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Ligusticum wallichii is a flowering plant in the carrot family best known for its use in traditional Chinese medicine where it is considered one of the 50 fundamental herbs.[1] It is known by the common names chuānxiōng (川芎) and Szechuan lovage. Biologically active compounds in the plant include tetramethylpyrazine. It is native to India and Nepal.

1: Microvasc Res. 2002 Mar;63(2):218-26. Links
Studies on single-cell adhesion probability between lymphocytes and endothelial cells with micropipette technique.Zhao H, Dong X, Wang X, Li X, Zhuang F, Stoltz JF, Lou J.
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, 100029, China.

An in vitro model with micropipette technique was used to investigate single-cell adhesion probability between lymphocytes and endothelial cells. The basal adhesion probability between lymphocytes and endothelial cells was low and was significantly increased when either lymphocytes were activated by phytohemagglutinin (PHA) or endothelial cells were stimulated by tumor necrosis factor. The adhesion probability of lymphocytes to human umbilical vein endothelial cells was similar to that of lymphocytes to human brain microvascular endothelial cells (HB-MVEC). However, lymphocyte adhesion probability was higher in HB-MVEC than in mouse brain microvascular endothelial cells (MB-MVEC) under both resting and activated conditions. Furthermore, lymphocytes preincubated with monoclonal antibodies to lymphocyte function-associated antigen-1 (LFA-1) or HB-MVEC preincubated with monoclonal antibodies to intercellular adhesion molecule 1 (ICAM-1) significantly down-regulated the adhesion probability between lymphocytes and endothelial cells, indicating that the adhesion probability is related to the expression of LFA-1 on lymphocytes and to the expression of ICAM-1 on endothelial cells. Lymphocytes isolated from patients with cerebral stroke exhibited increased adhesion probability to HB-MVEC as compared with lymphocytes from healthy donors. Preincubation of lymphocytes with tetramethylpyrazine (TMP), an extract from a Chinese traditional herb, effectively inhibited the adhesion probability to HB-MVEC, suggesting that TMP has a potential therapeutic value. These results indicate that the micropipette technique is a useful model for investigating single-cell adhesion probability between lymphocytes and endothelial cells in vitro.

PMID: 11866545 [PubMed - indexed for MEDLINE]

Background
Tetramethylpyrazine (TMP) is one of the most important active ingredients of a Chinese herb Ligusticum wallichii Franchat, which is widely used in many ischemia disorders treatments. However, the exact mechanism by which TMP protects the spinal cord ischemia/reperfusion (I/R) injury is still unknown. For this purpose, rabbits were randomly divided into sham group, control group and TMP group. After the evaluation of neurologic function, the spinal cords were immediately removed for biochemical and histopathological analysis. Apoptosis was measured quantitatively by the terminal transferase UTP nick end-labeling (TUNEL) method and confirmed by electron microscopic examination, the expression of Bax and Bcl-2 was immunohistochemically evaluated and quantified by Western blot analysis.

Results
Neurologic outcomes in the TMP-group were significantly better than those in the control group (P < 0.05). TMP decreased spinal cord malondialdehyde (MDA) levels and ameliorated the down regulation of spinal cord superoxide dismutase (SOD) activity. TMP significantly reduced the loss of motoneurons and TUNEL-positive rate. Greater Bcl-2 and attenuated Bax expression was found in the TMP treating rabbits.

Conclusion
These findings suggest that TMP has protective effects against spinal cord I/R injury by reducing apoptosis through regulating Bcl-2 and Bax expression.

: Phytochemistry. 2007 Apr;68(8):1179-88. Epub 2007 Mar 28. Links
Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery.Xu YC, Leung SW, Yeung DK, Hu LH, Chen GH, Che CM, Man RY.
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong Pokfulam Road, Hong Kong SAR, PR China.

Flavonoids are polyphenolic compounds that are widespread in the plant kingdom, and structure-activity relationships (SAR) for vascular relaxation effects were examined for 17 of them using porcine coronary arteries. Density functional theory was employed to calculate the chemical parameters of these compounds. The order of potency for vascular relaxation was as follows: flavones (apigenin and luteolin) >or= flavonols (kaempferol and quercetin)>isoflavones (genistein and daidzein)>flavanon(ol)es (naringenin)>chalcones (phloretin)>anthocyanidins (pelargonidin)>flavan(ol)es ((+)-catechin and (-)-epicatechin). SAR analysis revealed that for good relaxation activity, the 5-OH, 7-OH, 4'-OH, C2=C3 and C4=O functionalities were essential. Comparison of rutin with quercetin, genistin with genistein, and puerarin with daidzein demonstrated that the presence of a glycosylation group greatly reduced relaxation effect. Total energy and molecular volume were also predictive of their relaxation activities. Our findings indicated that the most effective relaxing agents are apigenin, luteolin, kaempferol and genistein. These flavonoids possess the key chemical structures demonstrated in our SAR analysis.

PMID: 17395220 [PubMed - indexed for MEDLINE]

1: Clin Appl Thromb Hemost. 2006 Apr;12(2):205-12. Links
Comparison of Pycnogenol and Daflon in treating chronic venous insufficiency: a prospective, controlled study.Cesarone MR, Belcaro G, Rohdewald P, Pellegrini L, Ledda A, Vinciguerra G, Ricci A, Gizzi G, Ippolito E, Fano F, Dugall M, Acerbi G, Cacchio M, Di Renzo A, Hosoi M, Stuard S, Corsi M.
Irvine2 Vascular Lab and Physiology, Department of Biomedical Sciences, G D'Annunzio, Chieti-Pescara University, San Valentino Vascular Screening Project, Faculty of Motory Sciences, L'Aquila University, Italy.

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol (Horphag Research Ltd., UK) in patients with severe chronic venous insufficiency (CVI) in comparison to the combination of diosmin and hesperidin (Daflon, Servier, France). A group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling) and previous history of venous ulcerations received either oral Pycnogenol (capsules) 150 mg or 300 mg daily for 8 weeks or Daflon, 1,000 mg/day. All patients completed the study without dropouts. At the end of the study, microcirculatory results indicated: a progressive decrease of skin flux at rest (RF); a significant decrease in capillary filtration (RAS); an improvement in the symptomatic venous score (ASLS); a reduction in edema; a significant improvement (increase) in pO(2) and a decrease in pCO(2) in the Pycnogenol group. A significant level of improvement was reached after 4 weeks of treatment in most patients (p < .05) of the Pycnogenol group while clinical improvement was significant only in 6 subjects in the Daflon group. The positive effects of treatment with Pycnogenol after 8 weeks were significantly larger in comparison with the Daflon group. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy and its superiority-considering the evaluated parameters-to the combination of diosmin and hesperidin.

PMID: 16708123 [PubMed - indexed for MEDLINE]

Angiology. 2008 Jun-Jul;59(3):385.
Rapid relief of signs/symptoms in chronic venous microangiopathy with pycnogenol: a prospective, controlled study.Cesarone MR, Belcaro G, Rohdewald P, Pellegrini L, Ledda A, Vinciguerra G, Ricci A, Gizzi G, Ippolito E, Fano F, Dugall M, Acerbi G, Cacchio M, Di Renzo A, Hosoi M, Stuard S, Corsi M.
Irvine2 Vascular Lab and Physiology, Department of Biomedical Sciences, G 'Annunzio, Chieti-Pescara University, San Valentino Vascular Screening Project, Faculty of Motory Sciences, L'Aquila University, Italy.

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol (Horphag Research Ltd, UK) in patients with severe chronic venous insufficiency. Patients with severe venous hypertension (chronic venous insufficiency, ankle swelling) and history of venous ulcerations were treated with Pycnogenol. Patients received oral Pycnogenol (50 mg capsules, 3 times daily for a total of 150 mg daily) for 8 weeks. A group of 21 patients was included in the treatment group and 18 equivalent patients were observed as controls (no treatment during the observation period). All 21 patients (age 53 years; range, 42-60 years; M:F=11:10) in the treatment group completed the 8-week study. Also the 18 controls completed the follow-up period. There were no drop-outs. The average ambulatory venous pressure was 59.3 (SD 7.2; range 50-68) with a refilling time shorter than 10 seconds (average 7.6; SD 3). There were no differences in ambulatory venous pressure or refilling time between the treatment and control patients. The duration of the disease-from the first signs/symptoms-was on average 5.7 years (SD 2.1). At 4 and 8 weeks, in all Pycnogenol-treated subjects, microcirculatory and clinical evaluations indicated a progressive decrease in skin flux, indicating an improvement in the level of microangiopathy; a significant decrease in capillary filtration; a significant improvement in the symptomatic score; and a reduction in edema. There were no visible effects in controls. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy. The study indicates the significant clinical role of Pycnogenol in the management, treatment and control of this common clinical problem. The treatment may be also useful to prevent ulcerations by controlling the level of venous microangiopathy.

PMID: 17067979 [PubMed - indexed for MEDLINE]

1: J Cardiovasc Pharmacol. 1998 Oct;32(4):509-15. Links
Endothelium-dependent vascular effects of Pycnogenol.Fitzpatrick DF, Bing B, Rohdewald P.
Department of Pharmacology, University of South Florida, Tampa 33612, USA.

Pycnogenol (P) is purported to exhibit effects that could be beneficial in terms of prevention of chronic age-related diseases such as atherosclerosis. The most studied of these effects is its antioxidant/free radical-scavenging activity. In this study, we investigated the possibility that this supplement might produce vascular effects by stimulation of nitric oxide (NO) production by vascular endothelial cells. In the in vitro experiments, P (1-10 microg/ml) relaxed epinephrine (E)-, norepinephrine (NE)-, and phenylephrine (PE)-contracted intact rat aortic ring preparations in a concentration-dependent manner. However, when the endothelial lining of the aortic ring was removed, P had no effect, indicating an endothelium-dependent relaxing (EDR) effect. This EDR response was caused by enhanced NO levels, because the NO synthase (NOS) inhibitor N-methyl-L-arginine (NMA) reversed (or prevented) the relaxation, and this response, in turn, was reversed by addition of L-arginine, the normal substrate for NOS. Pycnogenol-induced EDR persisted after exposure of intact rings to high levels of superoxide dismutase (SOD), suggesting that the mechanism of EDR did not involve scavenging of superoxide anion. In addition to causing relaxation, preincubation of aortic rings with P (1-10 microg/ml) inhibited subsequent E- and NE-induced contractions in a concentration-dependent manner. Fractionation of P by Sephadex LH-20 chromatography resulted in three fractions, one of which (fraction 3, oligomeric procyanidins) exhibited potent EDR activity. These results indicate that P, in addition to its antioxidant activity, stimulates constitutive endothelial NOS (eNOS) activity to increase NO levels, which could counteract the vasoconstrictor effects of E and NE. Furthermore, additional protective effects could result from the well-established properties of NO to decrease platelet aggregation and adhesion, as well as to inhibit low-density lipoprotein (LDL) cholesterol oxidation, all of which could protect against atherogenesis and thrombus formation.

PMID: 9781917 [PubMed - indexed for MEDLINE]