Potential role of curcumin in stroke prevention

The cause for a majority of ischemic strokes can be attributed to an underlying atherosclerotic disease process. Longitudinal epidemiologic studies have associated several risk factors with the initiation and progression of symptomatic atherosclerosis including hypertension, diabetes mellitus and dyslipidemia, and it is estimated that optimal control of these factors could substantially reduce the occurrence of stroke [1]. More recently, the realization that atherosclerosis is in part, an inflammatory condition [2], has prompted renewed interest in exploring additional avenues for identifying and treating high vascular risk patients, particularly since options for treating acute ischemic stroke remain limited.

Many conventional vascular risk factors have overlapping mechanisms, synergism or complementary actions in the formation of arterial thrombosis, and there tends to be a greater incidence in the frequency of vascular events with increasing number and severity of risk factors. This knowledge has fuelled a desire to find and utilize treatments that confer multifactorial vascular protection via favorable pleiotropic properties. Currently available therapies such as HMG-CoA reductase inhibitors (statins), renin–angiotensin system modulators and thiazolinediones are all believed to reduce vascular risk through additional mechanisms beyond their primary mode of action. Apart from efficacy through presumably varied actions, the recognition that single treatments with multiple pharmacologic actions could simplify treatment regimens, and thereby boost treatment adherence in the real world, has raised interest in the concept of a ‘polypill’that incorporates various vascular risk reduction drugs in the form of a single pill.

A promising single novel treatment that may simultaneously provide several vascular protective benefits for persons at risk for stroke is curcumin, which derives from the root of the plant Curcuma longa, and is regarded as the most biologically active constituent of the spice turmeric. Curcumin harbors several properties that could make it suitable for stroke prevention:

• • Neuroprotective: curcumin acts as a free-radical scavenger inhibiting lipid peroxidation and nitric oxide synthase expression in vitro[3]. Curcumin exerts indirect antioxidant effects by enhancing the synthesis of glutathione, an important intracellular antioxidant [3]. In fact, administration of curcumin after focal cerebral ischemia in rats significantly diminished infarct volume, improved neurological deficit, decreased mortality and reduced the water content of the brain in a dose-dependent manner [4,5].

• • Anti-inflammatory: curcumin suppresses the production of inflammatory cytokines such as IL-1β, TNF-α, IL-8 and the reactive astrocyte marker glial fibrillary acidic protein, as well as interfering with transcription factors NF-κB and activator protein-1 [3].

• • Antilipemic: curcumin attenuates diet-induced hypercholesterolemia in rats [3], and a small clinical trial demonstrated that low doses of curcumin lowered total cholesterol and boosted high-density lipoprotein cholesterol levels [6].

• • Antiaggregant: curcumin preferentially inhibits platelet aggregation induced by platelet-activating factor and arachidonic acid in vitro[3].

Since oxidative damage, inflammation and dyslipidemia all contribute to poor clinical outcomes in persons with or at risk for stroke, and several proven treatments for reducing stroke risk target these mechanisms, there is a rationale for testing the potential of curcumin to ameliorate stroke risk. Since these known curcumin targets all play important physiological roles in stroke occurrence, a relatively low dose influencing all of these pathways might be expected to have as great a clinical benefit as higher doses without dose-related toxicity. Indeed, a preclinical study found an antiatherogenic effect of low dose of curcumin in a mouse model of atherosclerosis [7]. However, most of the preliminary toxicology has been examined in humans largely while investigating curcumin as an anticarcinogen or cancer chemopreventive agent. Curcumin appears to be well tolerated in humans when administered daily (even up to doses as high as 8 g/day; the bulky volume of the drug is unpalatable beyond 8 g) over several months (up to 3 years in small trials) and dose-limiting toxicity has not been observed so far [3]. However, occasional reports of gastrointestinal adverse events, including nausea and diarrhea, during the first 1 month of use have been observed, and infrequent abnormal rises in serum alkaline phosphatase and lactate dehydrogenase levels noted [3]. Curcumin may also need to be used cautiously in patients with bleeding disorders and when being administered along with antithrombotic medications [3]. Relevant to a cerebrovascular disease population, which would consist largely of elderly persons, a study among persons with Alzheimer’s disease (mean age of 74 years; 62% female) tested the tolerability and safety of 4 g/day of curcumin in a 24-week, randomized, double-blind study [Ringman J, Cole G, Teng E et al. Oral curcumin for the treatment of mild-to-moderate Alzheimer’s disease: tolerability and clinical and biomarker efficacy results of a placebo-controlled 24-week study. Submitted]. Curcumin was well tolerated without any reported gastrointestinal side effects or elevated liver enzymes [Ringman J et al. Submitted].

In contrast to the extensive preclinical data on curcumin, the pharmacokinetic properties of curcumin in humans are still not completely understood [3]. Curcumin inhibits cytochrome P-450 isoenzyme 1A1 and undergoes avid metabolism by conjugation and reduction, and its disposition after oral dosing is characterized by poor systemic bioavailability (∼65% after oral administration) [3]. However, the daily doses given in several of these human studies that actually assessed curcumin bioavailability generally did not exceed 500 mg of curcumin, so it is conceivable that higher doses of curcumin that furnish measurable plasma curcumin concentrations will be required to elicit clinically relevant antilipid, anti-inflammatory and antioxidant effects. Supporting this notion, analyses of serum and urine samples in a study where subjects consumed 3.6 g daily of curcumin showed the definitive presence of curcumin and its conjugates in both sample types, thereby providing a reliable and easy method for potentially testing the compliance of subjects consuming curcumin in clinical trials [3]. It also appears that concomitant administration of piperine boosts curcumin’s bioavailability in humans by 2000% [3]. On the basis of extrapolating doses from rodents to humans (normalizing for the higher metabolic rate in rodents), the full range of doses to consider for likely efficacy in humans is presumed to range from 500 to 6000 mg/day. Curcumin is very hydrophobic and rapidly removed by tissues suggesting that CNS levels of 0.1 µM might be achievable at 4000 mg or lower doses [3]. Small clinical trials have observed single-dose effects on lipid, inflammatory and oxidative risk factors of stroke. For instance, 500 mg/day curcumin reduced markers for oxidative damage and total cholesterol while increasing HDL [6], while 1100–1200 mg/day has been used to control systemic inflammation [3]. Overall, curcumin appears to carry promise as stroke preventive agent. It may be worthwhile to conduct future clinical trials of oral curcumin supplementation in persons with, or at risk for stroke, to investigate its appropriate dosing, safety, and therapeutic activity.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.