y-Tocopherol, but Not a-Tocopherol, Improves Anti-Inflammatory; Decreases Adverse Effects of Aspirins

Nonsteriodal anti-inflammatory drugs (NSAIDs), including aspirin, are commonly used for pain relief, have consistently been shown to reduce the risk of cancers, and low-dose aspirin is effective in reducing cardiovascular disease risk because of its antithrombotic effect. However, the long-term use of aspirin and other NSAIDs has been hindered by their associated adverse effects, including upper gastrointestinal bleeding and ulcers.

NSAIDs (i.e., aspirin, acetaminophen, ibuprofen), while effective as agents for pain relief and cancer chemoprevention, frequently cause gastric mucosal injury. Aspirin causes gastrointestinal damage via its irreversible inhibition of the COX-1-mediated formation of gastric PGE2 (which is important for cytoprotection), and by increasing oxidative stress.

In a carrageenan-induced inflammation model in the rat (a model is known to mimic the pathological process occurring in joint diseases, which has been used to evaluate the anti-inflammatory efficacy of NSAIDs), researchers examined whether combinations of aspirin and α-tocopherol (33 mg/kg of αT) or γ-tocopherol (33 mg/kg γT), the two major forms of vitamin E, are better anti-inflammatory agents than aspirin alone (150 mg/kg), and whether these combinations alleviate aspirin-associated side effects.

Either aspirin alone or a combination of aspirin and γT inhibited pro-inflammatory prostaglandin E2 (PGE2) by 70% six hours after inflammation was initiated. However, at 18 hours, only the aspirin and γT combination decreased exudate volume (15%) and inhibited activity of PGE2 (40%) and lactate dehydrogenase (30%) in the fluid collected at the inflammation site.

γT, but not αT, also prevented aspirin-induced reduction in food intake, partially reversed aspirin-depressed gastric PGE2 and attenuated stomach lesions. Unlike the combination of aspirin+γT, aspirin alone or aspirin+αT caused prolonged depression of gastric PGE2. Not only did the combination of aspirin and αT (33 mg/kg) fail to produce any additional benefit compared to aspirin alone, the aspirin-αT combination worsened gastric injury and food intake reduction.

Why?

γ-tocopherol (γT), the predominant form of vitamin E in US diets, has unique bioactivities compared with αT. In both in vitro and animal studies, γT, but not αT, has demonstrated anti-inflammatory properties via its inhibition of COX-2-catalyzed proinflammatory PGE2. γT is more effective than αT in inhibiting lipid peroxidation and in scavenging electrophilic products of inflammation, such as peroxynitrite and other reactive nitrogen species. In addition, the metabolism of non-αT forms of vitamin E (e.g., γT) results in the production of long-chain carboxychromanols, which are potent COX inhibitors.

Previous studies investigating the potentially protective effect of αT supplementation on aspirin-induced damage have produced varied results, which may be explained by the fact that αT consistently fails to attenuate aspirin-induced stomach injury in animals with adequate vitamin E intake, but provides protection to vitamin E (αT)-deficient animals.

The surprisingly adverse effect of the addition of αT to aspirin in the current study is in line with the observation that individuals supplemented with αT and aspirin had increased gingival bleeding compared with individuals supplemented with aspirin alone, as observed in a controlled clinical trial, the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, which also showed that αT supplementation was associated with an increased risk of death due to hemorrhagic stroke, compared with placebo controls.

The combination of aspirin and γT may be superior to aspirin alone in the treatment of chronic inflammatory diseases and inflammation-associated disorders such as cancer due to prolonged anti-inflammatory action and protective effect against gastric injury, as well as the anticancer effect of γT itself. Because of the varied outcomes of aspirin+αT, however, caution should be taken in recommending this combination.

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