The regulatory mechanisms of active ingredients in traditional Chinese medicine for inflammation in Parkinson disease: A review

The TLR4/NF-κB pathway, activated by external stimuli like α-synuclein and cytokines,triggers a signaling cascade involving TIRAP and MYD88, leading to the activation of TAK1, IKKs, induction of phosphorylation of IκBα/IκBβ proteins, entry of p50 and p65 into the nucleus,transcription of pro-inflammatory genes, and upregulate inflammatory factors TNF-α, IL-6, COX-2, iNOSand other inflammatory factors. Then Active, the NF-κB/NLRP3 signaling pathway. The NF-κB/NLRP3 pathway is initiated by microglial activation. Microglia first activate NF-κB through cytokine-activated TLR to the assembly of a complex and release Pro-Caspase-1, Pro-IIL-1β, Subsequent hydrolysis of ProCaspase-1 to Caspase-1, that activates caspase-1, and the concomitant recruitment of ASCs, cleaves Pro-IL-1β to IL-1β resulting in the secretion of IL-1β,as illustrated in Figure. [,,] ^{28 29 35} [] ⁵⁸ [,] ^{59 60} [,] ^{61 62} 2

MAPK pathway is an essential signaling mechanism that relays signals from the cell surface to the nucleus, comprising various subfamilies: ERK, JNK, and p38. The p38 and JNK subfamilies are notably linked to inflammation. The activation of the classical MAPK pathway unfolds across 3 tiers: MAP3K, MAP2K, and MAPK,as illustrated in FigureB. [] ⁶³ 3

Four isoforms of the p38 MAPK family have been delineated: p38α, p38β, p38γ, and p38δ. p38α and p38β have 75% amino acid sequence homology and are abundantly expressed in neuronal cells and macrophages.Recognition of extracellular signals by PRRs triggers signal transduction through TIRAP and MYD88 to TRAF6, orchestrating the regulation of MAP3Ks (e.g., MEKK1-4, TAK1) and MAP2Ks (e.g., MKK3, MKK6),culminating in the phosphorylation of p38. This phosphorylated p38 translocates to the nucleus, activating MSK1/2 and MK2, which in turn can activate the NF-κB pathway,leading to inflammation through the phosphorylation of IκB and liberation of p65 from the cytosol. Phosphorylated p65 subunit enters the nucleus, triggering the release of inflammatory cytokines like IL-1β, COX-2, IL-6, and iNOS.MK2 modulates the phosphorylation of AU-binding proteins, affecting TNF-α secretion.Additionally, the p38 MAPK pathway, by activating the NLRP3 inflammasome, facilitates IL-1β release and induces neuroinflammation.Inhibiting the p38 MAPK pathway can diminish NF-κB and NLRP3 expression, thus mitigating neuroinflammation. [,] ^{64 65} [] ⁶⁶ [,] ^{67 68} [,] ^{69 70} [,] ^{71 72} [,] ^{67 73}

The JAK/STAT pathway facilitates a cascade of cellular protein interactions, transmitting extracellular chemical signals to the nucleus and activating genes via transcription.This pathway involves ligand-receptor complexes, JAK, which consists of 4 members, and STAT, which consists of 7 members.In the context of a PD rat model induced by α-synuclein, the JAK/STAT pathway mitigates the activation of microglia and reduces the infiltration of macrophages and CD4 T cells into dopaminergic neurons.Inflammatory cytokines, notably IFN-γ and IL-6, act as principal activators of the JAK/STAT pathway,prompting ligand-receptor complex dimerization, which in turn activates JAK2. This activation leads to the phosphorylation of JAK2, with 2 proximate JAK2 molecules each activating a STAT3.These dimerized STAT3 molecules then translocate into the nucleus to bind DNA,activating and transcribing genes for inflammatory cytokines such as NO, TNF-α, and IL-1β,as illustrated in FigureA. Inhibition of the JAK2/STAT3 pathway serves to dampen neuroinflammation. [] ⁷⁴ [] ⁷⁵ [] ⁷⁶ [,] ^{76 77} [] ⁷⁸ [,] ^{79 80} [] ⁷⁷ 3

Mitochondria, cellular powerhouses, orchestrate energy production through ATP synthesis via oxidative phosphorylation, whilst concurrently being prolific ROS generators. Compromised mitochondrial efficacy precipitates oxidative stress, undermining dopaminergic neuronal integrity.The mitochondrial architecture, with its outer membrane, intermembrane space, inner membrane, and matrix, houses the electron transport chain within the inner membrane. This assembly, comprised of complexes I-IV, coenzyme Q, and cytochrome C, is the linchpin of oxidative phosphorylation.Under physiological guise, mitochondria engage NADH and FADH2 in a dance with complexes I and II, birthing protons and electrons. These protons traverse into the intermembrane space via complexes I, III, and IV, engendering an electrical potential and proton gradient that catalyzes ATP synthesis from ADP and a phosphate moiety. [] ⁸⁴ [] ⁸⁵ [,] ^{85 86}

The aberrant agglomeration of α-synuclein inflicts dysfunction upon the electron transport chain in dopaminergic neurons,culminating in the overproduction of superoxide anions (O2). These anions, upon mingling with superoxide dismutase (SOD), give rise to hydrogen peroxide (H2O2), which, in cahoots with metal ions like Fe2, begets hydroxyl radicals (OH).This cascade of ROS ignites oxidative stress in dopaminergic neurons. The tumult wrought by mitochondrial malfunctions unleashes ROS and RNS (e.g., NO, iNOS), heralding the microglial activation and the onset of neuroinflammation.The Nrf2, a redox-sensitive transcriptional guardian, orchestrates cellular resilience against oxidative stress and inflammation by championing the Nrf2/HO-1 pathway. [] ⁸⁷ – + - [,] ^{88 89} [,] ^{83 90} [] ⁹¹

In the quiescent state, Keap1 binds to Nrf2, curbing its activity through ubiquitination and proteasomal degradation.The onslaught of oxidative stress activates the Nrf2/HO-1 pathway; Keap1 undergoes dimerization and rendezvous with CUL-3, facilitating Nrf2's combination with small Maf proteins.This combine forges a transcriptionally active heterodimer that ventures into the nucleus, allies with ARE, and spearheads the transcription of antioxidant bastions, including NQO1 and HO-1, thus staging a formidable stand against oxidative stress.HO-1 catalyzes the breakdown of heme into free iron ions, carbon monoxide, and biliverdin, subsequently transformed into bilirubin. Both Feand bilirubin orchestrate the suppression of NF-κB expression,as illustrated in Figure. Additionally, Nrf2 can neutralize NF-κB-mediated inflammatory responses by competitively binding to CBPand by reducing NLRP3 expression through caspase-1 cleavage, thereby lowering IL-1β levels and inhibiting neuroinflammation.Nrf2 expression, therefore, emerges as a strategic bulwark to dampen NF-κB and NLRP3 expression via the Nrf2/HO-1 pathway, heralding a reduction in neuroinflammation. [] ⁹² [,] ^{93 94} [,] ^{94 95} 2+ [] ⁹⁶ [,] ^{97 98} [] ⁹⁹ 4

①Vagal and Spinal Pathways: Groundbreaking autopsies by Braak et al have illuminated the pivotal role of the VN, emanating from the dorsal motor nucleus of the medulla, in the gut-brain communication network.This vital conduit offers a dual regulatory mechanism over the gastrointestinal tract, gut signals enabling direct transmission to the brain via the enteric nervous system and neuroendocrine links, intricately woven into the fabric of the gut-brain axis. [] ¹⁰³ [,] ^{104 105}

②Immunological Cross-Talk: The activation of immune cells within the gut modulates neuronal activity through the release of neurotransmitters and cytokines, which are then ferried to the CNS via the VN. This immunological brigade, comprising T cells, B cells, dendritic cells, and macrophages,launches pro-inflammatory cytokines like TNF-α, IFN-γ, IL-1β, and IL-6into the CNS through the gut-brain conduit, igniting neuroinflammation. [] ¹⁰⁶ [] ¹⁰⁷ [] ¹⁰⁸

③Metabolic Interplay: The metabolic contribution, highlighted by SCFAs and bile acids, emerges from the fermentation of dietary fibers by gut microbiota. These metabolic byproducts activate enteroendocrine cells, establishing a communication channel with the CNS. [] ¹⁰⁹

④Endocrine Dynamics: The HPA axis serves as a critical endocrine pathway facilitating this complex dialogue. [] ¹¹⁰

The integrity of the intestinal and BBB underpins the selective permeability to the CNS via the GBA. These barriers, orchestrated by intestinal epithelial cells and regulated by tight junction proteins like occludin and ZO-1, are the gatekeepers against unwarranted intrusions.However, disruptive agents such as MPTP, 6-OHDA, LPS, and Rotenone, alongside aggregates of α-synuclein,can unsettle the gut microbiota balance, compromise the intestinal barrier, and heighten permeability, thus fostering intestinal and systemic inflammation.This process not only breaches the CNS's protective barriers but also ushers pro-inflammatory agents and immune cells into the brain, precipitating neuroinflammation,as illustrated in Figure. Furthermore, persistent intestinal inflammation may fuel the accumulation of α-synuclein, which can navigate through the GBA to the SNpc, potentially triggering PD.Therefore, addressing peripheral intestinal inflammation stands as a promising avenue to mitigate neuroinflammation, offering a pathway to therapeutic interventions in PD. [,] ^{111 112} [] ¹¹³ [] ¹⁰³ [,] ^{107 114} [–] ^{115 117} 6

Curcumin, a natural polyphenolic compound, is derived from the rhizomes of plants within the ginger family, such as turmeric and zedoary. In PD mice induced by rotenone, curcumin suppresses Iba-1 expression, inhibits microglial activation, dampens the NF-κB/NLPR3 pathway, diminishes NF-κB activity, and restrains the activation of NLPR3 and caspase-1. Consequently, it reduces the discharge of IL-1β. [] ¹²⁶

Resveratrol, a polyphenolic organic substance, is extractable fromand grapes. In 6-OHDA-induced rat models of PD, resveratrol lowers the concentrations of TNF-α and COX-2 in the SNpc, mitigates neuroinflammation, protects dopaminergic neurons, and ameliorates the aberrant rotational behavior in mice.In rotenone-induced PD rats, resveratrol blocks microglial activation, lessens IL-1β levels, and suppresses neuroinflammation. Polygonum cuspidatum [] ¹²⁷ [] ¹²⁸

Icariin is a flavonoid compound that can be found in the stems and leaves of Epimedium. In PD rats, icariin has been shown to downregulate the levels of Iba-1, inhibit the activation of microglia, and decrease the release of IL-1β, TNF-α, NO, and iNOS by inhibiting the expression of the NF-κB/NLRP3 pathway. This action alleviates neuroinflammation and protects dopaminergic neurons. [] ¹²⁹

Apigenin is a flavonoid compound found in temperate and tropical regions, particularly abundant in celery. In PD rats induced by rotenone, apigenin reduces neuroinflammation by inhibiting the levels of NF-κB, thereby decreasing the levels of TNF-α, IL-6, NF-κB, and iNOS-1 in the striatum. [] ¹³⁰

The flavonoid compound kaempferol is widely found in tea leaves, broccoli, snapdragons, witch hazel, grapefruits, brussels sprouts, and apples. In PD rat models induced by 6-OHDA, kaempferol can inhibit the expression of GFAP and Iba-1, suppress the microglial activation and the astrocytic activation via the NF-κB/NLRP3 and p38/MAPK/NF-κB pathways, and decrease the concentrations of iNOS, COX-2, IL-1β, and IL-18, thereby inhibiting neuroinflammation.In PD rats induced by rotenone, kaempferol also decreases the level of TNF-α and IL-6, protecting dopaminergic neurons and alleviating the motor deficits of PD rats. [,] ^{131 132} [] ¹³³

Catechins, a class of phenolic compounds, are extracted from natural plants such as tea leaves and fruits. In PD rats induced by rotenone, catechins can reduce the content of IκKB, thereby decreasing the concentrations of IL-1β, IL-6, TNF-α, and NO by downregulating NF-κB pathway, thus inhibiting neuroinflammation. [,] ^{134 135}

Luteolin, a flavone subclass of flavonoids belonging to the natural polyphenolic compound, is found in plant-based foods. In PD rats induced by LPS, luteolin can inhibit microglial activation, reduce the release of TNF-α and NO, suppress neuroinflammation, and protect dopaminergic neurons. [] ¹³⁶

Farrerol is a flavonoid compound extracted from the Rhododendron genus, specifically.In rats afflicted with PD induced by LPS, farrerol mitigates the microglial activation by suppressing the level of Iba-1 via downregulating the expression of the MAPK/AKT/NF-κB pathway, decreasing the expression of TNF-α, IL-1β, IL-6, and iNOS, thus preventing the loss of dopaminergic neurons and easing motor dysfunction in PD rats. Rhododendron simsii [] ¹³⁷ [] ¹³⁸

Galangin, a flavonoid compound, is extensively found in the roots of the ginger family plant Alpinia galanga. In PD rats, galangin significantly reduces Iba-1 expression and suppress the activation of microglia. Downregulating the expression of the MAPK/Akt/NF-κB pathway decreases the release of COX-2, iNOS, TNF-α, IL-1β, and IL-6, thereby suppressing neuroinflammation. [] ¹³⁹

Hesperidin, a bioflavonoid with a high concentration in citrus fruits,can reduce the release of TNF-α, IFN-γ, IL-1β, IL-2, and IL-6 in the striatum of PD mouse models induced by 6-OHDA, inhibiting neuroinflammation, protecting dopaminergic neurons, and alleviating depressive, anxious, and dyskinetic behaviors in PD mice. [] ¹⁴⁰ [] ¹⁴¹

Isoliquiritigenin, extracted as a chalcone compound from licorice, targets BV2 cells from MPTP-induced PD mice. It reduces the expression of Iba-1, curbing the microglial activation. It lowers the concentration of COX-2 and iNOS by suppressing the JNK/NFκB/AKT pathway. In addition, in PD mice triggered by LPS, isoliquiritigenin decreases the expression of TNF-α, IL-1β, and IL-6 via the JNK/NFκB/AKT pathway, reducing neuroinflammation and safeguarding dopaminergic neurons. [] ¹⁴²

Rutin, a quercetin derivative and part of the flavonoid family, demonstrates neuroprotective properties in PD rat models induced by 6-OHDA. It lessens the level of NO, iNOS, TNF-α, and IL-1β, thereby reducing neuroinflammation and preserving dopaminergic neurons. As a result, rutin diminishes rotational behavior and motor deficits in PD rats. [] ¹⁴³

Ferulic Acid is a phenolic substance derived from the traditional Chinese herb Ferula.In PD models induced by rotenone in rats, Ferulic Acid effectively curtails the levels of GFAP and Iba-1, mitigates the activation of microglia and astrocytes, respectively. This action leads to a notable downregulation in the striatal concentrations of TNF-α, IL-1β, IL-6, COX-2, and iNOS, thereby mitigating neuroinflammation and safeguarding dopaminergic neurons. [] ¹⁴⁴ [] ¹⁴⁵

Phloretin, a dihydrochalcone compound prevalent in the peels and root bark of fruits like apples and pears,plays a pivotal role in neuroprotection within PD mouse models triggered by MPTP. By downregulating Iba-1 and GFAP, Phloretin inhibits the microglial and astrocytic activation. The suppression of the NF-κB pathway underlies its ability to diminish the release of iNOS, COX-2, TNF-α, and IL-1β, contributing to the protection of dopaminergic neurons. Additionally, Phloretin boosts balance and prolongs retention time while alleviating orientation impairments in PD mice. [] ¹⁴⁶ [] ¹⁴⁷

Morin is extracted from the bark of Morus alba and other members of the Moraceae family, presenting flavonoid-based therapeutic potential against PD. In MPTP-induced PD mouse models, Morin downregulates GFAP and Iba-1 expressions, thus impeding the microglial and astrocytic activation. By suppressing the ERK/MAPK pathway and reducing NF-κB expression, Morin effectively combats neuroinflammation. [] ¹⁴⁸

Mangiferin, a compound rich in xanthonoids and primarily harvested from mango trees, stands out for its potency.In PD rat models induced by 6-OHDA, Mangiferin showcases its therapeutic might by suppressing NF-κB expression. This action significantly diminishes the expressions of COX-2, IL-1β, IL-6, and TNF-α. It also targets and reduces the levels of Th1 and Th2 cells, further lowering the amounts of IFN-γ and increasing the amounts of IL-4, thereby robustly countering neuroinflammation. [] ¹⁴⁹ [] ¹⁵⁰

Nobiletin, a naturally occurring flavonoid in citrus fruits, plays a critical role in neuroprotection within PD models induced by MPTP in rats. By targeting and downregulating Iba-1 expression in the substantia nigra, it prevents microglial activation and decreases IL-1β levels, effectively preserving the integrity of dopaminergic neurons. [,] ^{151 152}

Andrographolide, a terpenoid derived from theherb, showcases profound neuroprotective properties in PD mouse models induced by MPTP. This compound achieves its effects through downregulating the NF-κB/NLRP3 pathway, leading to reduced Iba-1 expression, minimized microglial activation, and lowered NLRP3 and Caspase-1 activity. Consequently, there's a notable decrease in IL-1β levels, effectively dampening neuroinflammation, safeguarding dopaminergic neurons, and alleviating motor deficits seen in PD mice.Moreover, andrographolide impedes the activity of p65 and suppresses IκBα expression, thus inhibiting the levels of the NF-κB pathway triggered by TNF-α and IL-1β, further reducing neuroinflammation and enhancing both neuronal protection and motor function recovery in PD mice. Andrographis paniculata [] ¹⁵⁴ [,] ^{155 156}

Astragaloside IV, identified as a tetracyclic triterpenoid saponin from Astragali Radix, demonstrates potential therapeutic effects in MPTP-induced PD mouse models. It effectively downregulates Iba-1 expression, halts microglial activation, and prevents NLRP3 inflammasome activation. By curtailing phosphorylated nuclear NFκB/p65 levels and obstructing the NF-κB/NLRP3 pathway, Astragaloside IV reduces NLRP3 and IL-1β concentrations, thus protecting dopaminergic neurons and reducing motor impairments.Additionally, in SH-SY5Y cells from the PD model induced by 6-OHDA, Astragaloside IV inhibits the JAK2/STAT3 pathway, decreasing TNF-α, IL-6, and iNOS levels, which helps in mitigating neuroinflammation. [] ¹⁵⁷ [] ¹⁵⁸

Paeoniflorin, extracted fromand, is a monoterpenoid glycoside with notable neuroprotective capabilities in MPTP-induced PD mouse models. It downregulates CD11b and GFAP expression, inhibiting microglial and astrocytic activation, leading to reduced IL-1β, TNF-α, NO, and iNOS levels. This multifaceted approach helps protect dopaminergic neurons and enhances motor function in PD mice. Paeonia lactiflora Paeonia veitchii [,] ^{159 160}

Tanshinone is a diterpenoid derived from, and the main active ingredients are tanshinone I and tanshinone IIA.Tanshinone I showcases its neuroprotective prowess in MPTP-induced PD mouse models by reducing Iba-1 expression and inhibiting microglial activation. It also downregulates the NF-κB pathway transcription, decreases TNF-α levels, and increases IL-10 levels. Furthermore, in LPS-induced PD mouse BV2 cells, tanshinone I lowers TNF-α, IL-6, IL-1β, and iNOS levels, effectively countering neuroinflammation.In 6-OHDA-induced PD rat, tanshinone IIA mitigates NF-κB activity, reduces IL-1β, TNF-α, and INF-γ levels, and increases IL-10 levels, thereby alleviating neuroinflammation and easing abnormal rotation and muscle rigidity.Tanshinone IIA also diminishes CD11b expression in the SNpc, curtails microglial activation, and decreases iNOS levels in MPTP-induced PD mice, further reducing neuroinflammation. Salvia miltiorrhiza [] ¹⁶¹ [] ¹⁶² [] ¹⁶³ [] ¹⁶⁴

Ginsenosides, identified as triterpene glycosides and extracted from ginseng, with over 500 variants recognized, play a significant role in PD treatment.Specifically, ginsenoside Rg1 in MPTP PD models boosts CD3 and CD4 T cell levels in peripheral blood, lessens CD3 and CD8 T cell levels, and reduces the infiltration of CD3 T cells in the SNpc region. It inhibits T cell cytotoxicity and downregulates Iba-1 expression, thereby suppressing microglial activation, lowering the expression of IL-1β, IL-6, TNF-α, and IFN-γ, and preventing α-synuclein aggregation.In LPS-induced PD mice, ginsenoside Rg1 was able to downregulate GFAP and Iba-1, inhibit the microglial activation and the astrocytic activation, reduce the concentrations of TNF-α, IL-1β, and IL-6, by downregulating the levels of the NF-κB pathway, increase the concentrations of TGF-β and IL-10, and reduce neuroinflammation.Ginsenoside Rb1 in LPS PD mice by downregulates the levels of GFAP and Iba-1, inhibits microglial and astrocyte activation via the NF-κB pathway, increases IL-10 and TGF-β levels, and reduces IL-1β and TNF-α levels, mitigating neuroinflammation. [] ¹⁶⁵ [,] ^{166 167} [] ¹⁶⁸ [,] ^{169 170}

Menthol, a cyclic monoterpene found in mint leaves and stems, in LPS-induced PD rats, attenuates IBA-1 expression, inhibits the activation of microglia, and via the MAPK/AKT/NF-κB pathway, reduces IL-1β, IL-6, TNF-α, iNOS, and COX-2 levels. These actions protect dopaminergic neurons and lessen abnormal movement in PD rats. [] ¹⁷¹

Ginkgolides, distinguished terpenoid compounds within ginkgo leaves, have captured significant scientific interest, particularly Ginkgolide B and K. Ginkgolide K, in MPTP PD models, orchestrates a reduction in GFAP and Iba-1 expression, curtails the microglial activation and the astrocytic activation, thereby diminishes NO, TNF-α, and IL-1β levels while enhancing TGF-β and IL-10 concentrations. Additionally, it attenuates peripheral inflammatory cytokines like IFN-γ and IL-17, effectively mitigating neuroinflammation, curbing the depletion of dopaminergic neurons, and fostering the transformation of astrocytes into dopaminergic neurons.Ginkgolide B further demonstrates its neuroprotective efficacy by inhibiting TLR4 expression on microglia and astrocytes, reducing TNF-α levels, and suppressing iNOS expression in activated microglia. [] ¹⁷² [] ¹⁷³

Triptolide, a potent compound from, also known as Thunder God Vine, has shown neuroprotective effects in LPS-induced rat models of PD. By diminishing the levels of markers Iba-1 and GFAP, triptolide effectively curtails the microglial activation and the astrocytic activation, lowers the levels of neuroinflammatory mediators iNOS, TNF-α, IL-1β, and IL-6. Through these mechanisms, triptolide suppresses neuroinflammation, safeguarding dopaminergic neurons and offering a potential therapeutic avenue for PD. Tripterygium wilfordii [,] ^{174 175}

Glycyrrhizin, a triterpenoid compound extracted from licorice, a staple in TCM, demonstrates significant anti-inflammatory properties. The activation of microglial TLR2/TLR4 receptors by HMGB1 initiates a series of responses that include both MyD88-dependent and independent pathways, along with MAPKs and NLRP3, among others. This cascade results in the transcription of inflammatory genes and the subsequent microglial activation.In MPTP-induced PD mice, glycyrrhizin's binding to HMGB1 leads to a reduction in GFAP and Iba-1 levels, curtails the microglial activation and the astrocytic activation, lowers TNF-α levels, and effectively dampens neuroinflammation.Likewise, in a PD rat induced by rotenone, glycyrrhizin mitigates neuroinflammation by suppressing the levels of GFAP and Iba-1, reducing the activation of microglia and astrocytes, and decreasing the concentrations of iNOS, COX-2, TNF-α, IL-1β, and IL-6. This series of actions helps safeguard dopaminergic neurons.Moreover, in MPTP PD zebrafish, glycyrrhizin's interaction with HMGB1 and modulation of the TLR/NFκB pathway downregulates the release of IL-1β and IL-6, prevention of abnormal α-synuclein aggregation, inhibition of neuroinflammation, protection of dopaminergic neurons, and amelioration of motor impairments. [] ¹⁷⁶ [] ¹⁷⁷ [] ¹⁷⁸ [] ¹⁷⁹

Cannabinoids, belonging to the terpenophenolic compound family, have shown promising results in LPS-induced PD mice by diminishing Iba-1 expression and inhibiting microglial activation. This leads to a downregulation in the release of iNOS, IL-1β, and TNF-α thereby alleviating neuroinflammation.In the context of PD mouse models induced by MPTP, cannabinoids continue their protective role by lowering Iba-1 expression, inhibiting the activation of microglia, and consequently reducing TNF-α and IL-1β release. This concerted action preserves dopaminergic neurons and ameliorates motor impairments observed in PD mice. [] ¹⁸⁰ [] ¹⁸¹

Berberine, hailing from the traditional Chinese herb Coptis chinensis, is an isoquinoline alkaloid with pronounced neuroprotective effects in MPTP PD models. It adeptly navigates the NF-κB pathway to diminish IL-6 and TNF-α levels, effectively easing neuroinflammation and providing a shield for neurons. [] ¹⁸²

Piperine, a potent alkaloid present in the fruits of the Piperaceae family, notably black pepper, showcases therapeutic promise in 6-OHDA PD models. It lowers TNF-α and IL-1β levels, curtails neuroinflammation, and fortifies dopaminergic neurons, enhancing the rotational behavior of PD rats.Further, in rotenone-induced PD rats, piperine, in concert with quercetin, attenuates TNF-α, IL-1β, and IL-6 levels, thwarting the degeneration of dopaminergic neurons, refining narrow beam walking parameters, and boosting motor vitality. [] ¹⁸³ [] ¹⁸⁴

Salidroside, derived from the Rhodiola genus roots, emerges as a promising agent against PD.In MPTP-induced PD mice, salidroside exhibits mechanism involves downregulating the TLR4/NF-κB and NLRP3/Caspase-1 pathways, leading to reduced activity of NLRP3 and Caspase-1. Consequently, the production of IL-1β and IL-18 by NLRP3 inflammasomes is diminished, alongside a notable decrease in α-synuclein aggregation. These actions collectively contribute to the suppression of neuroinflammation and enhancement in motor impairments observed in PD mice. [] ¹⁸⁵ [] ¹⁸⁶

Derived from the Chinese herb, Octanol is a saturated fatty alcohol that exhibits neuroprotective capabilities in LPS-induced PD rat models. By reducing CD11b expression and staving off microglial activation, it decreases TNF-α, iNOS, and NO levels, thereby suppressing neuroinflammation. Rehmannia glutinosa [] ¹⁸⁷

α-Asarone, extracted from the, is a phenylpropene compound with notable neuroprotective attributes in MPTP PD models. It impedes the concentrations of Iba-1 and GFAP, inhibits microglial and astrocyte activation via the NF-κB pathway, and lessens COX-2 and iNOS levels, thus safeguarding dopaminergic neurons and curtailing neuroinflammation. Acorus calamus [] ¹⁸⁸

Osthole, a coumarin derivative sourced from, serves as a neuroprotective agent in MPTP-induced PD mice. It inhibits Iba-1 expression, dampens microglial activation, and reduces TNF-α, IL-6, IL-1β, and NO levels, effectively mitigating neuroinflammation. Cnidium monnieri [] ¹⁸⁹

Baicalin emerges from the revered Chinese herbas a flavonoid of notable potency. Its role in MPTP-induced PD mice models is pivotal, catalyzing the Nrf2/HO-1 pathway's activation, which escalates Keap1, Nrf2, and HO-1 levels, curtailing oxidative stress. Moreover, its ability to downregulate Iba-1, stifle microglial activation, and dampen the NLRP3 inflammasome's zeal by suppressing NF-κB, effectively diminishes TNF-α, IL-1β, and IL-6 levels, offering solace from neuroinflammation.Baicalin prowess extends to LPS-induced PD mice, where it elevates Nrf2 and HO-1, curbing IL-1β and TNF-α secretion and further easing neuroinflammation. Scutellaria baicalensis [] ¹⁹⁰ [] ¹⁹¹

In the milieu of 6-OHDA PD models, Icariin champions the Nrf2/HO-1 pathway, enriching the release of Keap1, HO-1, and NQO1, thus shielding against oxidative stress. Its suppression of GFAP and Iba-1 expression, alongside the inhibition of microglia and astrocytes, trims TNF-α and iNOS levels, mitigating neuroinflammation and safeguarding dopaminergic neurons. [] ¹⁹²

In the context of 6-OHDA PD mouse, isoliquiritigenin marks its territory by downregulating Iba-1, impeding microglial activation. Through the Nrf2/NQO1 pathway, it diminishes IL-1β, IL-6, and TNF-α levels, stanching the flow of neuroinflammation. [] ¹⁹³

Apigenin, within LPS-induced PD rats, reduces striatal concentrations of TNF-α, IL-1β, IL-6, iNOS, and NO by downregulating the TLR4/NF-κB pathway with precision and simultaneously amplifying the Nrf2/HO-1 pathway's voice, thus dialing down neuroinflammation. [] ¹⁹⁴

In BV2 microglial cells from rotenone PD models, luteolin ascends by upregulating the Nrf2 pathway, clamping down on microglial activation. This strategic maneuver decreases IL-1β levels, quelling the storm of neuroinflammation. [] ¹⁹⁵

In the challenging environment of MPTP-induced PD mouse models, curcumin shines as a beacon of hope. Through the SIRT1/NRF2 pathway, it significantly lowers the concentrations of IL-1β, IL-6, IL-18, and TNF-α in the gut, combats intestinal cell pyroptosis-induced inflammation, and fosters a healthier gut microbiome. This sequence of actions fortifies the intestinal barrier, reduces transmissions along the GBA, and notably diminishes neuroinflammation. The culmination of these effects is the protection of vital dopaminergic neurons and the amelioration of motor dysfunctions in affected mice. [,] ^{196 197}

In MPTP PD mouse, resveratrol emerges as a powerful ally for the gut microbiome, enhancing its potential and bolstering the intestinal barrier's functionality.Remarkably, through the innovative approach of fecal microbiota transplantation, it corrects the imbalance within the gut microbiome, leading to a reduction in intestinal TNF-α, IL-6, and IL-1β levels. This strategy effectively curtails both intestinal and neuroinflammation through the GBA, offering a shield for dopaminergic neurons and mitigating motor dysfunctions. [] ¹⁹⁸ [] ¹⁹⁹

FLZ demonstrates its efficacy in rotenone-induced PD mice by rejuvenating the gut microbiome, alleviating intestinal dysfunction, and curtailing inflammation and permeability through the TLR4/MyD88/NF-κB pathway. It lowers the levels of IL-1β, IL-6, TNF-α, iNOS, and COX-2, thereby enhancing the BBB's integrity. By moderating neuroinflammation via the gut-brain axis, it safeguards dopaminergic neurons, rectifies the irregular gait, and boosts walking speed in PD mice. [] ²⁰⁰

Korean Red Ginseng, rich in ginsenosides, in MPTP PD mice, plays a critical role by decreasing intestinal TNF-α and IL-1β levels, soothing intestinal inflammation, and promoting the expression of tight junction proteins. This not only protects the intestinal barrier and lowers permeability but also guards intestinal dopaminergic neurons and curtails intestinal α-synuclein levels. Through the gut-brain axis, it extends its protective arm to SNpc dopaminergic neurons, thus repressing abnormal rotational behaviors. [] ²⁰¹

Diosgenin is a steroidal saponin extracted from Dioscorea.Diosgenin engages with the gut microbiome to regulate the synthesis of bile acids from cholesterol, which, in turn, influences the metabolic landscape of the gut microbiome.In MPTP-induced PD mice, diosgenin amplifies bile acid expression and, via the GLP-1 pathway mediated by bile acids, suppresses the intestinal NF-κB pathway. This leads to decreased IL-6, NOX2, and ICAM levels, reducing intestinal inflammation and, by extension, neuroinflammation via the gut-brain axis. This intricate interplay results in the protection of dopaminergic neurons and improvements in gait irregularities and walking speed. [] ²⁰² [,] ^{203 204} [] ²⁰⁵

In the context of the MPTP PD mouse, CPS enhances DAO and S-IGA levels, which are crucial for maintaining intestinal barrier integrity. By downregulating Emr1 expression via the GBA and inhibiting microglial activation, they effectively reduce TNF-α, IL-β, and IL-6 levels, suppressing neuroinflammation and protecting dopaminergic neurons, thus alleviating motor slowness. [] ²⁰⁶

Morin offers a multifaceted approach to combatting PD in rotenone-induced models. By alleviating colon mucosal epithelial cell necrosis, it preserves the intestinal barrier and reduces inflammation. Furthermore, it downregulates Iba-1 and GFAP expression, inhibits SNpc microglia and astrocyte activation, and mitigates neuroinflammation by suppressing the TLR4 signaling pathway. This comprehensive action protects dopaminergic neurons and ameliorates motor coordination and dysfunction. [] ²⁰⁷