ME is a naturally occurring flavonoid with diverse biological activities. It is predominantly found in plant species belonging to the Myricaceae and Euphorbiaceae families, and the main sources include plant extracts such as berries and tea leaves (Taheri et al., 2020). Studies have demonstrated that ME exerts a broad range of pharmacological effects, including anti-inflammatory activity (by modulating the NLRP3 inflammasome, the NF-κB pathway, and various pro-inflammatory cytokines), antioxidant properties, improvement of mitochondrial dysfunction, and regulation of autophagy.

Liu. et al. (Liu et al., 2023) employed the 3×Tg-AD mouse model and integrated network pharmacology with molecular docking analysis to predict that ME can regulate the MAPK signaling pathway through multiple targets. The experimental findings revealed that ME significantly inhibited activation of the p38 MAPK pathway, thereby alleviating Aβ25-35-induced mitochondrial dysfunction, suppressing overactivation of the NLRP3 inflammasome, and improving cognitive and memory deficits in AD model mice.

Furthermore, Kyoung et al. (Kang et al., 2010; Ramezani et al., 2016; Wang et al., 2017) also found that ME has a neuroprotective effect on oxidative stress-induced mitochondrial-dependent and caspase-dependent apoptosis processes by regulating the p38 MAPK and JNK signaling pathways, suggesting that it may exert an anti-AD effect by regulating the MAPK signaling pathway.

NOB is a naturally occurring flavonoid that is predominantly found in the peel of citrus fruits belonging to the Rutaceae family (Chen et al., 1997; Nogata et al., 2006). Studies have demonstrated that NOB exhibits multiple pharmacological activities, including anti-inflammatory, antioxidant, anticancer, antidiabetic, antiatherosclerotic, neuroprotective, and anti-obesity effects (Tanaka et al., 2004; Choi et al., 2007; Hirata et al., 2008; Cui et al., 2010; Lee et al., 2010; Yoshim et al., 2004; Miyamoto et al., 2008; Lam et al., 2011; Lee et al., 2011; Mulvihill et al., 2011; Choi et al., 2011; Kanda et al., 2012). According to extant research, NOB has been demonstrated to ameliorate AD-related cognitive impairments, such as decline in learning and memory, by inhibiting apoptosis, alleviating oxidative stress, and reducing cerebral Aβ protein levels.

Neuroinflammation has been identified as a significant mechanism contributing to the progression of NDDs. In the mouse microglial BV-2 cell line, NOB exhibits potent anti-neuroinflammatory effects, significantly inhibiting the production and release of LPS-induced pro-inflammatory mediators, including NO, TNF-α, IL-1β, and IL-6 (Cui et al., 2010; Ho and Kuo, 2014; Wang Y. et al., 2019). A recent study demonstrated that mice administered 100 mg/kg of nobiletin daily for 6 weeks exhibited effective alleviation of LPS-induced memory impairment. The study also found that nobiletin inhibited the activation of microglia and the secretion of related pro-inflammatory cytokines.

Qi et al. (2019) further demonstrated that NOB treatment significantly decreased serum levels of iNOS, COX-2, TLR4, IL-1β, and TNF-α, inhibited NF-κB nuclear translocation, and enhanced phosphorylation and activation of key signaling proteins including AKT, JNK, ERK, and p38 MAPK.

Further experiments demonstrated that under NOB treatment, inhibitors of ERK (U0126), p38 (SB203580), and JNK (SP600125) can synergistically alleviate the inflammatory response induced by LPS, confirming that NOB may alleviate the inflammatory state of BV-2 microglia by regulating the MAPK signaling pathway.

In summary, NOB effectively alleviates inflammation-induced cognitive deficits and neuroinflammation by reducing neuronal damage, inhibiting microglial activation, suppressing inflammatory factor release, and restoring mitochondrial function, thereby highlighting its potential therapeutic value in the prevention and treatment of AD.

GA is a polyphenolic organic compound that is found in plants such as tea leaves, oranges, papayas, pomegranates, and cardamom (Latha and Daisy, 2011). It has been demonstrated that GA exhibits a variety of pharmacological activities, including anticancer and antioxidant effects, and has been extensively applied in medical research (Gu et al., 2025). Studies have demonstrated that GA reduces brain injury by decreasing infarct size in rat models of cerebral ischemia (Kumar et al., 2021). In neurological disorder models, GA significantly ameliorates cognitive impairment in rotenone-induced Parkinson’s disease (PD) rat models (Sheikhpour et al., 2023). Related studies indicate that GA improves learning and memory performance and enhances motor function in AD mice. As demonstrated in the experimental data from Wan et al. (2025), the application of GA has been shown to attenuate the damage induced by glutamate (Glu) in PC12, SH-SY5Y, and HT22 neural cells, exhibiting a dose- and time-dependent response. The protective effects of GA are more pronounced in PC12 and SH-SY5Y cells. Mechanistic studies suggest that GA mitigates AD pathological progression by inhibiting the expression of Gadd45g and Gadd45b and their downstream P38/MAPK signaling pathway, thereby attenuating oxidative stress responses. Transcriptomic analyses further reveal that the P38/MAPK signaling pathway plays a critical role in mediating GA’s neuroprotective effects against AD. In summary, GA attenuates the progression of AD by inhibiting the P38/MAPK signaling pathway. It has potential value as a natural candidate drug for the prevention of AD.

Resveratrol, a naturally occurring phenolic compound, functions as a plant antitoxin. It is produced in response to mechanical damage or attack by pathogens, including bacteria and fungi (Vestergaard and Ingmer, 2019). It exhibits diverse pharmacological activities, including anti-angiogenic, immunomodulatory, antibacterial, neuroprotective, anticancer, antidiabetic, and cardiovascular disease (CVD) preventive effects (Breuss et al., 2019). Resveratrol has been demonstrated to effectively ameliorate mitochondrial dysfunction, mitigate oxidative stress, modulate inflammatory responses, and inhibit apoptosis. Moreover, preliminary studies suggest that resveratrol may also have an improving effect on NDDs (Fantacuzzi et al., 2022). In aged C57BL/6 mice, oral administration of resveratrol at 200 mg/kg for 10 consecutive days restored brain microvascular endothelial function and suppressed ROS production, thereby improving the coupling response of cortical neurovascular and promoting neuronal activity and functional recovery (Toth et al., 2014). In a C57BL/6 mouse model, intraperitoneal injection of 100 mg/kg resveratrol for seven consecutive days alleviated hippocampus-dependent cognitive deficits via anti-inflammatory and anti-apoptotic mechanisms (Li et al., 2014). In male F344 rats, intraperitoneal administration of resveratrol at 40 mg/kg for 4 weeks significantly improved memory and emotional functions, facilitated hippocampal neurogenesis and microvascular remodeling, and suppressed glial cell activation (Kodali et al., 2015). Zhao et al. (2022) demonstrated that resveratrol ameliorates post-traumatic cognitive dysfunction in mice by activating the deacetylase Sirtuin one and inhibiting phosphorylation of p38 MAPK. Studies suggest that p38 MAPK is activated following traumatic brain injury (TBI), and resveratrol exerts regulatory effects on this pathway.

Pae is a water-soluble monoterpene glucoside predominantly extracted from the dried roots of Paeonia lactiflora Pall., a species within the Paeoniaceae family. It constitutes the major active component of total paeony glycosides (TGP), comprising over 40% of the total glycoside content. Pae exhibits diverse pharmacological effects, such as anti-inflammatory, antioxidant, antithrombotic, anticonvulsant, antidepressant, sedative, analgesic, antispasmodic, and immunomodulatory activities (Chen et al., 2011; Ye et al., 2016; Hino et al., 2012; Qiu et al., 2013; Zhang et al., 2009). Pae modulates multiple signaling pathways, including G protein-coupled receptors (GPCRs), MAPKs/NF-κB, PI3K/Akt/mTOR, JAK2/STAT3, and TGF-β/Smads pathways. Pae has been shown to regulate calcium ion (Ca²⁺) and reactive oxygen species (ROS) homeostasis, thereby exerting therapeutic effects against NDDs.

Gu et al. (2016) established an AD model using transgenic mice and demonstrated that Pae exerts significant neuroprotective effects, markedly improving cognitive functions in AD mice, as evidenced by enhanced escape distance and latency performance. The study revealed that Pae inhibits apoptosis by elevating the Bcl-2/Bax ratio and p-Akt expression in brain tissue of AD mice, concurrently downregulating p-P38 MAPK expression. This results in the attenuation of inflammatory responses and caspase-3 activity. Further investigations suggest that prolonged Pae treatment suppresses JNK and P38 MAPK activation while enhancing ERK activation. Pae effectively reverses ischemia-induced activation of the NF-κB signaling pathway and exerts marked neuroprotective effects in rats with cerebral ischemic injury by mitigating inflammatory responses within brain tissue.

GAA is a triterpenoid compound isolated from Ganoderma lucidum (reishi mushroom) has been shown to possess inherent natural neuroprotective properties. GAA exhibits diverse pharmacological activities, including anti-inflammatory, antioxidant, antitumor, neuropsychopharmacological, hepatoprotective, cardioprotective, nephroprotective, and pulmonary protective effects by modulating various signal transduction pathways (Jiang et al., 2018; Meng et al., 2020; Wan et al., 2019; Lixin et al., 2019; Yang et al., 2018; Zhang et al., 2020; Zhang L. et al., 2021; Zheng et al., 2022), underscoring its substantial clinical application potential. In a Caenorhabditis elegans model, GAA treatment significantly delayed cellular senescence and extended healthspan (Chen et al., 2025). Studies have reported that in an Aβ42-induced AD mouse model, GAA activates the Axl receptor tyrosine kinase (Axl)/CDC42-associated kinase 1 (Pak1) signaling pathway, stimulates autophagy in BV2 microglial cells, enhances Aβ42 clearance, and subsequently ameliorates cognitive deficits (Qi et al., 2021). Furthermore, GAA dose-dependently increased the viability of HT22 cells injured by Aβ25-35, while concurrently suppressing the expression of MAPK pathway-related proteins. GAA markedly downregulates cleaved caspase-3 levels, decreases apoptosis, and suppresses Aβ and phosphorylated tau (p-Tau) expression via inhibition of the ERK signaling pathway (Shao et al., 2025). Given its ability to inhibit apoptosis via the ERK/MAPK signaling pathway, GAA shows broad prospects as a potential candidate drug for the treatment of AD.

Elsholtzia ciliata, more commonly referred to as the Thousand-layer Tower, is a traditional Chinese medicinal herb that belongs to the Huperziaceae family. Modern studies have identified alkaloids and triterpenoids as the main bioactive constituents, among which Hup A is the important active compound. Hup A has been successfully utilized in the treatment of AD, dementia, and myasthenia gravis (College, 1985). It has been demonstrated that this agent functions by impeding the phosphorylation of p38 MAPK and ERK within the MAPK signaling pathway, leading to decreased expression of iNOS and cyclooxygenase-2 (COX-2), thereby suppressing the release of pro-inflammatory mediators. Hup A exhibits neurotrophic effects against oxidative stress by promoting nerve growth factor (NGF) synthesis in SH-SY5Y cells, a process contingent upon activation of the MAPK/ERK signaling pathway (Tang et al., 2005). Furthermore, the MAPK/ERK signaling pathway has been implicated in mediating the neuroprotective effects of Hup A in transient cerebral ischemia-reperfusion animal models (Wang et al., 2006). The MAPK/ERK signaling pathway plays a pivotal role in regulating various biological processes, including proliferation, differentiation, and the expression of multiple transcription factors.

The genus Tripterygium, which belongs to the family Celastraceae, contains Tripterygium lactone, a natural diterpenoid compound that is one of its principal bioactive constituents (Chen et al., 2018). This compound has been demonstrated to possess a wide range of pharmacological activities, including anti-inflammatory, immunomodulatory, antitumor, and anti-aging effects (Gao et al., 2021; Tong et al., 2021). Tripterygium glycoside has been identified as a regulator of β-amyloid (Aβ) levels, with the capacity to mitigate synaptic dysfunction and memory impairments associated with AD. Owing to its high lipophilicity and low molecular weight, Tripterygium glycoside has been observed to cross the blood-brain barrier (BBB), thereby demonstrating potential therapeutic efficacy in treating neurological disorders (Zhang et al., 2012). Reduction of oxidative stress is regarded as a key protective mechanism of Tripterygium wilfordii heterophyllum against AD; however, its potential preventive effects on AD pathology via anti-inflammatory pathways require further elucidation. TP inhibits the expression of MKP-1, which primarily deactivates ERK1/2, p38 MAPK, and JNK1/2 signaling pathways, thereby exerting anti-proliferative and pro-apoptotic effects (Koo et al., 2009). Cui et al. (2016) demonstrated that Tripterygium wilfordii significantly suppresses microglial activation in the cerebral cortex and hippocampus of APP/PS1 transgenic mice. Recent molecular biology studies have identified the MAPK signaling pathway is one of the core mechanisms for regulating inflammatory responses. Treatment with Tripterygium wilfordii lactone markedly reduced phosphorylation levels of p38, ERK, and JNK in the brain tissue of APP/PS1 mice, indicating inhibition of MAPK pathway activation. Furthermore, Tripterygium wilfordii lactone has been shown to suppress the expression of pro-inflammatory cytokines TNF-α and IL-1β, effects that are likely linked to its inhibitory action on the MAPK signaling pathway.

OABL is a natural 1,10-bislactone-type sesquiterpene lactone compound that has been isolated from Impatiens grandiflorum (Shi et al., 2022). It exhibits a broad spectrum of pharmacological activities and has been applied in the treatment of bronchitis, diabetes, intestinal ulcers, gastrointestinal disorders, and various inflammatory conditions (Zhao et al., 2006). In addition, OABL has demonstrated encouraging efficacy in the treatment of AD. Its anti-inflammatory mechanisms mainly involve the inhibition of inflammatory mediator production (including NO, PGE2, TNF-α, iNOS, and COX-2) and the suppression of nuclear translocation of the transcription factor NF-κB (Chen et al., 2017). Furthermore, OABL has been shown to possess antioxidant properties that protect neurons against oxidative damage (Wang et al., 2022). In AD animal models, OABL has been shown to significantly improve cognitive performance, restore neuronal morphology in the hippocampus, reduce Aβ amyloid protein deposition, and inhibit excessive phosphorylation of the Tau protein. Research has shown that its structural analog, ABL, also suppresses the expression of COX-2 and NF-κB and alleviates Aβ23-35-induced learning and memory deficits in rats (Wang et al., 2008).

In the 5xFAD transgenic AD mouse model, OABL significantly reduced the immunofluorescence signal intensity of the NF-κB p-p65 subunit in both the cortex and hippocampus.This reduction occurred through modulation of the TLR4/NF-κB and p38 MAPK signaling pathways, and decreased the mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-1β. It has also been demonstrated to promote the M1/M2 transformation of microglia, enhance the expression of arginase-1 (Arg-1) and IL-10, and suppress the production of TNF-α, PGE2, iNOS, and COX-2, thereby reducing the inflammatory response of the CNS and exerting potential neuroprotective effects (Tang et al., 2022).

BBR is a naturally occurring isoquinoline alkaloid primarily derived from the roots, bark, and stems of various medicinal plants, such as the rhizomes of Coptis chinensis (Ye et al., 2009). It exhibits a wide range of pharmacological activities, including anti-inflammatory, cardioprotective, neuroprotective, antitumor, and antimalarial properties (Ma et al., 1999; Küpeli et al., 2002; Le Tran et al., 2003; Zheng et al., 2003; Kettmann et al., 2004; Račková et al., 2004; Letašiová et al., 2006). In the domain of AD research, BBR has demonstrated a variety of mechanisms of action, indicating its potential for therapeutic use.Recent studies have demonstrated that BBR can inhibit the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2), in Aβ-stimulated primary microglia and BV-2 cell lines. Furthermore, it has been observed to downregulate the expression of COX-2 and iNOS. While the precise mechanisms through which BBR exerts its anti-inflammatory effects remain to be fully elucidated, current evidence suggests that it may do so primarily through the modulation of signaling pathways, including NF-κB, phosphoinositide 3-kinase (PI3K), and MAPK.

Wang and Zhang’s research in 2018 revealed that BBR demonstrated neuroprotective effects in preventing learning and memory deficits induced by traumatic brain injury. These effects were potentially attributable to the reduction of inflammation, oxidative stress, and neuronal apoptosis, as well as the modulation of the Sirt1/p38 MAPK signaling pathway (Wang and Zhang, 2018). In addition, BBR has demonstrated protective effects in rat models of heavy metal-induced neurotoxicity and AD-like pathology. Jia et al. (2012) utilized network pharmacology to identify cross-targets of BBR in AD and pinpointed the JNK–p38 MAPK signaling pathway as a critical regulatory pathway. Subsequent in vitro and in vivo experiments confirmed that BBR exerts its therapeutic effects in AD by activating autophagy, modulating the JNK–p38 MAPK signaling pathway to clear Aβ deposits, suppressing neuroinflammation, and promoting neuronal repair.

The Chinese herbal medicine Sesame is rich in sesame oil, which is the main natural source of sesamin. Sesamin has been demonstrated to possess a variety of pharmacological activities, including anti-inflammatory, antioxidant, antitumor, and cardiovascular protective effects (Jayaraj et al., 2020). SO has also been demonstrated to reduce monoamine oxidase (MAO) activity by inhibiting the production of nitric oxide (NO) and hydrogen peroxide (H₂O₂) in astrocytes. Given that MAO plays a critical role in the pathogenesis of NDDs, sesamol is considered to have significant potential in the prevention and treatment of CNS diseases.

Hou et al. (2003) demonstrated that SO significantly reduces NO production as well as iNOS mRNA and protein expression in LPS-stimulated BV-2 microglial cells. Furthermore, SO markedly inhibited the activation of p38 MAPK. The specific p38 MAPK inhibitor SB203580 also exhibited dose-dependent inhibition of NO production, further supporting the hypothesis that polyphenolic compounds capable of suppressing NO generation may exert neuroprotective effects.

In a related study, Wu et al. (2015) treated RAW 264.7 macrophages with sesamol followed by LPS stimulation to induce an inflammatory response. Their findings indicated that sesamol exhibited the capacity to impede NF-κB nuclear translocation and MAPK pathway activation, while concomitantly promoting the activation of AMP-activated protein kinase (AMPK). These findings suggest that sesamol improves inflammatory responses and oxidative stress damage by activating the AMPK and Nrf2 signaling pathways while inhibiting the NF-κB and MAPK pathways.

Mohamed et al. (2021) reported that SO significantly ameliorated AlCl₃-induced learning and memory deficits in mice. It reduced AChE activity and Aβ levels, downregulated the expression of pro-inflammatory cytokines TNF-α and IL-1β, suppressed NF-κB and p38 MAPK signaling, and upregulated the expression of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These results suggest that SO alleviates neuroinflammation and oxidative stress damage by modulating the NF-κB/p38MAPK/BDNF/PPAR-γ signaling pathway, thereby contributing to the recovery of cognitive function and showing its potential value in the treatment of AD.

SCH A is a bioactive lignan compound that has been isolated from Schisandra chinensis, a traditional Chinese medicinal herb. In recent years, SCH A has attracted growing scientific interest owing to its broad spectrum of pharmacological activities. It has been demonstrated to exert diverse biological effects, including anti-inflammatory, anticancer, hepatoprotective, antioxidant, neuroprotective, antidiabetic, and musculoskeletal protective properties (Choi, 2018; Cui et al., 2020; Kong et al., 2018; Meng et al., 2019; Jeong et al., 2019; Wang et al., 2014; Zhang et al., 2010). Notably, Schisandra and its active constituents have shown promising potential in the prevention and treatment of AD.

A series of experimental studies have demonstrated SCH A (10, 20, and 50 μM) suppresses the expression of NO, tumor necrosis factor-α (TNF-α), and IL-6 in LPS-stimulated BV-2 microglia and primary microglial cells, thus exerting anti-inflammatory properties. It mitigates microglia-mediated neuroinflammation by inhibiting key signaling pathways, such as TRAF6–IKKβ–NF-κB and JAK2–STAT3, thereby exerting neuroprotective effects (Song et al., 2016).

Furthermore, schisandrin has been shown to enhance neuronal viability in Aβ1–42-induced SH-SY5Y cell models of AD through activation of the PI3K/Akt signaling pathway, thus exerting protective effects (Zhao et al., 2019). Jia et al. (2024) reported that SCH A significantly reduces oxidative stress response and downregulates inflammatory cytokine expression in cells induced by Aβ25-35, while also increasing the p-ERK1/2 to ERK1/2 ratio, indicating that its underlying mechanism may involve activation of the ERK/MAPK pathway.

Further research by Kwon et al. (2018) using an in vitro RAW 264.7 macrophage model demonstrated that SCH A attenuates LPS-induced inflammation and oxidative stress by activating the Nrf2/HO-1 signaling pathway, while concurrently suppressing the NF-κB, MAPK, and PI3K/Akt pathways. Among these, SCH A pretreatment markedly inhibited the phosphorylation of ERK, JNK, and p38 MAPK, providing further evidence of its multi-target anti-inflammatory and antioxidant effects.

Crocin (CRO) is a natural carotenoid that is found in high concentrations in the stigmas of saffron (Crocus sativus) and the fruits of gardenia (Gardenia jasminoides) (Liu T. et al., 2020). Extensive in vitro, in vivo, and clinical studies have demonstrated that CRO exerts beneficial effects across multiple organ systems, including the nervous, immune, cardiovascular, gastrointestinal, reproductive, and endocrine systems (Khorasany and Hosseinzadeh, 2016).

Research indicates that CRO exerts significant memory-enhancing effects, which are partly attributed to its anti-inflammatory properties and modulation of the ERK/MAPK signaling pathway. In a D-galactose-induced aging model, CRO improves cognitive function via its anti-glycation and antioxidant activities, thereby suppressing the expression of neuroinflammatory mediators (e.g., IL-1β, TNF-α, and NF-κB) and activating the PI3K/Akt and ERK/MAPK signaling pathways (Adabizadeh et al., 2019; Heidari et al., 2017; Looti Bashiyan et al., 2021).

Furthermore, the use of CRO has been shown to markedly decrease total tau protein levels and phosphorylation, suppresses β- and γ-secretase activities, and reduces the deposition of Aβ precursor protein (AβPP) accumulation in AD models by inhibiting ERK1/2 kinase activity (Chalatsa et al., 2019). Another study shows that CRO mitigates acrolein-induced neurotoxicity, potentially through the attenuation of oxidative stress via the ERK/MAPK pathway, thus delaying the progression of NDDs (Rashedinia et al., 2015).

Ginsenosides Re, Rg1, and Rg2 are the major triol-type natural saponins in ginseng and represent the principal active constituents of this traditional Chinese medicinal herb. These compounds have been demonstrated to exert a variety of pharmacological effects, including the enhancement of cognitive function, the inhibition of apoptosis, and the exertion of neuroprotective activities (Li et al., 2020). Among them, ginsenoside Re is a pivotal component (Shi et al., 2019) and remains the most extensively investigated ginsenoside to date. It has been demonstrated to possess antioxidant and anti-inflammatory properties, suppressing the production of IL-6, tumor necrosis TNF-α, and NO in microglial cells without impairing cellular viability (Lee et al., 2020; Lee I-A. et al., 2012). The reduction in the release of pro-inflammatory and neurotoxic mediators from microglia has been demonstrated to provide a protective effect on hippocampal neurons (Madhi et al., 2021). Furthermore, ginsenoside Re has been shown to attenuate neuroinflammation progression by inhibiting LPS-induced MAPK phosphorylation (Lee K-W. et al., 2012).

Among the diverse ginsenosides, Rg1 demonstrates notable neuroprotective benefits, especially in NDDs such as AD and PD. Hu et al. (2011) demonstrated that ginsenoside Rg1 suppresses LPS-induced microglial activation via downregulation of Iba-1 and iNOS expression. Furthermore, Rg1 effectively inhibits the phosphorylation of p38 MAPK, ERK1/2, and JNK, and prevents the degradation of IκB as well as the nuclear translocation of the NF-κB p65 subunit. Rg1 attenuates LPS-induced inflammatory responses by activating the phospholipase C-γ1 signaling pathway in mouse BV-2 microglia. It inhibits the phosphorylation of p38 MAPK, IκB-α, CREB, and ERK1/2, significantly reduces NF-κB expression, and decreases the production of pro-inflammatory cytokines, including TNF-α, IL-1β, iNOS, and COX-2 (Zong et al., 2012). The neuroprotective effect of ginsenoside Rg1 against LPS-induced neuronal degeneration in rats is mediated via the glucocorticoid receptor, involving inhibition of the p38 MAPK signaling pathway to suppress LPS-induced inflammation in midbrain dopaminergic neuronal microglia (Sun et al., 2016).

Treatment with ginsenoside Rg2 significantly elevates the ratios of phosphorylated ERK to total ERK (p-ERK/ERK) and phosphorylated MAPK to total MAPK (p-MAPK/MAPK) in the brain tissue of 3xTg-AD mice, thereby mitigating neurovascular damage in this AD model (Ye et al., 2023).

Panax ginseng, which is more commonly referred to as Korean ginseng, contains primary active components including ginsenosides (-Rg3, -Rg5, and -Rk1), polysaccharides, and phenolic compounds, with particularly high concentrations in Korean BGE (Metwaly et al., 2019). Research has demonstrated that extracts of Korean BGE, when administered as an ethanol solution, have been shown to attenuate neuroinflammation by inhibiting the NF-κB and MAPK signaling pathways in LPS-stimulated BV2 microglia. This attenuation is achieved via a Toll-like receptor 4 (TLR4)-MyD88-dependent mechanism (Kim et al., 2023). Furthermore, BGE has been demonstrated to significantly enhance cognitive function in the 5xFAD AD mouse model, concomitant with reduced Aβ accumulation in the frontal cortex and hippocampus (Ha et al., 2025). BGE has been demonstrated to suppress the activation of microglia and astrocytes, as well as to downregulate pro-inflammatory cytokines, including IL-6 and tumor necrosis factor-alpha (TNF-α), along with the expression of enzymes such as COX-2 and iNOS. Further studies have demonstrated that BGE reduces Aβ plaque deposition via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and suppresses p38 MAPK, NF-κB, and STAT3 signaling pathways, as well as NLRP3 inflammasome activation, thus protecting cognitive function in 5xFAD mice and highlighting its therapeutic potential in AD.

Esculetin is a natural dihydroxy coumarin; it is mainly extracted from twig skin and the trunk bark of the Chinese herbal medicine Fraxinus rhynchophylla Hance.Natural coumarin derivatives have demonstrated anti-inflammatory effects through various inflammatory signaling pathways, including TLRs, JAK/STAT, inflammasomes, MAPK, NF-κB, and TGF-β/SMAD. Possesses antioxidant (Wang et al., 2011), antiinflammatory (Kirsch et al., 2016), antiapoptotic (Kim et al., 2015), anticancer (Pinto and Silva, 2017), antidiabetic (Li et al., 2017), neuroprotective (Delogu and Matos, 2017), and cardiovascular protective activities (Najmanová et al., 2015). Pruccoli et al. (2020) demonstrated the ability of ESC to prevent and counteract ROS formation in neuronal SH-SY5Y cells, suggesting its profile as a bifunctional antioxidant. In particular, ESC increased the resistance of the SH-SY5Y cells against OS through the activation of Nrf2 and increase of GSH. In similar experimental conditions, ESC could also protect the SH-SY5Y cells from the OS and neuronal death evoked by oligomers of Aβ1-42 peptides. Further, the use of the inhibitors PD98059 and LY294002 also showed that Erk1/2 and Akt signaling pathways were involved in the neuroprotection mediated by ESC.

ESC, a common coumarin derivative, was reported by Song et al. (2018) to exhibit protective potential against diabetic nephropathy (DN). In this study, a diabetic mouse model was established in 6-week-old male C57BL/6J mice by a single intravenous injection of streptozotocin (STZ, 30 mg/kg). Two weeks after STZ injection, the mice received intravenous administration of ESC at doses of 5, 10, or 20 mg/kg for an additional 2 weeks. The results demonstrated that ESC markedly suppressed STZ-induced renal expression of AP-1, p-p38 MAPK, and p-JNK, while upregulating p-ERK1/2. These findings suggest that ESC may alleviate experimental DN-associated cognitive impairment through modulation of the MAPK signaling pathway, exerting both antioxidative and anti-inflammatory effects.