Ligusticum chuanxiong (Chuan Xiong) is used extensively in Chinese medicine and passes through the BBB. Ligustrazine, Ligustilide, Senkyunolide I, Ferulic acid and Chuanxiongzine are all isolates from Chuan Xiong and some are available as IV delivery as well as oral. See below
Ligustrazine: Key Component of the Chinese Herb Chuanxiong
Chuanxiong is a frequently used Chinese herb, commonly called ligusticum or cnidium. The latter name is the term most often used in the ITM literature, adopted from the common name offered by Oriental Healing Arts Institute (OHAI) in publications 30 years ago. The herb has been obtained from Ligusticum chuanxiong (= Ligusticum wallichii) in China and from Cnidium officinale in Japan; the OHAI literature was heavily influenced by Japanese herb scholars. Recent evaluation of the genetic material of these two source materials has led to the suggestion that they are, in fact, the same plant, and that Cnidium officinale should be renamed as Ligusticum chuanxiong (1).
There are several active constituents in chuanxiong, but one of the most interesting is the alkaloid ligustrazine, which has the chemical name tetramethylpyrazine (because it is a pyrazine ring with four symmetrically placed methyl groups); it is sometimes simply called TMP. Isolated alkaloids from chuanxiong, and purified synthetic ligustrazine, have been used in China as medicinal agents for 30 years. The initial applications were based on traditional uses of the crude herb in decoctions and pills: for vitalizing blood circulation in the treatment of cardiovascular diseases and for treatment of headache and vertigo.
PYRAZINES IN NATURE AND IN FOOD
Methyl pyrazines are not uncommon in nature, and a typical source is maple syrup, which owes a significant part of its characteristic flavor-aside from sweetness-to a combination of methyl, dimethyl, and trimethyl pyrazines. In fact, trimethylpyrazine is used in making artificially flavored syrups that substitute for maple syrup. Pyrazines are produced in cheeses during heat treatment, with trimethylpyrazine as a major component; the flavor characteristic is said to be "chocolate" or "coffee" like. Dimethylpyrazine is used by the Chinese in food preparations; it has a "fried peanut, chocolate, butter, or potato-like flavor." Methylpyrazine is also used as a food additive, due to its aroma and odor which resembles "bread crust, nuts, popcorn, potato, and chocolate." The methyl and dimethyl pyrazines convey a roasted character to foods. Tetramethylpyrazine is used for its chocolate-like taste and fragrance. Pyrazines can be extracted from waste materials in production of coffee and chocolate. Pyrazines are considered safe to use in foods. The chocolate and maple-syrup like tastes are found in the Chinese chuanxiong rhizomes because of the presence of TMP. Chuanxiong is one of the most commonly used of the Chinese herbs; it has an excellent safety record and no evident toxicity.
LIGUSTRAZINE BY IV ADMINISTRATION
Ligustrazine is rapidly absorbed when taken orally, but it is also rapidly excreted in the urine. In order to maintain high blood levels, oral doses must be taken every few hours. Alternatively, ligustrazine can be given by IV drip over several hours to keep the blood levels high. Such administration is typical for hospitalized patients in China who have suffered heart attack or stroke and for treatment of serious childhood diseases (it is administered to infants who can not swallow herbal decoctions or pills). However, for most non-emergency uses, the IV form of administration is not convenient; further, it is not routinely available outside of China. Still, the IV use of this compound over the past three decades, both for adults and children, illustrates the lack of toxicity from TMP.
LIGUSTRAZINE BY ORAL ADMINISTRATION
Ligustrazine as a component of chuanxiong is only present in small amounts, perhaps 1%, so that a 9-12 gram quantity of the crude herb in decoction (as might be used in modern clinical practice in China) yields about 90 mg-120 mg of ligustrazine for a one-day dose. While this quantity may provide some benefits, contributing one active component to a complex mixture, it is not adequate to get the full benefit of ligustrazine that has been described in clinical and laboratory work with the isolated compound. Oral dosing of 100 mg or more each time, at least three times a day would be necessary to get sufficient blood levels for the desired effects.
To enhance the action of ligustrazine, even when given in adequate dosage, Chinese doctors often combine it with one or more herbs that have the related therapeutic action of vitalizing blood. The main herb used in combination with ligustrazine is salvia, either alone or with tang-kuei.
The applications of ligustrazine in China are many, and at first may appear quite diverse. However, upon examining the various applications, one can appreciate ligustrazine as providing a "protective effect." Following are brief reviews of a few of the uses of ligustrazine.
Renal failure and dialysis: Ligustrazine has been used to slow or halt the progress of renal failure in Chinese patients (2). Experimental studies have been conducted to demonstrate this effect in laboratory animals (3). One of the proposed mechanisms is the superoxide scavenging effect, one type of antioxidant action (4). Salvia has also been used to protect against renal failure (see ITM review: The use of salvia for patients with renal failure). Ligustrazine with salvia and tang-kuei have been used to aid patients undergoing renal dialysis (5). TMP is also used in conjunction with prednisone for patients with primary nephritic syndrome, which is said to function better than prednisone therapy alone (6). In the treatment of infants, ligustrazine was used to protect against the renal toxicity of gentamycin (7). Ferulic acid, possibly the primary active component of tang-kuei and one of the active components of chuanxiong, has shown benefits for treatment of patients with diabetic nephropathy (8).
Lung diseases with fibrosis: Ligustrazine is known to be a pulmonary vasodilator (9), but an area of particular interest is its action to protect against pulmonary fibrosis (10). Salvia and an active fraction of salvia (labeled IH764-3) have also been used for protection against pulmonary fibrosis (11-13), alone or with ligustrazine.
Neuroprotection for stroke: Chinese physicians have used chuanxiong and ligustrazine for treatment of stroke patients. Ligustrazine has been shown to have protective effects for the neurons, possibly based on anti-inflammatory activity (14-15). In clinical applications, ligustrazine in high dosage (480 mg/day) was found to lower fibrinogen and improve blood circulation in patients who suffered a stroke (16). Salvia is also known to confer neuroprotective effects in case of stroke (see review article: Neuroprotective herbs and active ingredients). Ferulic acid or its sodium salt (sodium ferulate) is used in Chinese medicine to treat stroke patients; in laboratory studies, it was shown to limit damage and help reactivation of impaired nerve cells (17).
In sum, ligustrazine alone or with salvia may provide protection to the kidneys, lungs, and brain through antioxidant and anti-inflammatory effects; these substances reduce fibrosis and improve blood circulation. The addition of tang-kuei, especially as a good source of ferulic acid (see structure, below), may further improve the effects.
1. Liu YP, et al., matK and its nucleotide sequencing of crude drug chuanxiong and phylogenetic relationship between their species from China and Japan, Journal of Crude Drug Studies 2002; 37(1): 63-68.
2. Tang X, Effect of ligustrazine on proliferative glomerulonephritis, Chinese Herbal Drugs 2003; 26(8): 611-612.
3. Cao WF, Li RH, and Chen BX, Status of experimental and clinical studies in retarding kidney damage of chronic nephropathy by ligustrazine, Chinese Journal of Integrated Chinese and Western Medicine 1997; 17(5): 314-315.
4. Liu CF, et al., Protective effect of tetramethylpyrazine on absolute ethanol-induced renal toxicity in mice, Journal of Biomedical Science 2002; 9(4): 299-302.
5. Li JC, Yang ZR, and Zhang K, The intervention effects of Angelica sinensis, Salvia miltiorrhiza and ligustrazine on peritoneal macrophages during peritoneal dialysis, Chinese Journal of Integrated Chinese and Western Medicine 1997; 22(3): 190-192.
6. Huang LC and Zhan F, Effects of tetramethylpyrazine and prednisone on 38 cases of nephritic syndrome, Chinese Journal of Integrated Traditional and Western Medicine 1998; 4(1): 51-52.
7. Yang DS and Ren XH, Observation on the protection by ligustrazine from renal toxicity of gentamycin, Chinese Journal of Integrated Chinese and Western Medicine 1994; 14(10): 621.
8. Zheng FM, Ren YZ, and Zhao TF, Preliminary clinical observation on effect of soduim ferulate in treating diabetic nephropathy, Chinese Journal of Integrated Chinese and Western Medicine 2005; 25(5): 419-421.
9. Oddoy A, et al, Effects of ligustrazine on the pressure/flow relationship in isolated perfused rat lungs, European Respiratory Journal 1991; 4: 1223-1227.
10. Dai L, Hou J, and Cai HR, Using ligustrazine and Angelica sinensis treat the bleomycin-induced pulmonary fibrosis in rats, Chinese journal of tuberculosis and respiratory diseases 1996; 19(1): 26-28.
11.Dai LJ, Hou J, and Cai HR, Experimental study on treatment of pulmonary fibrosis by Chinese drugs and integrative Chinese and Western medicine, Chinese Journal of Integrated Chinese and Western Medicine 2004; 24(2): 130-132.
12. Chen XY, Effects of Salviae miltiorrhizae, Ligustrazine, and hydrocortisone on the bleomycin-induced lung fibrosis in mice, Chinese journal of tuberculosis and respiratory diseases, 1987 Apr;10(3):152-4, 191, 12.
13. Liu J, et al., Experimental study of the effect of IH764-3 on pulmonary fibrosis, Chinese Medical Science Journal 1993; 8(1): 9-14.
14.Liao SL, et al., Tetramethylpyrazine reduces ischemic brain injury in rats, Neuroscience Letter 2004; 372 (1-2): 40-45.
15. Kao TK, et al., Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats, Neurochemistry International 2005;
16.Cai Y, Ren M, and Yang R, Observation on curative effect of acute ischemic cerebrovascular disease treated with different dosage of ligustrazine, Chinese Journal of Integrated Chinese and Western Medicine 2000; 20(10): 747-749.
17.Wang Q, Xiong LZ, Chen SY, Effect of sodium ferulate on activation of extracellular signal regulated kinase after cerebral ischemia/reperfusion injury in rats, Chinese Journal of Integrated Chinese and Western Medicine 2003; 23(12): 918-921.
Pharmacokinetics and metabolism of ligustilide, a major bioactive component in Rhizoma Chuanxiong, in the rat.
Yan R, Ko NL, Li SL, Tam YK, Lin G. Drug Metab Dispos. 2008 Feb;36(2):400-8. Epub 2007 Nov 26.
Ligustilide is the most abundant bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular ailments. The present study reported, for the first time, the pharmacokinetics of ligustilide, administered in its pure form and in an herbal extract, in rats. After i.v. administration of pure ligustilide, it was distributed extensively (V(d), 3.76 +/- 1.23 l/kg) and eliminated rapidly (t(1/2), 0.31 +/- 0.12 h). The i.v. clearance (CL) of ligustilide after Chuanxiong extract administration was significantly higher than that dosed in its pure form [CL, 20.35 +/- 3.05 versus 9.14 +/- 1.27 l/h/kg, p < 0.01; area under the curve (AUC), 0.79 +/- 0.10 versus 1.81 +/- 0.24 mg x h/l, p < 0.01], suggesting significant interaction between ligustilide and components present in the extract. Dose-dependent pharmacokinetics was observed after i.p. administration, and a significantly higher dose-normalized AUC (1.77 +/- 0.23 mg x h/l) at 52 mg/kg was obtained than that at 26 mg/kg (0.93 +/- 0.07 mg x h/l, p < 0.05).
Oral bioavailability of ligustilide was low (2.6%), which was partly because of extensive first-pass metabolism in the liver. Seven metabolites of ligustilide were identified, and three of them were unequivocally characterized as butylidenephthalide, senkyunolide I, and senkyunolide H. These three compounds also occurred naturally in the herb and were reported to be bioactive.
Pharmacokinetics, tissue distribution and metabolism of senkyunolide I, a major bioactive component in Ligusticum chuanxiong Hort. (Umbelliferae).
He CY, Wang S, Feng Y, Liang S, Lin X, Xu DS, Ruan KF. J Ethnopharmacol. 2012 Aug 1;142(3):706-13. doi: 10.1016/j.jep.2012.05.047. Epub 2012 Jun 2.
Ligusticum chuanxiong Hort. (Umbelliferae) is widely prescribed for treatment of cardiovascular diseases in China for centuries. One of the major bioactive components in L. chuanxiong is senkyunolide I (SEI), which shows pharmacological activities in anti-migraine and anti-oxidative damage.
The aim of this study was to investigate in vivo pharmacokinetics, tissue distribution and metabolism of SEI in rats. The concentrations of SEI in plasma and tissues were determined by a high performance liquid chromatography (HPLC) method, and the pharmacokinetic parameters were calculated using and non-compartmental analysis. The metabolites were identified using high performance liquid chromatography tandem mass (HPLC-ESI-MS/MS) method.
After oral and intravenous administration, SEI was quickly eliminated from plasma and its oral bioavailability (BA) was about 37.25%, which was smaller than intraportal BA (81.17%), but similar to intraduodenal BA (36.91%), suggesting that gastric first-pass effect of SEI is negligible, and hepatic first-pass effect was approximately 18.83%. After oral administration, SEI could penetrate blood brain barrier and extensively distribute in tested tissues, with the descending order of AUC being kidney, liver, lung, muscle, brain, heart, thymus, and spleen in rat. The parent compound and nine metabolites were found and identified in rat bile after oral administration of SEI (36 mg/kg). The metabolic mechanism of SEI in rat mainly involves methylation, glucuronidation and glutathione conjugation during the phase II biotransformation pathway in rats.
The information gained here may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines.
Ferulic Acid Reduces Cerebral Infarct Through Its Antioxidative and Anti-Inflammatory Effects Following Transient Focal Cerebral Ischemia in Rats
Cheng C-y, Ho T-Y, Lee E-J, et al. Am. J. Chin. Med. 36, 1105 (2008). DOI: 10.1142/S0192415X08006570
Both Angelica sinensis (Oliv.) Diels (AS) and Ligusticum chuanxiong Hort. (LC) have been used to treat stroke in traditional Chinese medicine for centuries. Ferulic acid (FA), a component in both AS and LC, plays a role in neuroprotection. The purpose of this study was to investigate the effects of FA on cerebral infarct and the involvement of neuroprotective pathway. Rats underwent 2 hours and 24 hours of reperfusion after 90 min middle cerebral artery occlusion (MCAo). The cerebral infarct and neurological deficits were measured after 24 hours of reperfusion. Furthermore, the expression of superoxide radicals, intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO), nuclear factor-κB (NF-κB) immunoreactive cells were assessed after 2 hours and 24 hours of reperfusion.
Administration of 80 and 100 mg/kg of FA at the beginning of MCAo significantly reduced cerebral infarct and neurological deficit-score, similar results were obtained by 100 mg/kg of FA administered 30 min after MCAo. FA treatment (100 mg/kg i.v.) effectively suppressed superoxide radicals in the parenchyma lesion, and ICAM-1 immunoreactive vessels in the ischemic striatum after 2 hours of reperfusion. FA (100 mg/kg i.v.) reduced the expression of ICAM-1 and NF-κB in the ischemic cortex and striatum, also down-regulated MPO immunoreactive cells in the ischemic cortex after 24 hours of reperfusion. These results showed that the effect of FA on reducing cerebral infarct area and neurological deficit-score were at least partially attributed to the inhibition of superoxide radicals, ICAM-1 and NF-κB expression in transient MCAo rats.