Salicylates, including salicylic acid (SA), methyl salicylate (MeSA), saligenin and
their respective glucosides, are natural products of plant metabolism that have been
known to possess medicinal properties since the 4th century B.C. (Sci. Am. 264:84-90,
1991). During the 19th century, these salicylates were identified and isolated from
plant extracts. Soon thereafter SA was chemically synthesized; it was subsequently
replaced by the synthetic derivative acetyl salicylic acid (aspirin), which produces
less gastro-intestinal irritation but appears to have similar therapeutic properties.
Aspirin is widely used as a non-steroidal anti-inflammatory drug and pain and fever
reliever. Additionally, its prophylactic use reduces the risk of heart attack, stroke,
and certain cancers. The primary action of salicylates in mammals is attributed to
disruption of eicosanoic acid metabolism (PNAS 90:11693-11697, 1993), thereby altering
the levels of prostaglandins and leukotrienes, through irreversible inhibition of
cyclooxygenase 1 and 2 (Cox1 and Cox2). Are these the only targets of aspirin and its
major metabolite in animals SA? Several facts suggest not. First, in contrast to aspirin,
SA is a poor inhibitor of cyclooxygenases, yet it still reduces pain, fever, and
inflammation. Second, in animals aspirin is rapidly converted into SA. SA is stable for
many hours. Third, for nearly 50 years before there was aspirin, SA was the major drug
used to reduce pain, fever, and inflammation. Fourth, even before there was man-made SA,
plants containing high levels of SA and related compounds were used by many different
cultures for thousands of years and are still used today to reduce pain, fever, and
inflammation.
Thus, we reasoned that there must be other targets, in addition to the cyclooxygenases,
through which SA/aspirin work and set out to identify them using the high-throughput
screens we developed to uncover SA targets in plants. To date we have identified at least
six novel SA targets, all of which are associated with one or more of most of the most
prevalent and devastating diseases, including cancer, atherosclerosis, arthritis,
inflammatory bowel disease, sepsis, diabetes, Parkinson's, and Alzheimer's. Natural SA
derivatives from medicinal plants and synthetic derivatives also have been discovered
that are 10 - 4000 times more potent than SA at inhibiting the disease-associated
activities of one or more of these newly revealed targets.
|
Table 1. Plant processes affected by exogenous application of salicylic acid |
| Process | Effect | Reference |
|---|
| Flowering | + | Cleland and Ajami (1974); Nanda et al. (1976); Goto (1981); Hew (1987); Lee and Skoog (1965) |
| Thermogenesis | + | Raskin et al. (1987) |
| Alternative respiratory pathway | + | Elthon et al. (1989) |
| Glycolysis | + | Raskin (1992) |
| Krebs cycle | + | Raskin (1992) |
| Wound response | - | Doherty et al. (1988) |
| Disease resistance | + | Cutt and Klessig (1992a) |
| Ethylene biosynthesis | - | Leslie and Romani (1988) |
| Potassium ion absorption | - | Harper and Balke (1981) |
| Transpiration | - | Larque-Saavedra (1979) |
| Stomatal closure | - | Rai et al. (1986) |
| Leaf abscission | - | Apte and Laloraya (1982) |
| Seed germination | - | Aberg (1981); Khan and Ungar (1986) |
| + | Cohn et al. (1989) |
| Growth inhibition | + | Kefeli and Kadyrov (1971) |
| Adventitious root initiation | + | King and Meyer (1983) |
| Fruit yield | + | Singh and Kaur (1980) |
| Somatic embryogenesis | - | Meijer and Brown (1988) |
| Photonastic leaflet movement | + | Saeedi et al. (1984) |
| Scotonastic leaflet movement | - | Saeedi et al. (1984) |
| | + induces or enhances; - reduces or inhibits. |
|
