The treatment of addiction is a complex problem. Many compounds derived from traditional Chinese medicine have been proved to have good anti-addiction activity. THP completely inhibits the effects of methamphetamine (METH) in all stages of the conditional place preference (CPP) task (Su et al., 2013). From the perspective of neuropharmacology, THP can selectively activates key regions of the brain’s dopaminergic, serotonergic, and norepinephrine systems according to pharmacological magnetic resonance imaging (Liu et al., 2012). Additionally, THP can significantly inhibit morphine-induced CPP acquisition and expression in a dose-dependent manner (Jiang et al., 2020). Treatment with THP blocks the morphine-induced downregulation of dopamine D2 receptors (D₂R) and upregulation of GluA1 AMPA receptors in the prefrontal cortex, hippocampus (Hip), and striatum. THP inhibits dopamine-induced dopamine D1 receptor (D₁R) activity and dopamine autoreceptor activity (Wu et al., 2018; Ahn et al., 2020). These results suggest that the possible mechanism may be linked to antagonizing morphine-induced changes in brain dopamine and glutamate transmission. Furthermore, the mechanism by which THP improves METH-induced behavioral phenotype is regulating brain-derived neurotrophic factor pathway, 5-HT neuronal activity, and dopamine D3 receptor (D₃R) expression (Yun, 2014; Liu et al., 2021b). Meanwhile, THP combined with low-dose naltrexone (LDN) is used to treat cocaine relapse(Sushchyk et al., 2016). Combined treatment with THP and LDN can upregulate plasma β-endorphin and hypothalamic pro-opiomelanocortin. THP inhibits nicotine addiction by blocking neuronal α 4 β 2-nAChR functions and elevating extracellular dopamine levels in the nucleus accumbens shell, reducing nicotine intake and preventing relapse (Faison et al., 2016; Huang et al., 2021). The combination of L-THP and imperatorin (IMP) synergistically reduces EtOH-induced CPP, and the inhibition of inflammatory cytokines and the regulation of neurotransmitter receptor levels are the potential pharmacological mechanisms (Xu et al., 2021). Moreover, THP decreases ethanol drinking and the mechanism associated with D₂R-mediated PKA signaling in the caudate-putamen (CPu) (Kim et al., 2013). These results fully prove that the combination of THP and other drugs, such as LDN and IMP, can significantly increase its anti-addiction effect.

Although THP by itself does not induce CPP or conditioned position aversion, THP significantly reduces the high expression of METH-induced extracellular signal-regulated kinase (ERK) phosphorylation (Su et al., 2020). In addition, THP (20 mg/kg) inhibits the enhanced phosphorylation of ERK and cAMP-responsive element-binding proteins in CPu, nucleus accumbens (NAc), and prefrontal cortex (PFC), and Hip (Du et al., 2017; Du et al., 2021). THP improves METH-induced hyper-locomotor activity, locomotor sensitization, and concomitant ERK1/2 activation in the NAc and CPu (Zhao et al., 2014) and may prevent addiction through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms (Zhang Y. et al., 2018). Furthermore, THP reverses the impairment of spatial memory acquisition and retention (Cao et al., 2018), and the mechanism may be related to the expression of ERK1/2 in the PFC (Chen et al., 2012). METH self-administration was reduced when treated with THP at different doses (1.25, 2.50, and 5.00 mg/kg) (Gong et al., 2016). When THP was administered at 2.50 and 5.00 mg/kg, the METH-induced recovery of METH-seeking behavior was prevented. Interestingly, neither dose had an effect on locomotor activity (Yue et al., 2012; Cao et al., 2018). The effects of THP (3 mg/kg) on recovery may not be related to nonspecific motor impairment (Figueroa-Guzman et al., 2011). Collectively, these findings suggest that the anti-addiction effect of THP may be mainly related to the inhibition of METH in all stages of a CPP task, providing a basis for revealing the anti-addiction effect of THP.

In China, some traditional Chinese medicines (e.g., Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su and C.Y.Wu [Papaveraceae; Corydalis rhizoma]) containing THP are extensively used to treat pain. THP has an outstanding analgesic effect with different mechanisms and can decrease the abundance of protonated current mediated by acid-sensing ion channels (ASICs) in rat dorsal root ganglion (DRG) neurons, inhibit the functional activity of isolated primary sensory neuron ASICs, and relieve pain caused by acidosis (Liu et al., 2015). Mice that received an intraperitoneal injection at doses of 5 and 10 mg/kg showed increased mechanical threshold, thermal latency, and nonrapid eye movement sleep because THP had analgesic effects through D₁R agonist and D₂R antagonism (Liu YY. et al., 2019). Furthermore, THP can inhibit formalin-induced second-stage pain behavior through the sig-1R mechanism in the spinal cord (Kang et al., 2016). Moreover, THP can produce anti-hyperalgesia effects in a dose-dependent manner by intensifying dopaminergic transmission mediated by D₁R (Zhou et al., 2016). In addition, the analgesic effect of THP on bone cancer pain induced by tumor cell implantation was observed in rats. In fact, THP can prevent or reverse bone cancer-related pain behavior because it inhibits microglial activation and proinflammatory cytokine increase (Zhang et al., 2015; Liu et al., 2021a). A paw withdrawal threshold test showed that THP had a dose-dependent analgesic effect on oxaliplatin-induced neuropathic pain in mice and possessed a strong analgesic effect on neuropathic pain in mice (Guo et al., 2014). A bee venom test was used in determining the antinociception of THP in rats. Accordingly, THP may be more effective for supraspinal processed nociceptive behavior than spinally mediated nociceptive behavior (Cao et al., 2011). Pain relief is a major goal of medications for endometriosis. One study conducted surgery on a rat to induce endometriosis. THP significantly reduced the size of the injury and significantly improved response to heat-damaging stimuli. The treatment expressively reduced immune reactivity to all mediators involved in central sensitization, such as histone deacetylase 2 (HDAC2) in dorsal root ganglion (DRG) and tyrosine kinase receptor A (TrkA) and calcitonin gene-related peptide (CGRP) in ectopic endometrium (Zhao et al., 2011). In addition, treatment with THP can inhibit myometrium infiltration, alleviate systemic hyperalgesia, and reduce uterine contraction amplitude and irregularity (Mao et al., 2011). THP can significantly reduce the severity of experimental primary dysmenorrhea. When THP is utilized with imperatorin (IMP), the severity of experimental primary dysmenorrhea was alleviated more effectively than THP or IMP alone. Mechanisms may include reduction of oxidative stress, inhibition of excessive inflammatory response, and reduction of in vitro rat uterine contraction by inhibition of extracellular Ca²⁺ influx (Chen et al., 2013). THP is a potent ingredient that alleviates dysmenorrhea in women. Moreover, a combination of ligustrazine, ferulic acid, and THP suppresses epithelial-mesenchymal transformation by inactivating MMP/TIMP signaling and Wnt/beta-catenin pathway in endometriosis (Chen et al., 2018; Tan et al., 2021; Zhang et al., 2021). In summary, the analgesic effects of THP mainly include relief of neuropathic pain and pain induced by endometriosis. Figure 3 lists the potential analgesic targets and pathways of THP. It may act through several pathways, including the MMP/TIMP signaling and Wnt/β-catenin pathways. Notably, THP can be used in the treatment of bone cancer pain. However, further research is required to determine whether it can be used to alleviate pain caused by other cancer types.

Inflammation is involved in the progression and development of many clinical diseases, such as atherosclerosis, pneumonia, and hepatitis. Hence, anti-inflammatory drugs remain a major topic of interest. THP can alleviate neuropathic and inflammatory pain by downregulating P2X ligand-gated ion channel 3 (P2X3) receptors and transient receptor potential vanilloid 1 (TRPV1), which play a key role in the occurrence and maintenance of pain (Wang et al., 2021). The anti-inflammatory effect of THP on acute lung injury (ALI) induced by limb-ischemia/reperfusion (I/R) surgery was found in vivo (Wen et al., 2020). The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) is crucial to the regulation of cellular growth and metabolism. THP protects ALI, and possible mechanisms are associated with the inhibition of PI3K/Akt/mTOR phosphorylation (Zhang et al., 2015). THP can inhibit ERK/nuclear factor κB (NF-κB) signaling pathway and reduce hepatocyte apoptosis and autophagy (Yu et al., 2019). In RAW264.7 macrophages, THP decreases the expression of various proinflammatory cytokines (TNF-α, IL-1α, and IL-1β) in a dose-dependent manner possibly because of the inhibition of the NF-κB signaling pathway (Yodkeeree et al., 2018; Zhi L. et al., 2020). In a myocardial IR injury model, THP reduces inflammatory cytokines (TNF-a and MPO), which are associated with PI3K/Akt/eNOS/NO pathway activation (Han et al., 2012). In a mouse tumor-cell-implantation-induced pain model, THP decreases the levels of TNF-α and IL-18 but had no effect on IL-1β (Zhang et al., 2015). Moreover, THP reduces the release of inflammatory cytokines (IL-6 and TNF-α) and inhibits apoptosis and autophagy through the TRAF6/JNK pathway (Yu et al., 2018). Additionally, THP down-regulates the transcription and translation levels of vascular cell adhesion molecule-1 and the mRNA and protein levels of TNF receptor-associated factor-6, Toll-like receptor 4, and intercellular adhesion molecule-1 (Yang et al., 2015; Sun C. et al., 2018). In a mouse Japanese encephalitis virus (JEV) model, THP inhibited a decrease in proinflammatory cytokines (THF-α, MCP-1, IFN-γ, and IL-6) (Lixia et al., 2018). THP exerts a potential radio-protective effect on irradiation-induced lung injury (Yu et al., 2016). Given that THP not only reduces bronchoalveolar lavage fluid (BALF) cell recruitment but also reduces BALF protein levels. THP decreases the expression of monocyte chemotactic protein-1, NF-κB, and glial fibrillary acidic proteins (Qu et al., 2016; Wang et al., 2018). These results suggest that the anti-inflammatory effect of THP is closely related to the P2X3/TRPV1, TRAF6/JNK, PI3K/Akt/eNOS/NO, NF-κB, and ERK/NF-κB signaling pathways (Figure 4).

The effect of neuroprotective agents is to reduce the cell damage after ischemia, so as to prolong the time window of cerebral perfusion therapy and achieve the purpose of delaying the death of nerve cells and alleviating brain dysfunction. THP has a neuroprotective effect on neuronal apoptosis induced by brain I/R injury (Sun R. et al., 2018). THP can improve c-Abl expression and neuronal apoptosis. The number of viral populations; expression level of caspase-2; levels of reactive oxygen species, nitrogen, microglia, proinflammatory mediators, and stress-related protein molecules; and neuronal apoptosis decreased after the THP treatment of JEV (Lixia et al., 2018). THP can inhibit the delayed rectifier Kv1.5 channel expressed in HEK293 cells (HEK293 is a cell line derived from human embryonic kidney cells grown in tissue culture). This line was initiated by the transformation and culturing of normal HEK cells with sheared adenovirus 5 DNA (Li K. et al., 2017). The antinociceptive effect of THP is related to the modulation of spinal sigma-1 receptor (Sig-1R) activation (Kang et al., 2016). On D-galactose-induced memory impairment in rats, THP not only reverses the abnormal levels of acetylcholine and acetylcholinesterase activities related to several neuropsychiatric functions, such as learning, memory, and sleep. But also reduces the expression of NF-κB and glial fibrillary acidic protein (GFAP) (Qu et al., 2016). Activated NF-κB can increase the expression of inflammatory cytokines and astrocytes, thus causing memory impairment. Meanwhile, GFAP is a specific marker of astrocyte activation (Ali et al., 2015). Likewise, THP inhibits the functional activity of ASICs. In addition, THP can alter the membrane excitability of rat DRG neurons to acid stimulation and significantly reduce action potential and depolarization amplitude induced by extracellular pH drop (Liu et al., 2015), as shown in Figure 5. THP has potential anxiolytic-like and antidepressant effects and can inhibit a decrease in hypothalamic neuropeptide Y level. This effect is related to a predisposition to anxiety or stress-induced depression (Serova et al., 2013). THP can inhibit the increase in the expression level of the adrenocorticotropin-releasing factor in the hypothalamus. Important genes involved in serotonin, dopamine, acetylcholine, and gamma-aminobutyric acid neurotransmitter systems showed significant transcriptional folding changes in rodent models of post-traumatic stress disorder after the subcutaneous injection of THP (Ceremuga et al., 2013; Lee B. et al., 2014). Overall, these results suggest that THP has a good neuroprotective effect, including anti-memory damage, antidepression, and anti-anxiety effects. These neuroprotective effects may be realized through targets and pathways, such as inhibiting neuronal apoptosis, reducing the level of free radicals, regulating inflammatory factors and their pathways, and regulating neurotransmitters and related receptors.

Cancer is a serious threat to human health and quality of life and has high morbidity and mortality. To date, no miracle drug for cancer is available, and novel drugs for cancer treatment should be developed. A recent study confirmed that THP can treat glioblastoma multiforme by inhibiting the ERK/NF-κB cascade (Xue and Chen, 2021). THP is effective in treating melanoma by inhibiting the activity of CDK2, which is a unique target among the CDK family members in melanoma therapy (Tang and Chen, 2014). In ovarian cancer A2780/DDP cell line, THP can increase the sensitivity of ovarian cancer cells to cisplatin by regulating the miR-93/PTEN/AKT pathway (Gong et al., 2019). Moreover, THP alleviates kidney injury induced by cisplatin through the selective inhibition of organic cation transporter 2 (OCT2) but does not affect its antitumor effect (Li et al., 2020). THP can inhibit the uptake of oxaliplatin (OXA), which has severe peripheral neurotoxicity (Yi et al., 2021). In another report, p53 null leukemia EU-4 cells coped with THP, and the result showed that THP downregulated XIAP protein by inhibiting MDM2, which is a primary cellular inhibitor of p53 and a therapy target of cancer (Wang S. et al., 2017) and is associated with proteasome-dependent pathway; hence, THP result in p53-independent apoptosis and increased the sensitivity of EU-4 cells to doxorubicin (Li S. et al., 2017). In addition, THP increases the sensitivity of ER alpha (+) BCa cells to tamoxifen and fulvestrant, which are the inhibitors of antiestrogen and are applied to patients with ERα-positive breast cancer (Xia et al., 2020). In vitro, THP markedly restrains the proliferation of ER alpha (+) BCa cells by inducing cell cycle arrest rather than apoptosis. Nitidine chloride has anticancer activity. As an OCT2 inhibitor, THP can reduce its accumulation and toxicity in the kidney, and as OCT1 and OCT3 inhibitors, THP can reduce their accumulation and toxicity in the liver (Li et al., 2014; Li et al., 2016). These results suggest that THP can be used as a potential treatment compound for glioblastoma multiforme, melanoma, ovarian cancer, leukemia, and breast cancer and can attenuate cancer patients’ resistance to anticancer drugs, such as cisplatin, doxorubicin, fulvestrant, and tamoxifen. However, the underlying mechanism of THP in combination with other chemicals has not been fully elucidated and will be the focus of future research.

THP exerts hypotensive effects. The post-perfusion of THP (15 mg/kg/day) can reduce systolic blood pressure by decreasing diameter (Wang et al., 2018). The mechanism of the THP dilation of the rat aorta mainly involves the PI3K/Akt/eNOS/NO/cGMP signaling pathway and Ca²⁺ and K⁺ channels but not COX2, β-adrenergic receptor, and renin-angiotensin system (Zhou et al., 2019). Further, the activation of NO/cGMP signaling pathways results in the activation of an endothelium-dependent pathway (Qu et al., 2015). In addition, THP activates the K_ATP channel and plays a role in vascular relaxation, and promotes angiogenesis by regulating the sequence of citrulline-to-arginine flux, arginine biosynthesis, and VEGFR2 expression in endothelial cells (Cui et al., 2021), as shown in Figure 6. Furthermore, THP can inhibit osteoclast formation in a dose-dependent manner and has no cytotoxicity at a concentration lower than 19.00 μg/ml (Zhi X. et al., 2020). In vitro experiments, THP suppressed early osteoclast differentiation, downregulated the transcription level of osteoclast-related genes, and impaired the function of osteoclasts in bone marrow monocytes cells and mouse leukemic monocyte/macrophage cell line RAW264.7 cells. In vivo, THP significantly inhibits ovariectomy-induced bone loss and osteoclast formation in mice. It mineralizes nodule density and increases osteoblast proliferation (Wang et al., 2019).

THP can enhance MyoD activation through the upregulation of p38MAPK and Akt, which can promote premature muscle development (Lee SJ. et al., 2014). Accordingly, THP can serve as a potential drug for preventing fibrosis and promoting muscle regeneration and repair. The mechanism of THP in anti-adipogenic effect is that THP suppresses hepatic lipid accumulation and decreases the serum levels of serum cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as demonstrated in golden hamsters fed with a high-fat diet (Sun C. et al., 2018). In addition, THP inhibits lipid accumulation and decreases the level or activity of lipid droplets, triglyceride, and glycerol-3-phosphate dehydrogenase in 3T3-L1 adipocytes through the AMPK signaling pathway (Piao et al., 2017). THP inhibits extracellular matrix (ECM) deposition and hepatic stellate cells (HSCs) autophagy by regulating the PPAR gamma/NF-κB and TGF-beta 1/Smad pathways, thereby reducing liver fibrosis, which is a necessary stage in the progression of chronic liver disease to cirrhosis (Yu et al., 2021) (Figure 7). Other studies demonstrated that THP has a certain resistance to plasmodium(Baghdikian et al., 2013; Bory et al., 2013; Malebo et al., 2013), parasites (Dutta et al., 2016), and pathogenic fungi (Zhao et al., 2019).

Studies used THP or corydalis with caution in patients with heart diseases because of its potential cardiac and neurotoxic effects (Chan et al., 1999). A randomized, placebo-controlled, and double-blind clinical study assessed the safety of THP for cocaine users. The results showed that a short 3.5-days course of THP was well tolerated and safe and did not affect the pharmacokinetics of cocaine or its acute cardiovascular effects (Hassan et al., 2017). The liver toxicity of THP in mice revealed that THP suppressed the expression of CYP1A2, and no obvious pathological changes were observed in liver tissues after THP administration (Wang D. et al., 2017). Some reports mentioned the toxicity of THP as a natural substance but did not study it in depth(Wu H. et al., 2013; Zeng et al., 2015). Although THP has proven to be a promising compound with a variety of pharmacological actions, it also has some disadvantages, such as poor intestinal absorption, rapid clearance, and some potential toxicity. To further clarify its pharmacokinetic and toxicological characteristics, we used ADMETlab 2.0 (Xiong et al., 2021) to predict the ADMET of THP. The ADMET characteristics of THP are shown in Figure 8. The results indicated that THP is toxic at concentrations above the maximum recommended daily dose by the FDA and potentially toxic to the respiratory system. In conclusion, experimental evaluation of THP toxicity is limited, especially in terms of the cytotoxicity, long-term toxicity, and acute toxicity of THP.