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• Aconite extract oralled which was based on the migraine model, because of that, a dual model was created. • The pharmacokinetic effects containg tetramethylpyrazine and ferulic acid on GAS of gastrodia elata was studied. • The blood-brain microdialysis method was used to study the pharmacokinetics of constituents of traditional Chinese medicine. Gastrodia elata and Ligusticum chuanxiong are used to treat primary headaches for many years. Gastrodin (GAS) and tetramethylpyrazine (TMP)/ferulic acid (FA) are the main active ingredients of Gastrodia elata and Ligusticum chuanxiong, respectively. Previous studies demonstrated the pharmacokinetics of GAS, TMP, and FA in the blood and brain interstitial fluids (BIF) in healthy animals but not in animal model with liver–yang hyperactivity migraine. Hence, this study examined the pharmacokinetics of GAS after its oral administration in the presence of different concentrations of TMP and FA in animals with liver–yang migraine hyperactivity. In the control group, GAS was administrated without TMP and FA. Pharmacokinetic parameters were determined using the blood-brain microdialysis in combination with the high-performance liquid chromatography method. Results revealed that the maximum drug concentrations (C max) in the serum, area under curve (AUC), and mean residence time (MRT) of GAS decreased in normal animals, whereas C max increased significantly in model animals. These findings indicate that varying concentrations of TMP and FA play an important role in the pharmacokinetics of GAS in both normal and migraine model animals, validating the utility of the ancient formulation. [ABSTRACT FROM AUTHOR]

• Cold stimulate vasoconstriction which was based on the migraine model, because of that, a dual model was created. • The pharmacokinetic effects containing Gastrodin and Gastrodigenin on TMP and FA of Ligusticum chuanxiong was studied.. • The PK of active constituents of traditional Chinese medicine was studied by blood-brain microdialysis method. Tianma pills, a traditional formula made from Ligusticum chuanxiong and Gastrodia elata , are efficacious for the treatment of primary headache. Tetramethylpyrazine (TMP) and Ferulic acid (FA) are the bioactive ingredients of Ligusticum chuanxiong , while Gastrodin and Gastrodigenin are the bioactive ingredients of Gastrodia elata. Pharmacokinetic assessment of TMP, FA, gastrodin or gastrodigenin in blood or brain interstitial fluid (BIF) has been reported in healthy animals. However, the pharmacokinetic properties of TMP and FA have not been studied when they are co–administered in a blood–stasis migraine model. The present research investigated the pharmacokinetic behavior of TMP and FA after oral administration in the presence of different concentrations of gastrodin and gastrodigenin in a blood–stasis migraine model. Pharmacokinetic parameters were determined using blood–brain microdialysis in combination with the UHPLC–MS method. Compared to the control group, in which TMP and FA were administrated without gastrodin or gastrodigenin, the T 1/2 , MRT, C max and AUC 0–∞ of TMP and FA were increased. These results indicate that varying concentrations of gastrodin and gastrodigenin play an important role in affecting the pharmacokinetics of TMP and FA. Low concentrations of gastrodin and gastrodigenin (similar to those found in Tianma pills) were more efficacious, validating the utility of the ancient formulation. [ABSTRACT FROM AUTHOR]

According to the basic theories of traditional Chinese medicine, Gastrodia elata (GE) is clinically utilized for the treatment of cephalalgia and migraine. The gastrodigenin (p –hydroxybenzyl alcohol, HBA), one of the effective components of GE , may pass through the blood–brain barrier (BBB) to exert its pharmacological effects. This study aimed to investigate BBB permeability of HBA via in vitro hCMEC/D3 BBB model and in vivo microdialysis in rats. For the establishment of in vitro BBB model, hCMEC/D3 cells were used to construct the monolayer. The integrity of the monolayer was evaluated by TEER measurements, expression analysis of tight junction proteins (claudin-5, zo-1 and occludin) and apparent permeability coefficients (P app) of fluorescein disodium. During the 6-day incubation of hCMEC/D3 cells, the values of TEER gradually increased and maintained above 100 Ω·cm2. Besides, the expression levels of claudin-5 and zo-1 in hCMEC/D3 cells increased over time, and tended to be stable, suggesting that integrity of the monolayer has been completely established. Moreover, the P app of fluorescein disodium was 3.94 × 10−7 cm·s−1 after administration for 180 min, indicating that the monolayer retains the characteristics of BBB and can restrict the diffusion of hydrophilic small-molecule compounds. A sensitive HPLC method was established for HBA detection, and the transport rate of HBA was assessed by a transwell system. HBA crossed the hCMEC/D3 BBB model rapidly, but a plateau was observed when HBA concentrations were relatively similar between the two sides of transwell. Permeability assay revealed that 32.91% of HBA could penetrate the in vitro BBB model after 240 min of administration. In vivo BBB permeability was evaluated by determining the concentrations of HBA in blood and brain simultaneously. Following HBA administration, the samples of microdialysis were collected at 20, 40 and 60 min, and then every 30 min until the procedure ended. Pharmacokinetic parameters of HBA showed that HBA could pass through BBB and reach its maximum concentration at 40 min in blood and brain tissue. Furthermore, AUC 0–t and AUC 0–inf for the brain–to–blood distribution ratio of HBA were 0.1925 and 0.2083, respectively, indicating that approximately 20% of HBA in blood could pass through the BBB and subsequently transported into the brain. Both in vitro and in vivo experiments confirmed that HBA could penetrate the BBB. In summary, the findings of this study highlight that a promising amount of HBA in blood can pass through the BBB and exerts its pharmacological effects on central nervous system (CNS) diseases. Unlabelled Image [ABSTRACT FROM AUTHOR]

Longdan zhike tablet (LDZK) is a Tibetan medicine formula commonly used in the highland region of Tibet, China, to ameliorate respiratory diseases, such as acute bronchitis and asthma. In Chinese traditional medicine, some herbal formulas with anti-inflammatory properties targeting the respiratory system are clinically adopted as supplementary therapies for chronic obstructive pulmonary disease (COPD). However, the specific anti-COPD effects of LDZK remain to be evaluated. The aim of this study is to identify the principal bioactive compounds in LDZK, and elucidate the effects and mechanisms of the LDZK on COPD. High-resolution mass spectrometry was utilized for a comprehensive characterization of the chemical composition of LDZK. The therapeutic effects of LDZK were assessed on the LPS-papain-induced COPD mouse model, and LPS-induced activation model of A549 cells. The safety of LDZK was evaluated by orally administering a single dose of 30 g/kg to rats and monitoring physiological and biochemical indicators after a 14-day period. Network pharmacology and Western blot analysis were employed for mechanism prediction of LDZK. A comprehensive analysis identified a total of 45 compounds as the major constituents of LDZK. Oral administration of LDZK resulted in notable ameliorative effects in respiratory function, accompanied by reduced inflammatory cell counts and cytokine levels in the lungs of COPD mice. Acute toxicity tests demonstrated a favorable safety profile at a dose equivalent to 292 times the clinically prescribed dose. In vitro studies revealed that LDZK exhibited protective effects on A549 cells by mitigating LPS-induced cellular damage, reducing the release of NO, and downregulating the expression of iNOS, COX2, IL-1β, IL-6, and TNF-α. Network pharmacology and Western blot analysis indicated that LDZK primarily modulated the MAPK signaling pathway and inhibited the phosphorylation of p38/ERK/JNK. LDZK exerts significant therapeutic effects on COPD through the regulation of the MAPK pathway, suggesting its potential as a promising adjunctive therapy for the treatment of chronic inflammation in COPD. [Display omitted] • Longdan zhike tablet (LDZK) is effective for chronic obstructive pulmonary disease (COPD). • LDZK improves lung injury, respiratory function, and inflammation in COPD mice. • LDZK exhibits excellent clinical safety profile in medication. • LDZK inhibits COPD progression via MAPK pathway. [ABSTRACT FROM AUTHOR]