Oligonol Supplementation Attenuates Body Temperature and the Circulating Levels of Prostaglandin E 2 and Cyclooxygenase-2 After Heat Stress in Humans

Abstract

Oligonol, a phenolic production from lychee, has been reported to exhibit anti-oxidative and anti-inflammatory effects. This study investigated the effect of Oligonol supplementation on circulating levels of prostaglandin E₂ (PGE₂) and cyclooxygenase (COX)-2, as well as body temperature, after heat stress in 17 healthy human male volunteers (age, 21.6±2.1 years). All experiments were performed in an automated climate chamber (26.0°C±0.5°C, relative humidity 60%±3.0%, air velocity less than 1 m/sec) between 2 and 5 p.m. Subjects ingested an Oligonol (100 mg)–containing beverage or placebo beverage before half-body immersion into hot water (42°C±0.5°C for 30 min). Tympanic and skin temperatures were measured and mean body temperatures were calculated. Serum concentrations of PGE₂ and COX-2 were analyzed before, immediately after, and 60 min after immersion. Oligonol intake significantly prevented elevation of tympanic (temperature difference: 0.17°C at Post, P<.05; 0.17°C at Re-60, P<.05) and mean body temperatures (temperature difference: 0.18°C at Post, P<.05; 0.15°C at Re-60, P<.05), and lowered concentrations of serum PGE₂ (increased by 13.3% vs. 29.6% at Post, P<.05) and COX-2 (increased by 15.6% vs. 21.8% at Post, P<.05), compared to placebo beverage. Our result suggests that Oligonol has the potential to suppress increases in body temperature under heat stress, and this is associated with decreases in serum levels of PGE₂ and COX-2.

Introduction

F ever is a defensive response and a common symptom of infection and systemic inflammation. The development of fever is a complex event that involves both the peripheral immune system and the brain. It is generally accepted that prostaglandin E₂ (PGE₂) is the principal mediator of fever and that it exerts its pyrogenic action by binding to receptors on thermoregulatory neurons in the anterior hypothalamus.¹ PGE₂ is formed in most cells from cyclooxygenase (COX)-mediated metabolism of arachidonic acid.² The COX-2 isoform, the rate-limiting enzyme for PGE₂ synthesis, is inducible.^2,3 Previous studies showed the connection between COX-2 enzymes and production of PGE₂ is involved in febrile and inflammatory responses.^3,4

Circulating cytokines, most prominently interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), are thought to be involved in PGE₂ production in response to fever.⁵ The contribution of these cytokines to the fever response has been identified by investigating the transcription factors, such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), which are activated by these cytokines.^6,7 These mechanisms lead to the induction of COX-2⁸ and, consequently, fever production.⁹

Our two recent studies revealed that supplementation with Oligonol decreased serum concentrations of cortisol, IL-1β, and IL-6, which are fever-related hormone or cytokines, after heat stress.^10,11 These results led us to hypothesize that Oligonol has an antipyretic potential. Therefore, the present study aimed to investigate the effects of Oligonol supplementation on the circulating levels of PGE₂ and COX-2, key molecules for thermoregulation, as well as body temperature after heat stress.

Oligonol is a novel compound produced from the oligomerization of polyphenol. It is an optimized phenolic product containing catechin-type monomers and oligomers (dimers, trimers, and tetramers) of proanthocyanidin that are easily absorbed.¹² Over the last decade, several studies have demonstrated the antioxidative and anti-inflammatory effects of Oligonol.^10,11,13,14 However, the antipyretic potential of Oligonol manifest through regulation of PGE₂ and COX-2 in response to fever has never been studied.

Materials and Methods

A double-blind cross-over design was used. Subjects consumed an Oligonol-containing beverage (100 mg Oligonol in 500 mL water) or a placebo beverage (plain water 500 mL) before the heat stress. Two trials were separated by a 1-week washout period. On the basis of previous studies,^15
–17 half-body immersion into the hot water was undertaken as a heat stress. To investigate the effect of hyperthermia alone, the passive heating trial involved seated immersion in hot water during which rectal temperature was intended to significantly increase.

Subjects

After approval of the experimental protocol by the University of Soonchunhyang Research Committee and obtaining written informed consent, 17 healthy male college students (age 21.6±2.1 years; height 175.6±3.5 cm; weight 75.3±4.1 kg; body mass index 21.4±2.7; body fat 17.9%±3.5%; VO₂max 50.1±5.9 mL/kg per minute) were enrolled in the study. Each subject provided written informed consent after the purpose of the study and experimental procedures as well as any potential risks were thoroughly discussed. The protocol complied with the Helsinki Declaration of 1975. Subjects refrained from alcohol consumption, smoking, medication, and vigorous physical activity during the testing period.

Supplements

Oligonol is produced by oligomerization of polyphenols found abundantly in lychees. Typically, the constituents of Oligonol are 15%–20% monomers, 8%–12% dimers, and 5%–10% trimers. The Oligonol used in this study was supplied by Amino Up Chemical Co. (Sapporo, Japan). The dose of Oligonol (100 mg) was determined previously to be safe for repeated intake of doses <200 mg/day,¹⁸ and the median lethal dose was 5 g/kg, which equates to a dose of ∼300 g for an average human with a 60 kg body weight.¹⁸ Fujii et al. further report that supplementation studies in healthy human volunteers using Oligonol at doses of 100 and 200 mg/day for 92 days showed good Oligonol bioavailability.¹⁸ Plain water was used as the placebo beverage.

Heat stress

All experiments were conducted in a thermoneutral climate chamber (26°C±0.5°C, 60%±3% relative humidity, and <1 m/sec air velocity) at 2–5 p.m. Upon arrival to the climate chamber, the subjects wore short pants and sat in a chair in a relaxed posture for 60 min to become conditioned to the chamber climate before the commencement of the experiments. After 60 min of rest, heat load was applied to each subject via immersion of half of their body into a hot water bath of 42°C±0.5°C for 30 min. Measurements were taken at rest, Post (immediately after immersion), and Re-60 min (60 min after the immersion). Subjects drank 500 mL of the Oligonol beverage or the placebo beverage 1 h before the immersion. Because water temperature was uncomfortably hot, subjects could take breaks of up to 1 min at the 5-, 10-, and 20-min check points during the 30-min immersion. Participants did not consume caffeine, smoke, or consume alcohol for 48 h before the test, and refrained from intense physical activities 24 h before the test.

Tympanic temperature measurement

Tympanic temperature (T _ty) was assessed in the left ear via the insertion of a model K923 thermistor probe with a small spring into the ear canal (Takara Instrument Co. Ltd., Yokohama, Japan), connected to a PC-8801 personal computer (NEC, Yamagata, Japan), which was in turn connected to a model K-720 data logger (Technol Seven, Yokohama, Japan). As the thermistor probe contacted the tympanic membrane, the subject felt slight discomfort and could hear a scratching noise. The inner pinna was then filled with small cotton balls to fix the position of the probe.¹⁹

Skin temperature and mean body temperature measurements

Local skin temperatures on the chest (T ₁), upper arm (T ₂), thigh (T ₃), and leg (T ₄) were measured using model PXK-67 thermistor thermometers (Technol Seven) connected to a model K-270 data logger (Technol Seven). The mean skin temperature (mT _s) was calculated in accordance with the Ramanathan equation:²⁰ mT _s=0.3·(T ₁+T ₂)+0.2·(T ₃+T ₄). Mean body temperature (mT _b) was calculated from T _ty and mT _s with the following equation:^11,20 mT _b=0.9·T _ty+0.1·mT _s.

Blood sampling

Blood samples were collected from the antecubital vein of the participants according to the guidelines of the Clinical and Laboratory Standards Institute to identify the changes in the serum markers 1 h before, immediately after, and 60 min after the immersion. Blood was transferred into serum separation tube and immediately centrifuged at 4°C and 1500 g for 10 min. The serum was subsequently removed and stored in 1-mL aliquots at −80°C until analyses of PGE₂ and COX-2.

Analyses of PGE₂ and COX-2

Serum concentrations of PGE₂ and COX-2 were measured by using commercially available enzyme-linked immunosorbent assay kits (Prostaglandin E₂ Parameter Assay Kit, R&D Systems, Minneapolis, MN, USA; COX-2 [human] EIA Kit, Enzo Life Sciences, Farmingdale, NY, USA). Values below the detection limit were assumed to be zero for the statistical analysis. The inter- and intra-assay coefficients of variance were <10%.

Statistical analysis

Descriptive statistics were expressed as the mean±standard deviation using SPSS for Windows, version 12.0 (SPSS, Chicago, IL, USA). Repeated two-way analysis of variance was used to compare values, and a contrast method was used to compare values within each group. Pearson product–moment correlation was used to test the relationship between changes of PGE₂, COX-2 and body temperature. The level of significance was set at P<.05.

Results

Tympanic and mean body temperatures

Differences in body temperatures between the two trials were not significant at baseline. Tympanic and mean body temperatures of both trials increased significantly from resting level immediately after (Post) and 60 min after heat stress (Re-60). However, the Oligonol beverage resulted in lower tympanic (temperature difference: 0.17°C at Post, P<.05; 0.17°C at Re-60, P<.05) and mean body temperatures (temperature difference: 0.18°C at Post, P<.05; 0.15°C at Re-60, P<.05) compared with the placebo beverage immediately (placebo; Post, P<.05) and 60 min after exercise (Table 1).

Table 1.

Temporal Changes of Tympanic and Mean Body Temperatures

Trials	Rest	Post	Re-60
T _ty (°C)
Placebo	36.60±0.17	37.81±0.37 ^***	36.95±0.19 ^***
Oligonol	36.57±0.19	37.64±0.35 ^#, ^***	36.78±0.21 ^#, ^***
mT _b (°C)
Placebo	36.20±0.15	37.35±0.30 ^***	36.51±0.16 ^***
Oligonol	36.19±0.16	37.17±0.29 ^#, ^***	36.36±0.15 ^#, ^***

Values are presented as the mean±SD.

P<.05 indicates a significant difference between two trials.

***

P<.001 compared with rest in each trial.

T _ty, tympanic temperature; mT _b, mean body temperature; Rest, pre-passive heating; Post, post-passive heating; Re-60, 60 min after passive heating.

Serum level of PGE₂ and COX-2

The mean serum concentrations of PGE₂ over time in the two trials are shown in Fig. 1. PGE₂ levels were significantly increased immediately after passive heating in both trials, but there was a significant difference between trials. The placebo beverage induced a greater increase in PGE₂ than the Oligonol beverage (29.6% vs. 13.3%, P<.05). Sixty minutes after heating, serum levels of PGE₂ in both trials were reduced to nearly resting levels.

FIG. 1.

Concentrations of prostaglandin E₂ (PGE₂) over time in the two trials. Rest, pre–passive heating; Post, post–passive heating; and Re-60, 60 min after passive heating. White bar denotes the placebo beverage and the black bar denotes the Oligonol beverage. Values are presented as the mean±standard deviation (SD). ***P<.001, compared with the rest in each trial. ^# P<.05 indicates a significant difference between two trials.

Concentrations of COX-2 over time in the two trials are shown in Fig. 2. In subjects drinking the placebo beverage, COX-2 levels were significantly increased immediately after passive heating (from 15.1±2.9 ng/mL to 18.4±3.4 ng/mL, P<.001), but not in those drinking the Oligonol beverage (from 14.1±2.5 ng/mL to 16.3±2.2 ng/mL, P>.05). Sixty minutes after heating, serum levels of COX-2 in both trials were similar to resting levels respectively, with or without significant alteration of COX-2.

FIG. 2.

Concentrations of cyclooxygenase (COX)-2 over time in the two trials. Rest, pre–passive heating; Post, post–passive heating; and Re-60, 60 min after passive heating. White bar denotes the placebo beverage and the black bar denotes the Oligonol beverage. Values are presented as the mean±SD. ***P<.001; compared with the rest in each trial. ^# P<.05 indicates a significant difference between two trials.

Correlation

Changes in body temperature were significantly correlated with changes in serum PGE₂ (r ²=0.661, P<.001) and COX-2 (r ²=0.658, P<.001).

Discussion

Several recent studies have demonstrated the antioxidative and anti-inflammatory potential of Oligonol and its capacity to inhibit COX-2 expression.^14,21 In the present study, the antipyretic potential of Oligonol manifest through the regulation of PGE₂ and COX-2 in response to fever was evaluated. The major findings of the present study were as follows. First, there was a positive relationship between circulating levels of PGE₂ and COX-2 and body temperature, which is evidence of peripherally-produced PGE₂ and COX-2 involvement in thermoregulation. Second, Oligonol intake decreased body temperature and the serum levels of PGE₂ and COX-2 after passive heating compared with placebo. These results suggest that Oligonol has the potential to suppress increases in body temperature under heat stress, and this is associated with decreases in serum levels of PGE₂ and COX-2.

In the process of the polyphasic fever, peripherally-produced PGE₂ plays a critical role in the early phase, whereas centrally-produced PGE₂ is crucial for later phases of fever.²² In the early phase, PGE₂ synthesis and COX-2 immunoactivity due to macrophages increased in the liver and lungs, but not in the brain.^23,24 The rapid increase in PGE₂ synthesis spurs a surge in the concentration of circulating PGE₂ early during the fever response in both the venous and arterial blood.^24,25 Our result supported the view that the blood level of PGE₂ must be considered an important factor in the generation of fever, for both the serum level of PGE₂ and body temperature showed a similar pattern with time. Understandably, intravenous or intracarotid PGE₂ or PGE₁ readily causes fever when administered.^24,26,27

Mechanisms regulating fever have two major pathways: neural and humoral. The humoral pathway, which involves the transport of cytokines or prostaglandin to the brain to elevate the thermoregulatory set point, seems more likely to be responsible for maintaining a fever response. Therefore, we focused on the humoral pathway mediated by prostaglandins. However, there is a limitation in this human study. Presently, it was difficult to precisely identify the origin of the circulating PGE₂. In addition, PGE₂ is a rapidly acting and short-lived mediator.²⁸ However, it is considered that as the blood concentration of PGE₂ changes, the processes of transport, and catabolism of PGE₂ in peripheral organs can affect the level of PGE₂, not only in peripheral tissues but also in the brain.²⁶

Research interest has focused on inhibitors of COX-2 that act as analgesic and antipyretic agents. However, no studies of passive heat-induced peripheral levels of COX-2 have been performed in humans. Thus, the present study evaluated the influence of altering circulating COX-2 levels in fever. As a result, similar to PGE₂, peripheral COX-2 was elevated immediately after heat stress and depressed when the heat condition was removed. Previous in vivo animal studies²⁹ and human blood in vitro ³⁰ demonstrated that the injection of COX-2-specific inhibitors decreases the activity of COX-2, whereas lipopolisaccaride administration induces the upregulation of COX-2 and PGE₂.^30,31 Additionally, it has been well established that inflammatory cytokines induce fever and activation of COX-2 in the brain.^32,33 Using a COX-2 inhibitor, Bradford et al. tested the hypothesis that prostaglandin-mediated pyrogenicity may contribute to elevated body temperature in exercising humans, and concluded that PGE-mediated inflammatory processes may contribute to exercise-induced heat strain.³³ However, they did not investigate the alteration of PGE₂ and COX-2 in their study. To our knowledge, the present study is the first report that has identified the changes of serum levels of PGE₂ and COX-2 according to the fever process.

The passive heating elevated serum PGE₂ and COX-2 concentrations as the body temperature increased with or without Oligonol. Changes in body temperature were significantly correlated with changes in serum PGE₂ and COX-2. However, there was a significant difference between the two trials. Oligonol intake decreased the elevation of the tympanic and mean body temperatures, as well as PGE₂ and COX-2 concentrations, after heat stress compared to placebo. The result supports the antipyretic effects of Oligonol, even though we could not identify the mechanism by which Oligonol affects the circulating levels of PGE₂ and COX-2. Since the anti-inflammatory effect of Oligonol has been conclusively established,^10,11,13,14 we speculated that the antipyretic effect of Oligonol could be due to its anti-inflammatory action, which suppresses the proinflammatory cytokines that act as endogenous pyrogens. Cytokines, including IL-1β, TNF-α, and IL-6, are “endogenous pyrogens” involved in the febrile response during infection or inflammation.⁵ It is believed that fever occurs as a result of cytokine-stimulated PGE₂ production in brain, as shown in Fig. 3. As an exogenous pyrogen, passive heating, by increasing ambient temperature, was followed by endogenous heat production. Hyperthermia resulted in significant activation of inflammatory cells with cytokine production. A few studies demonstrated that passive heating increased serum levels of IL-6 and IL-1β.^34,35 We also demonstrated that serum IL-1β and IL-6 concentrations increased significantly under passive heating, but they were lower with Oligonol than without Oligonol.^10,11 These previous studies supported that Oligonol has the potential to suppress the proinflammatory cytokines acting as endogenous pyrogens under heat stress.

FIG. 3.

Scheme for the febrile response. IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; COX, cyclooxygenase; PGE, prostaglandin E.

Recently, several studies have been initiated worldwide to find natural healing agents with an improved safety profile, instead of synthetic drugs that can cause multiple unwanted effects. These natural products could be considered potential candidates for the bioactivity of antipyretic, analgesic, and anti-inflammatory agents against fever, algesia, and inflammation associated with several pathological conditions. Examples of the natural agents include mangrove plants,³⁶ Viola betonicifolia whole plant,³⁷ and natural polyphenol chlorogenic acid.³⁸ Just as was done in these prior studies, the current study also aimed at evaluating the antipyretic bioactivity of the Oligonol against the hyperthermia.

In conclusion, Oligonol intake decreased the serum levels of PGE₂ and COX-2 and body temperature after passive heating compared with placebo. These results lend credence to the view that Oligonol could be used to suppress the elevation of body temperature under heat stress.

Footnotes

Acknowledgment

The authors extend their thanks to the subjects whose participation made this study possible.

Author Disclosure Statement

No competing financial interests exist.

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Oligonol Supplementation Attenuates Body Temperature and the Circulating Levels of Prostaglandin E 2 and Cyclooxygenase-2 After Heat Stress in Humans

Abstract

Introduction

Materials and Methods

Subjects

Supplements

Heat stress

Tympanic temperature measurement

Skin temperature and mean body temperature measurements

Blood sampling

Analyses of PGE2 and COX-2

Statistical analysis

Results

Tympanic and mean body temperatures

Serum level of PGE2 and COX-2

Correlation

Discussion

Footnotes

Acknowledgment

Author Disclosure Statement

References

Analyses of PGE₂ and COX-2

Serum level of PGE₂ and COX-2