**5.2 Plants**

While salicylic acid (initially from plant sources) has been used in therapeutics for millennia detailed knowledge of its role in plants is relatively recent. Although plant phenolics are diverse and ubiquitous they were traditionally assumed to be unimportant secondary metabolites but SA in plants is a critical hormone playing a direct role in the regulation of many aspects of growth and development as well as

in thermogenesis and disease resistance [37]. The first clear evidence came, intriguingly (in relation to its antipyretic qualities in animals), from its role in voodoo lily thermogenesis; that appears to be mediated by stimulation of the mitochondrial alternative respiratory pathway [38]. Soon thereafter its role as a defence signalling hormone was documented—though the ability of plants to develop acquired immunity after pathogen infection was first proposed many years earlier. In the acquired immunity—called "systemic acquired resistance" (SAR)—of plants to biotrophic (i.e. threatening living cells) pathogens, the role of SA is pivotal. Careful study has identified two pathways for its synthesis, numerous proteins that regulate its synthesis and metabolism and some signalling components, including a large number of potential targets/receptors, which operate downstream of SA [39]. This is a perplexing field; for example while the non-specialist can readily appreciate methylation of SA to a volatile ester for transport through the phloem (before demethylation at a site where SA levels are low) subsequent steps are complex. As these authors point out it is increasingly evident that SA does not signal immune response by itself but as part of an intricate network of other plant hormones. We would highlight, from the viewpoint of the present review, their suggestion that it is important to differentiate SA "targets" from the subset (whose criteria, they concede, will be difficult to specify) that meet additional conditions to be designated "receptors" [40]. That idea is particularly relevant when later considering the propensity of aspirin to acetylate many animal protein "receptors"—see Section 5.3.4.

in a unitary and coherent way, the multiple pharmacological actions of ASA. The ester prevailed—particularly as SA itself had no significant anti-COX-1 effect on

This emphasis arose from the apparent efficacy, in cancer chemo-protection, of

There is a trend to describe non-COX, indeed increasingly non-platelet, effects

a. It is generally accepted that although SA is a much weaker inhibitor of COX activity in vitro their anti-inflammatory effects in vivo are comparable [3].

(almost certainly total salicylates were determined) through the blood/brain barrier is slow and incomplete [42]. That observation is particularly relevant

c. ASA's antipyretic effect was first validated centuries ago using plant extracts;

d. There is a clear dose/response relationship between the analgesic effect of ASA up to a dose of 1.2 g [45] compared with the plateau above 100 mg/day for the effect on platelets and its efficacy in chemoprevention of colorectal

The eminent facility for ASA to acetylate proteins has been known for decades and proteomic studies—*see above*—have shown its very marked extent. While the functional relationship between such activity and its effects are unclear the blockade of glucose6phosphate dehydrogenase (G6PD), affecting the pentose phosphate

pathway, and disruption of mitochondrial respiration may explain platelet autophagy [41]. Clearly, as for SA in plants, caution is required in the strict

b. ASA has a very short serum half-life compared with SA [2]; its passage

it is mainly due to inhibition of COX-2 in the hypothalamus [44].

to the oft forgotten central action of salicylates [43].

of ASA as "non-canonical". That tag appears to include almost all actions not demonstrably due to COX acetylation with the possible exception of inhibition of

ASA at the low doses (70–100 mg/day) used to inhibit platelet aggregation. Irreversible inhibition of COX-1 in the circulating anucleate platelets ensures that thromboxane A2 formation is prevented throughout their lifespan without, at these doses, suppressing the production of prostacyclin (PGI2) which mediates platelet inhibition and vasodilatation. While that is the principle effect required in vascular disease platelet activation also triggers a host of processes leading to leucocyte recruitment into various tissues and subsequent phenotypic changes in stromal cells contributing to atherosclerosis, intestinal inflammation and cancer as well as atherothrombosis [41]. That review also encompasses the non-COX effects of the widespread acetylation of other proteins by ASA—quoting one study which revealed over 12,000 ASA-mediated acetylations in over 3700 proteins!

*5.3.3 Do earlier accepted effects of ASA and SA still hold?*

We should, however, remind ourselves that

platelets.

*5.3.2 Platelet effects predominant?*

*Salicylic Acid Sans Aspirin in Animals and Man DOI: http://dx.doi.org/10.5772/intechopen.91706*

COX-2 gene transcription [4].

adenomas [46].

definition of ASA receptors [39, 40].

*5.3.4 ASA "receptors"*

**187**

The wide range of basal SA levels between and within plant species, and potential for a biphasic/concentration dependent response may explain some conflicting reports on the spectrum of plant processes it influences. Despite these caveats the long list affected by exogenous SA includes resistance to biotic (pathogen-associated) stress and tolerance to many abiotic stresses (drought, chilling, heat, metal, UV radiation, and salinity/osmotic stress) as well as multiple aspects of plant growth and development. These include photosynthesis, senescence, thermogenesis, respiration, glycolysis, the Krebs cycle and the alternative respiratory pathway [40].

#### **5.3 Salicylic acid and aspirin (ASA) in animals and man**

Although the use of willow extracts had been known for centuries the report of its first well documented use—as a cheaper remedy for "the agues" than expensive cinchona bark—focused on its antipyretic properties. Then, particularly in the decades following the isolation of SA as the active principle, evidence steadily accrued for its efficacy as an analgesic and anti-inflammatory in e.g. acute rheumatic fever.

#### *5.3.1 After the discovery of aspirin*

Following Hoffman's synthesis of the apparently better tolerated ester in 1897 use of that compound prevailed. ASA was the prototype non-steroidal antiinflammatory drug (NSAID); it seems that term arose from a need to distinguish it from the undesirable effects of synthetic steroids. As a prodrug for a long recognised active agent its mode of action was naturally linked to the effects of SA.

It was not until the 1960s that work by Vane and Piper led to the proposal of a single mode of action of ASA in the inhibition of prostaglandin synthesis. The resulting paradigm-shifting series of experiments led to the discovery that inhibition of constitutive COX-1 and of COX-2 (predominantly inducible) by serine sidechain acetylation altered levels of prostaglandins and leukotrienes. This revelation came at a time when the potency of ASA as an inhibitor of platelet aggregation in the treatment of vascular disease was coming to the fore. So Vane's work explained, in a unitary and coherent way, the multiple pharmacological actions of ASA. The ester prevailed—particularly as SA itself had no significant anti-COX-1 effect on platelets.
