Salix alba, its exceptional properties
From plant to aspirin
Salix Alba is a tree in the salicaceae family commonly known as white willow. It can reach 25 m in height and live for a hundred years. Its adult leaves are petiolate and very finely toothed, measuring 5 to 12 cm long (Figure 7). It is mainly found in the temperate regions of Europe, North Africa, the Middle East and the Far East (Laffont et al. 2007). It is mainly its bark that is used as a medicinal substance, due to its high salicin content (5 to 50%). Historically, willow bark has been used for over 2000 years. Originally used in Mediterranean regions including Egypt and Greece. But also in traditional Chinese and Ayurvedic medicine (Frawley et al. 2004). In his writings, Dioscorides mentions preparations based on this bark to fight joint pains (Dioscorides of Anazarbe 1555). Then the bark fell into oblivion for a few centuries, before reappearing to treat fevers in 1753, thanks to Edward Stone. " If the willow grows with its feet in water, it must be able to be used to treat diseases caused by humidity and cold, and therefore fevers " (Wick et al. 2012). As early as 1763 in England, the use of willow bark was described in medical treatises to treat pain and fever. It is recommended to relieve inflammatory joint pain: arthritis, headaches, tendonitis, menstrual pain and various symptoms related to fever (Laffont et al. 2007).
The 19th century was marked by the development of modern chemistry and pharmaceutical laboratories.
A Frenchman, Pierre-Joseph Leroux, isolated the active ingredient from willow bark: salicin, to which the pharmacological properties of the bark are attributed. It was German and Italian scientists who made it possible to develop salicylic acid, the future aspirin. The methods are complex and a way has yet to be found to dispense with willow bark to enable larger-scale manufacturing. This step was the work of Kolbe, who found a method for reacting phenol with carbon dioxide and ultimately obtaining salicylic acid (Laffont et al. 2007). Salicylic acid then becomes extremely popular for treating all kinds of pathologies. But its major drawback is to cause severe heartburn. In 1853, Charles-Frédéric Gerhardt, an Alsatian chemist, produced acetylsalicylic acid which was less aggressive for the stomach mucosa. Thirty years later, the story accelerated with the German laboratory Bayer, where the chemist Félix Hoffmann resumed and refined the research of his colleagues until he filed a patent: aspirin was born (Wick et al. 2012). Bayer mainly develops its production in the United States and France. During the 20th century, the precious medicine entered the pharmacies of every household, all over the world. Since then, the use of aspirin has notably extended to cardiovascular diseases. Today each year, 40,000 tons of aspirin are produced in the world (Laffont et al. 2007).
Chemical Constituents of Salix Alba Bark
If salicin is the major constituent of the bark, it is not the only one. Chromatography analyzes coupled with mass spectrometry revealed about ten other salicylated derivatives present. Such as salicortin, saligenin, isosalicin, picein, or salipurpuroside (Kammerer et al. 2005). Salicin and salicortin are the main salicylates. Once ingested, 80% of these active ingredients are assimilated during digestion (Steinegger et al.1972), then metabolized into glucose and salicylic alcohol. This salicylic alcohol is then broken down into salicylic acid by the liver (Julkunen-Tiitto et al. 1992). Nevertheless, the observed pharmacological effects cannot be attributed solely to salicin and salicylate derivatives (Nahrstedt et al. 2007). Several polyphenols and flavonoids have also been found in significant quantities in willow bark (Kammerer et al. 2005; Nahrstedt et al. 2007). Catechin, amelopsin and taxifolin are among the 16 active ingredients mainly found (Agnolet et al. 2012). These components are known for their highly antioxidant, antiseptic or immune system modulating properties (Shara et al. 2015). They thus participate in the pharmacological activity of the bark by combining with the effects of salicin and salicylates.
Anti-inflammatory properties of Salix Alba
In recent decades, many in vivo and in vitro studies have evaluated the effectiveness of willow bark's anti-inflammatory properties. The Bonaterra team compared the activity of human monocytes and macrophages stimulated by lipopolysaccharides in the presence of aspirin, Diclofenac and willow bark extract (Bonaterra et al. 2010). They conclude that the bark extract is effective by inhibiting pro-inflammatory cytokines, TNF-α, COX-2 and an action on the NF-κB pathway (Note 3). Other studies have confirmed these results. Freischmidt's team indicates that the results observed are not only related to the presence of salicin or salicylate derivatives, but also largely to catechin and other flavonoids (Freischmidt et al. 2012). In line with this statement, a study of an extract lacking salicin, but containing the other salicylates, showed activation of nuclear erythroid factor-2 sensitive to redox potentials. The extract then shows a strong antioxidant power. This confirms the importance of other compounds present in willow bark (Ishikado et al. 2013). The Shakibaei team conducted a study aimed at characterizing the anti-inflammatory mode of action of several plant extracts. With regard to willow bark, the extract inhibited the activation of NF-κB by interleukin-1β, this by opposing the degradation of the NF-κB-IκB complex and the phosphorylation of the p65 subunit. The expression of COX-2 and metalloproteases (MMP-9 and MMP-13) is then significantly reduced (Shakibaei et al. 2012).
In humans, the effectiveness of willow bark has been evaluated several times.
In 2009, Vlachojannis' analysis brought together several clinical studies evaluating the effectiveness of the bark in lower back pain (Vlachojannis et al. 2009). The analysis covered 415 patients in total and concluded that the plant was significantly effective compared to placebo. The doses then related to 240 mg of salicin per day, over a treatment period of two to six weeks. Biegert's study on 127 patients concluded that it was effective in rheumatoid arthritis for similar doses, the duration of a six-week treatment (Biegert et al. 2004). In each of these studies, no side effects were reported. In a longer study, involving six months and 436 patients with rheumatic pain, the authors are investigating the combination of willow bark with NSAIDs or opioids. They conclude that the combinations are well tolerated over the long term and that it is beneficial to combine the willow bark extract to increase the efficacy of the treatment (Uehleke et al. 2013). All of these data were analyzed by the European Medicines Agency which, in 2007, validated the therapeutic use of white willow bark for minor joint inflammatory pain. However, no details on the salicin content are given.
Serotonin modulating activity
Several studies have shown a correlation between increased pro-inflammatory markers and the onset of depression. Thus, interleukins-1 and 6, as well as C-reactive protein, are inflammatory markers frequently increased during depression (Ovaskainen et al. 2009; Milaneschi et al. 2009). Interleukin-6 was found in the cerebrospinal fluid of depressive patients at higher amounts than in the placebo group (Lindqvist et al. 2009). Based on these observations, Ulrich-Merzenich's team raised the question of a potential effect of white willow bark as an antidepressant (Ulrich-Merzenich et al. 2012). In rats, they then compared the effectiveness of several bark extracts with imipramine. They observe that the more the extract is rich in salicin, the closer the antidepressant effect of the plant is to that of imipramine. Secondly, in these same groups of animals, they observed an increase in the concentration of serotonin within the hippocampus and a decrease in its degradation product, 5-HIAA. The results observed are similar in all the groups and the HIAA/serotonin ratio decreases proportionally to the concentrations administered. Thus, willow bark could have a modulating action in the secretion of serotonin.
