-induced toxicity [116-118]. Additionally, Pandareesh et al. [119-120]demonstrated that Bacopa Monnieri Extract can downregulate the expression of inducible nitric oxide synthase (iNOS) in the brains of rats exposed to smoke, thereby inhibiting the expression of heme oxygenase (HO-1) and NO production, and reducing ROS levels, with results also validated at the cellular level.

2.7 Anti-inflammatory and analgesic effects

2.7.1 Anti-inflammatory effects

Increasing evidence suggests that Bacopa Monnieri Extract can inhibit the activity of cyclooxygenase-2, lipoxygenase, and the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) [121-123]. Channa et al. [124]found that the ethanol extract of Bacopa Monnieri exhibited anti-inflammatory activity in paw edema induced by carrageenan in mice and rats. carrageenan-induced paw edema in mice and rats, and selectively inhibit prostaglandin E2 (PGE2)-induced inflammatory responses. Williams [125]reported that extracts of false purslane reduce the production of nitric oxide (NO), TNF-α, and γ-interferon in human blood cells, and increase the release of IL-10 in human blood cells stimulated by lipopolysaccharide (LPS) in RAW 246.7 macrophages.

Vijayan et al. [126]evaluated the effect of Bacopa monnieri extract on lysosomal instability during adjuvant-induced arthritis in rats. The results showed that the extract significantly inhibited lysosomal instability in different tissues, increased the levels of glycoproteins in synovial fluid and glycosaminoglycans in cartilage, thereby reducing the spread of inflammation. Following administration of purified Bacopa monnieri trichloromethane extract (50 mg/kg) to arthritic rats, the expression of IL-6 in blood mononuclear cells and PGE2 levels in cartilage tissue were significantly downregulated. Additionally, betulinic acid (43) was found to inhibit the production of IL-6 in LPS-stimulated peripheral blood mononuclear cells and prevent the nuclear translocation of the p65 nuclear transcription factor-κB (NF-κB) in LPS-induced peripheral blood mononuclear cells [127]. Nemetchek et al. [128]found that Bacopa Monnieri Extract can inhibit the release of pro-inflammatory cytokines (TNF-α and IL-6) in microglia, and inhibit the expression of enzymes associated with inflammation in the brain (caspase-1, caspase-3, and matrix metalloproteinase-3), suggesting that Bacopa Monnieri may limit inflammatory responses in the central nervous system and provide new therapeutic approaches for central nervous system diseases.

2.7.2 Analgesic effects

Recent studies have shown that false pennywort also possesses analgesic effects. Kishore et al. [129]investigated the effects of false pennywort on heat and mechanical hyperalgesia, abnormal pain, motor nerve conduction velocity (MNCV), and oxidative nitrosative stress in experimental diabetes induced by streptozotocin. The results indicated that Pseudopyrrosin ethanol extract and bacosine (42) reversed pain responses in diabetic rats by regulating oxidative nitrosation stress and reducing the formation of advanced glycation end products (AGEs), thereby potentially enabling their clinical application in the treatment of neuropathic pain in diabetic patients. Additionally, ig extract of P. indicum in mice significantly reduced the number of acetylsalicylic acid-induced gastric contractions in a dose-dependent manner, with even the lowest dose (50 mg/kg) exhibiting better analgesic activity than aspirin [130].

2.8 Antitumor activity

Peng et al. [131]determined the antitumor activity of the methanol extract of P. indicum and its different fractions (petroleum ether fraction, CHCl₃ fraction, ethyl acetate fraction, and n-butanol fraction), finding that the n-butanol fraction exhibited the strongest antitumor activity. Additionally, the single compounds bacopaside I (23) and bacopaside VII (24) isolated from the n-butanol fraction exhibited significant cytotoxic effects on the proliferation of various tumor cell lines (MDA-MB-231, SHG-44, HCT-8, A-549, and PC-3M) in vitro, Furthermore, the two monomer components (50 μmol/kg) significantly inhibited the growth of sarcoma S180 implanted into mice in vivo, but the underlying mechanism remains unclear. Rohini et al. [132]found that the ethanol extract of Bacopa monnieri induced apoptosis in mouse S180 cells in a time- and dose-dependent manner, with maximum cytotoxic effects observed at a concentration of 550 μg/mL after 48 hours. Other reports have indicated that water extracts of Pseudostellaria heterophylla activate the expression of Bax-related caspase-3, upregulate the expression of the pro-apoptotic protein Bax in mouse breast cancer cells EAT, and downregulate the expression of the anti-apoptotic gene Bcl-2, thereby inducing apoptosis in EAT cells [133]. Studies have shown that bacoside A has the potential to protect endogenous enzymes and non-enzymatic antioxidant activity, effectively preventing N-nitrosodimethylamine-induced liver cancer by scavenging free radicals, quenching lipid peroxidation, and enhancing antioxidant status [134].

2.9 Hepatoprotective and renoprotective effects

2.9.1 Hepatoprotective effects

An increasing number of studies have demonstrated that false purslane exhibits excellent protective effects on the liver, with its protective functions potentially attributed to its antioxidant properties. Ghosh et al. [135-136]found that the ethanol extract of the aboveground parts of false purslane exhibited significant protective effects against liver toxicity induced by CCl₄ or acetaminophen. The results showed that in rat models of liver toxicity induced by the two agents, the extract significantly reduced serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, total cholesterol, and lipid peroxidation levels in the body, and increased the levels of antioxidant enzymes (SOD and CAT), glutathione (GSH), and high-density lipoprotein cholesterol (HDL-C) in the livers of treated rats. The ethanol extract of Pseudocallium officinale also exhibited hepatoprotective effects against liver toxicity induced by D-galactosamine, morphine, isoniazid, and rifampicin [137-141].

Janani et al. [142]investigated the hepatoprotective effects of bacoside A using a rat liver toxicity model induced by N-nitrosodiethylamine. The results showed that pre-treatment with bacoside A restored lipid peroxidation and serum marker enzyme levels [AST, ALT, lactate dehydrogenase (LDH), ALP, and γ-glutamyl transpeptidase (GGT) increased, and the activities of antioxidant enzymes (SOD, CAT, GSH-Px, GR, GST) and GSH in the liver were significantly elevated. Menon et al. [143]evaluated the protective effects of a pseudo-purslane ethanol extract on nitrobenzene-induced acute experimental liver injury. In liver-injured experimental rats treated with the extract, serum marker enzymes AST, ALT, and ALP returned to normal levels, and the activities of SOD, CAT, and GSH-Px were significantly increased.

Notably, CDRI-08 can also prevent neurochemical changes induced by hepatic encephalopathy in chronic liver failure, potentially through regulating the expression of NMDA receptor subunits (NR2A and NR2B) in the cerebellum and the neuronal nitric oxide synthase (nNOS)-apoptosis pathway [144]. 2.9.2 Renal protective effects Kamesh et al. [145]investigated the protective effects of Polygonum cuspidatum ethanol extract on kidney disease induced by hypercholesterolemia in rats. The results indicated that the ethanol extract of false purslane increased the activity of antioxidant enzymes such as SOD, CAT, GSH-Px, GST, and GR, as well as non-enzymatic antioxidants like GSH, vitamin C, and vitamin E. It also up-regulated the expression of endothelial nitric oxide synthase (eNOS) and down-regulated the expression of iNOS genes, thereby exerting renal protective effects.

2.10 Antidiabetic Effects

Recent studies have shown that Pseudocallium indicum exhibits significant antidiabetic effects. Taznin et al. [146]evaluated the antidiabetic activity of Pseudocallium indicum using an oral glucose tolerance test (OGTT), finding that the methanol extract of Pseudocallium indicum significantly inhibited the increase in serum glucose concentration in a dose-dependent manner. High doses of CDRI-08 (150 mg/kg and above) not only restored spatial memory impairments in streptozotocin-induced type 2 diabetic rats but also exhibited antidiabetic effects [147]. 

Ghosh et al. [148]found that bacosine (42), a triterpenoid isolated from the ethyl acetate fraction of the methanol extract of false purslane, exhibited hypoglycemic activity. This compound reversed weight loss in streptozotocin-induced diabetic rats, inhibited the increase in glycated hemoglobin, and increased the amount of glycoproteins in the livers of diabetic rats. Additionally, this compound reduced malondialdehyde (MDA) levels in the livers of diabetic rats, increased glutathione (GSH) levels, and activated superoxide dismutase (SOD) and catalase (CAT) activity, suggesting that bacosine may possess insulin-like activity, and its anti-hyperglycemic effects may be due to increased peripheral glucose consumption and protection against oxidative damage. Kishore et al. [149]also found that extracts of Pueraria lobata, 40% ethanol extracts, and stigmasterol (62) protect against streptozotocin-nicotinamide-induced diabetic nephropathy, and reduced serum glucose, uric acid, and creatinine levels.

2.11 Antimicrobial activity

2.11.1 Antibacterial activity

Studies have shown that bacoside A, P. pseudolysimani methanol extract, P. pseudolysimani leaf methanol extract, and P. pseudolysimani leaf ethanol extract all exhibit significant inhibitory effects against Staphylococcus aureus and Pseudomonas aeruginosa [150-153]. Additionally, the methanol extract of Pseudocentaurea leaves demonstrated antifungal activity [153]. Emran et al. [152]used molecular docking to demonstrate that luteolin (50) exhibits greater specificity for the DNA gyrase binding site, and speculated that luteolin might be the active component responsible for the antibacterial activity of Pseudocorydalis. Chaudhuri et al. [31]found that three components isolated from the aboveground parts of Pseudocorydalis, including betulinic acid (43), baicalin (47), and morin (51) isolated from the aerial parts of Pseudocentaurea pseudopyrrula exhibited significant inhibitory effects on two fungi, Aspergillus niger and Fusarium moniliforme. Additionally, Katoch et al. [154-155]found that endophytic fungi parasitizing plant tissues exhibit inhibitory activity against various microorganisms, including Staphylococcus aureus, Bacillus subtilis, Candida albicans, Salmonella typhimurium, and Escherichia coli.

2.11.2 Anti-Leishmania

Bacopasaponin C (20) is a triterpenoid saponin component isolated from Bacopa monnieri. Its anti-Leishmania activity was studied in four forms: free, liposome, microsphere, and nanoparticle. The results showed that all these formulations exhibited significant activity and had no adverse effects on liver and kidney function, making them suitable for clinical application [156].

2.12 Other effects

Russo et al. [157]confirmed that the methanol extract of Bacopa monnieri protects human non-immortalized fibroblasts from H₂O₂-induced cytotoxicity and DNA damage. Additionally, after treatment with the methanol extract of Pseudocontortum for 18 hours, the formation of reactive substances and DNA breaks in rat astrocytes induced by the NO donor S-nitroso-N-acetylpenicillanide were significantly inhibited, with a dose-dependent effect [158]. Furthermore, studies have shown that Bacopa monnieri extract pretreatment restored the reduced levels of DNA and RNA in the cerebellum caused by methyl mercury exposure and alleviated the induced toxicity [159].

In acute and chronic stress models in rats, Bacopa Monnieri Extract also demonstrated strong adaptogenic effects [160]. It has been reported that Bacopa Monnieri Extract can inhibit morphine-induced motor hyperactivity without altering norepinephrine concentrations [161]. Sharath et al. [162]observed that Bacopa monnieri methanol extract and bacoside A exhibited significant wound healing activity in various wound models, and bacoside A demonstrated more effective wound healing effects compared to the standard skin ointment furacin.

3 Conclusion and Outlook

With further research, it is anticipated that more new chemical components will be isolated from the false pennywort plant. This paper provides a systematic summary and classification of the chemical components of false pennywort. The main types of compounds isolated from false pennywort include triterpenes and their glycosides, flavonoids, phenethyl alcohol glycosides, and sterols. Modern pharmacological studies have demonstrated that false purslane exerts certain effects on the central nervous, cardiovascular, digestive, respiratory, and endocrine systems. Additionally, it exhibits anti-inflammatory, analgesic, antioxidant, hypoglycemic, antitumor, antimicrobial, and hepatoprotective and nephroprotective activities. Its pharmacological activities are largely associated with triterpenoid saponins, thereby offering significant potential for the development of this plant. However, current research on the active components and mechanisms of action of false purslane remains incomplete and insufficient. Despite its widespread distribution and abundant resources in China, false purslane has not been fully utilized. Therefore, further research is needed to fully harness the potential of this plant resource in modern medicine. 

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