1203ISSN 1479-6694Future Oncol. (2014) 10(7), 1203–1214

Review

Ginseng (Panax ginseng C.A. Meyer) has long been considered by several Eastern traditional medicines as a panacea for a series of ailments (the botanical genus name Panax derives from the ancient Greek pan and axos, meaning ‘cure all’) [1,2]. In traditional Asian medicines moreover, ginseng has been used as an ‘adaptogen’ substance, due to its purported ability to counteract stress, fatigue and weakness, re-establishing the body homeostasis in response to stressors [2]. Indeed, ginseng has a long history of use, particularly in China, for the treatment of patients who have been debilitated by prolonged illness, especially when the illness has come from poor habits; these traditional uses of ginseng often used considerably larger doses than currently recommended [3]. According to the WHO and the German Commission E, ginseng root is used as a tonic for invigoration and fortification in times of fatigue and debility, for declining capacity for work and concentration, and also during convalescence [4,5]. The beneficial reported effects of ginseng include antihyperglycemia in diabetes, erectile dysfunction and gastritis. Currently, ginseng is widely used in the USA for its relief on overall energy and vitality, particularly during times of fatigue or stress. It is believed that ginseng reduces fatigue by action on: the CNS, including cognition/memory, sleep disturbance, anxiety/depression [6–8]; pain [9,10]; and inflammatory cytokines [11–13]. The numerous saponin glycosides, ginsenosides, constitute the active ingredients of ginseng and are likely responsible for its wide range of pharmacological effects [2,4,14].

In view of its antiangiogenic and anti-inflammatory activities, and inhibitory effects on tumor progression [1–2,15], ginseng is commonly used – in traditional Asian medicines – to treat several types of cancers, including stomach, liver, pancreas and colon cancer [16–18]. Additional beneficial effects to cancer patients may be afforded by the ability of ginseng to reduce the unpleasant and debilitating

Review

part of

10.2217/FON.13.276 © 2014 Future Medicine Ltd

ReseaRch aRticle

Protective effect of Panax ginseng in cisplatin-induced cachexia in rats

Carla Lobina1, Mauro AM Carai1, Barbara Loi1, Gian Luigi Gessa1, Antonella Riva2, Walter Cabri2, Giovanna Petrangolini2, Paolo Morazzoni2 & Giancarlo Colombo*,1

1Giancarlo Colombo Neuroscience Institute, National Research Council of Italy, Section of Cagliari, S.S. 554, km. 4,500 I-09042

Monserrato (CA), Italy 2Indena S.p.A., I-20139 Milan (MI), Italy

*Author for correspondence: Tel.: +39 070 675 4342 Fax: +39 070 675 4320; colomb@unica.it

AbstrAct: aim: This study investigated the protective effect of a standardized extract of Panax ginseng on multiple cisplatin-induced ‘sickness behaviors’ (model of cancer-induced cachexia) in rats. Materials & methods: Cisplatin was administered twice weekly (1–2 mg/kg, intraperitoneal) for 5 consecutive weeks. Panax ginseng extract (0, 25 and 50 mg/kg, intragastric) was administered daily over the 5-week period of cisplatin exposure. Malaise, bodyweight and temperature, pain sensitivity, and endurance running were recorded at baseline and at 5 weekly intervals. Results: Treatment with cisplatin produced severe signs of malaise, marked loss of bodyweight, hypothermia, hyperalgesia and reduction in running time. Treatment with Panax ginseng extract completely prevented all cisplatin-induced alterations. conclusion: These data indicate that treatment with Panax ginseng extract exerted a protective effect in a rat model of cachexia and suggest that Panax ginseng extract may be a therapeutic promising tool for supportive care in oncology.

Keywords • cachexia • cisplatin • Panax ginseng • rat • sickness behaviors

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side effects and complications of chemotherapy, including fatigue, lassitude, pain, vulnerability to infections, anemia, diarrhea, loss of appetite, nausea and vomiting [16–18].

In the wake of these notions, and in the search for potentially effective supportive care options for cancer patients, the present study was designed to evaluate the effect of a standardized extract of Panax ginseng on multiple ‘sickness behaviors’ produced in rats by the administra-tion of the chemotherapeutic drug, cisplatin [19]. These ‘sickness behaviors’, which include loss of bodyweight, hypothermia, fatigue and hyper-algesia, reproduce several aspects of malaise and cachexia experienced by patients receiving chemotherapy [20–24].

In the present study, cisplatin was administered to rats twice weekly, at doses of 1 and 2 mg/kg, for 5 consecutive weeks, according to the pro-cedure proposed by Authier and colleagues [25]. This protocol resulted in the progressive onset and development of several signs of malaise, marked loss of bodyweight, hypothermia, hyper-algesia (measured as reduced response threshold to a mild noxious stimulus) and exhaustion (measured as inability to complete an endurance running). Panax ginseng extract was administered daily over the entire 5-week period of exposure to cisplatin.

Materials & methodsAll experimental procedures employed in the pre-sent study were in accordance with the Italian Law on the ‘Protection of animals used for experimental and other scientific reasons’ and approved by the Italian Ministry of Health.

●● Plant material & preparation of plant extractPanax ginseng extract (GINSELECT®), supplied by Indena S.p.A. (Milan, Italy), was prepared from Panax ginseng C.A. Meyer root (drug extract ratio [(DER] 1:3–5; batch no. 30550/M1) and standardized to contain ≥7.0% of ginsenosides and malonylginsenosides (≥0.9% Rg1 ≤1.4%; ≥1.7% Rb1 ≤3.0%). The manufacturing percent-age range (mean ± standard error of the mean) of ginsenosides was 12 ± 3%. The extract was prepared through hydroalcoholic extraction (EtOH 70%).

●● animalsSixty healthy, adult, male Wistar rats (Charles River Laboratories, Calco, Italy) were used. Rat

bodyweight averaged approximately 180 g at the start of the 4-week training period at the tread-mill (see below). Rats were housed four per cage in standard plastic cages with wood (spruce) chip bedding (Litter Plus, Safe, Augy, France). The animal facility was under a 12:12-h light–dark cycle (lights on at 7:00 a.m.), at a constant tem-perature of 22 ± 2°C (lower and upper limit of the room temperature) and relative humidity of approximately 60%. Over the 10 days preced-ing the beginning of the experimental study, rats were habituated to handling and to receive intra-peritoneal (ip.) injections (3 ml/kg saline) and intragastric (ig.) infusions by gavage (2 ml/kg dis-tilled water). Food pellets (standard rodent chow; Mucedola, Settimo Milanese, Italy) and water were always (24 h/day) available in the homecage.

●● experimental procedureTraining at the treadmill & habituation to loose restraint and thermometer probe insertionInitially, rats were trained to run on the mov-ing belt of a motor-driven treadmill (2Biological Instruments, Besozzo, Italy) in daily sessions (Monday to Friday) for 4 consecutive weeks. Treadmill lanes (400 × 100 mm) ended with independent electric shock grids; failure to run resulted in the rat sliding off the moving belt and onto the shock grid (electric shock was thus used to motivate the rats to run). Rats underwent an initial 3-day phase of familiarization with the apparatus and the running task; these initial sessions lasted 5 min; slope, speed and electrical stimulus were kept at -15°, 20 cm/s and 0.2 mA, respectively. On the subsequent 12 days, session duration was progressively increased from 5 to 11 min (1-min increase every other day); slope was kept at -15°; speed was incremented from 20 to 100 cm/s (20-cm/s increase every other day); electrical stimulus was kept at 0.8 mA. On the final 5 days, the training sessions were conducted adopting the following parameters: 11-min ses-sion duration; constant slope of -15°; incremental speed of 40–70 cm/s for 1 min, 50–90 cm/s for one min, 90–100 cm/s for 1 min and constant speed of 100 cm/s for the remaining 8 min; and electrical stimulus at 0.8 mA. According to Koch and colleagues [26], exhaustion was operationally defined as the time of the session when the rat had touched the shock grid for a total of 2 s. At the time of exhaustion, the current to the grid was stopped and the rat was removed from the treadmill. The measured variable was the total distance (expressed in m) covered by each rat.

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Rats (n = 17) unable to meet the selection crite-rion of completing at least the last three sessions were excluded from the study.

Over the last week of the treadmill training, rats were also habituated to stay inside the Plexiglas box of the Dynamic Plantar Aesthesiometer (i.e., the apparatus subsequently used to assess pain sensitivity; see below). These habituation sessions lasted 10 min. They were conducted to ensure that rats were well adapted to staying inside the box on test days (see below), thus reducing consider-ably the time between rat spontaneous movement inside the box and filament application.

Immediately after removal from the Plexiglas box, rats were subjected to rectal insertion of a thermometer probe; this manipulation was performed to accustom rats to monitoring of body temperature in subsequent test sessions (see below).

Baseline assessment & group allocationOn day 0, the day after the last training session at the treadmill, the selected 43 rats were moved from the animal facility to a soundproof, adjacent room and submitted to a sequence of tests and measurements to assess their baseline bodyweight, body temperature, pain sensitivity (see below) and treadmill performance (see above). Rats were then divided into four groups, matched for all the above parameters and assigned to the four follow-ing treatments: cisplatin vehicle + Panax ginseng extract vehicle (control group) (n = 10); cisplatin + Panax ginseng extract vehicle (n = 11); cispl-atin + 25 mg/kg Panax ginseng extract (n = 11); and cisplatin + 50 mg/kg Panax ginseng extract (n = 11).

Cisplatin (Sigma, Milan, Italy) was dissolved in saline and administered ip. (injection vol-ume: 3 ml/kg) at the doses of 1 mg/kg (given on Fridays) and 2 mg/kg (given on Tuesdays) for 5 consecutive weeks (cumulative dose: 15 mg/kg); the first injection (2 mg/kg) took place on day 0 immediately after the end of the baseline tests. Each administration of cisplatin was associated to the subcutaneous injection of 2 ml/rat saline (provided to limit, via hyperhydration, cisplatin-induced kidney damage). Panax ginseng extract was dissolved in distilled water and administered ig. once a day, for 35 consecutive days (starting from day 0), at a volume of 2 ml/kg. Food supple-mentation, comprising 5 g/rat Meritene Protein (Nestlé Italiana, Milan, Italy), was given daily to rats in which bodyweight loss (in comparison to baseline) was equal to or higher than 15%. The

dose was calculated as to provide approximately a third of the daily energy requirement of rats. ‘Meritene Protein’ was suspended in water and administered ig. at the volume of 5 ml/rat.

Weekly recordingsOn days 7, 14, 21, 28 and 35 (test sessions), rats were submitted to the following sequence of tests and measures (taking place during the first 6 h of the 12-h light phase of the daily light–dark cycle).

Signs of malaiseCisplatin-induced malaise was scored by a ‘yes-or-no’ six-point scale that evaluated the pres-ence or absence (presence: 1 point; absence: 0 points) of the following six signs: tail and paw paleness, piloerection, gastrointestinal disor-ders, muscle flaccidity, hindlimb weakness and tremors/convulsions. Rats were first observed in their homecage (with no handling) and then gently moved onto the bench surface. Evaluation of each rat lasted approximately 5 min and was performed by an operator who was unaware of group allocation.

BodyweightRat bodyweight was evaluated by means of a scale with a 0.1-g accuracy. Data were expressed in grams of bodyweight and percentage change compared with baseline.

Body temperatureBody temperature was monitored by means of a rectal thermometer for rodents (Keithley Instruments, OH, USA), with a 0.1°C accu-racy. Two consecutive recordings (2-min apart) were performed in each rat; the value assigned to each rat was given by the average of these two recordings.

Pain sensitivityThe Von Frey filament test, used for the nocicep-tion assay, was performed to assess the response threshold to a noxious stimulus. In this test (Dynamic Plantar Aesthesiometer, Ugo Basile, Comerio, Italy), rats were loosely restrained inside a Plexiglas box (100 × 200 × 140 mm) with a wire mesh floor. Rats were allowed to become accustomed to the Plexiglas box for approximately 10 min; specifically, acclimation lasted until exploratory behavior ended and the rat became calm and motionless. Subsequently, the filament was applied from beneath to the plantar side of one of the hindpaws. The filament was applied

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with a 40-g force, reached progressively in 20 s. The measured variables were: force at which the paw was removed and the latency (in s) to paw removal. A 20-s cutoff was applied. The filament was applied twice (2-min apart) on each of the hindpaws. The value assigned to each rat was given by the average of these two recordings.

Fatigue & exhaustionIn test sessions, the following parameters were adopted: 11-min session duration; constant slope of -15°; incremental speed of 40–70 cm/s for one min (rat performance during this first min was not recorded), 50–90 cm/s for 1 min, 90–100 cm/s for 1 min and constant speed of 100 cm/s for the remaining 8 min; electrical stimulus at 0.8 mA. Exhaustion was defined as described above. The measured variable was the total distance (expressed in meters) covered by each rat.

●● statistical analysisFor each variable, data collected on day 0 (baseline) were analyzed by separate one-way ANOVAs, and data collected on days 7, 14, 21, 28 and 35 (test sessions) were analyzed by sepa-rate two-way ANOVAs (treatment, time) with repeated measures on the factor time, followed by the Newman–Keuls test for post hoc comparisons.

Results●● Malaise

ANOVA revealed a significant effect of treatment (F[3,39] = 28.61; p < 0.0001), a significant effect of time (F[4,156] = 45.14; p < 0.0001), and a signif-icant interaction (F[12,156] = 18.53; p < 0.0001) on the total score of malaise. Treatment with cis-platin alone produced a progressive increase in malaise score, achieving the highest score possible on day 35 (table 1). Treatment with both doses of Panax ginseng extract produced a protective effect on cisplatin-induced malaise (table 1).

●● BodyweightAt baseline (day 0), bodyweight did not dif-fer among the four rat groups (F[3,39] = 0.28; p > 0.05) (Figure 1a).

When data were expressed in terms of grams of bodyweight, ANOVA revealed a significant effect of treatment (F[3,39] = 8.48; p < 0.0005), a significant effect of time (F[4,156] = 7.44; p < 0.0001), and a significant interaction (F[12,156] = 34.92; p < 0.0001) on rat body-weight. Treatment with cisplatin alone produced a progressive decrease in rat bodyweight that was partially attenuated by treatment with both doses of Panax ginseng extract (Figure 1a).

When data were expressed as percentage of change with respect to baseline, ANOVA revealed a significant effect of treatment (F[3,39] = 60.04; p < 0.0001), a significant effect of time (F[4,156] = 7.56; p < 0.0001) and a significant interac-tion (F[12,156] = 35.88; p < 0.0001) on rat bodyweight. Control rats progressively gained bodyweight (up to approximately 20%), while rats treated with cisplatin alone lost bodyweight markedly and progressively (up to approximately 15%) (Figure 1B). Treatment with both doses of Panax ginseng extract left bodyweight nearly unaltered in comparison to day 0, producing a remarkable protective effect on cisplatin-induced loss of bodyweight (Figure 1B).

Food supplementation (given to rats in which bodyweight loss was higher than 15%) was provided to 0, 8, 0 and 1 rats treated with cisplatin vehicle + Panax ginseng vehi-cle, cisplatin + Panax ginseng extract vehicle, cisplatin + 25 mg/kg Panax ginseng extract and cisplatin + 50 mg/kg Panax ginseng extract, respectively.

●● Body temperatureAt baseline (day 0), body temperature did not differ among the four rat groups (F[3,39] = 0.46; p > 0.05) (Figure 2).

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table 1. Protective effect of the repeated administration of Panax ginseng extract on the total score of cisplatin-induced signs of malaise in rats.

Day

  7 14 21 28 35

Cisplatin vehicle + Panax ginseng vehicle 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0Cisplatin + Panax ginseng extract vehicle 0.0 ± 0.0 0.5 ± 0.2 1.8 ± 0.5* 3.5 ± 0.5* 4.7 ± 0.4*Cisplatin + 50 mg/kg Panax ginseng extract 0.0 ± 0.0 0.0 ± 0.0 0.2 ± 0.1** 0.5 ± 0.2** 1.2 ± 0.4*,**Cisplatin + 100 mg/kg Panax ginseng extract 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0** 0.5 ± 0.3** 0.7 ± 0.3**Data are mean ± standard error of the mean of 10–11 rats. *p < 0.05 with respect to cisplatin vehicle + Panax Ginseng extract vehicle; **p <0.05 with respect to cisplatin + Panax Ginseng extract vehicle (Newman–Keuls test).

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ANOVA revealed a signif icant effect of treatment (F[3,39] = 91.67; p < 0.0001), a significant effect of time (F[4,156] = 24.71; p < 0.0001) and a signif icant interaction (F[12,156] = 12.38; p < 0.0001) on rat body temperature. Treatment with cisplatin alone produced a marked and progressive decrease in body temperature; in comparison to day 0, the decrease in body temperature on day

35 averaged approximately 2.3°C. Cisplatin-induced hypothermia was completely pre-vented by treatment with both doses of Panax ginseng extract (Figure 2).

●● Pain sensitivityAt baseline (day 0), neither the force applied at the time of paw removal (F[3,39] = 0.44; p > 0.05) nor the latency to paw removal

Figure 1. Protective effect of the repeated administration of Panax ginseng on cisplatin-induced loss of bodyweight in rats. (a) Bodyweight expressed in grams; (B) percentage changes in comparison to baseline (day 0). Each bar is the mean ± standard error of the mean of 10–11 rats. *p < 0.05 with respect to cisplatin vehicle + Panax ginseng extract vehicle; **p < 0.05 with respect to cisplatin + Panax ginseng extract vehicle (Newman–Keuls test).

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(F[3,35] = 0.28; p > 0.05) differed among the four rat groups (Figure 3).

When data were expressed in terms of force, ANOVA revealed a significant effect of treat-ment (F[3,39] = 8.97; p < 0.0005), no effect of time (F[4,156] = 0.86; p > 0.05) and no signifi-cant interaction (F[12,156] = 1.27; p > 0.05) on response threshold. Treatment with cisplatin alone progressively reduced the response thresh-old, as documented by a 32% reduction, in com-parison to day 0, in the force applied at the time of paw removal recorded on day 35 (Figure 3a). This effect was completely prevented by treat-ment with both doses of Panax ginseng extract (Figure 3a).

When data were expressed in terms of latency, ANOVA revealed a significant effect of treat-ment (F[3,39] = 8.69; p < 0.0005), no effect of time (F[4,156] = 0.88; p > 0.05) and no signifi-cant interaction (F[12,156] = 1.16; p > 0.05) on response threshold, as documented by a 32% reduction, in comparison to day 0, in the latency to paw removal recorded on day 35 (Figure 3B). This effect was completely prevented by treatment with 50 mg/kg Panax ginseng extract (Figure 3B).

●● Fatigue & exhaustionAt baseline (day 0), motor performance did not differ among the four rat groups (F[3,39] = 0.35; p > 0.05) (Figure 4).

ANOVA revealed a significant effect of treat-ment (F[4,39] = 2.85; p < 0.05), a significant effect of time (F[3,156] = 5.38; p < 0.0005), but not a significant interaction (F[12,156] = 1.61; p > 0.05) on motor performance. Treatment with cisplatin alone produced a detrimental effect on motor performance, that was particularly evident on day 35 when duration of running time was reduced by approximately 45% in comparison to day 0 (Figure 4). Treatment with both doses of Panax ginseng extract produced a protective effect (Figure 4).

DiscussionIn the present study, and in close agreement with a large body of literature evidence [20–24], the repeated administration of the cytotoxic agent, cisplatin, produced several ‘sickness behaviors’ in rats. These ‘sickness behaviors’, which may also be produced similarly by treatment with conca-navalin A and vincristine, represent a validated

Figure 2. Protective effect of the repeated administration of Panax ginseng extract on cisplatin-induced decrease in body temperature in rats. Each bar is the mean ± standard error of the mean of 10–11 rats. *p < 0.05 with respect to cisplatin vehicle + Panax ginseng extract vehicle; **p < 0.05 with respect to cisplatin + Panax ginseng extract vehicle (Newman–Keuls test).

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animal model of cachexia or ‘chemotherapy-related malaise’ [21–24,27] and offer a valid exper-imental tool for studies aimed at testing new and potentially effective supportive therapies for cancer patients.

Specifically, ten injections of 1–2 mg/kg cis-platin, distributed over 5 consecutive weeks, resulted in the progressive development of: several clinical signs of malaise (tail and paw paleness, piloerection, gastrointestinal disorders, muscle

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Figure 3. Protective effect of the repeated administration of Panax ginseng extract on cisplatin-induced decrease in response to a noxious stimulus in rats. (a) Force applied at the time of paw removal (expressed in grams); (B) latency to paw removal (expressed in seconds). Each bar is the mean ± standard error of the mean of 10–11 rats. *p < 0.05 with respect to cisplatin vehicle + Panax ginseng extract vehicle; **p < 0.05 with respect to cisplatin + Panax ginseng extract vehicle (Newman–Keuls test).

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flaccidity, hindlimb weakness and tremors/con-vulsions), the occurrence and severity of which increased progressively over the 5-week period of cisplatin administration; marked bodyweight loss and hypothermia that progressed relatively steadily over the 5-week period of cisplatin administration; and hyperalgesia (measured as reduced response threshold to the presentation of a mild noxious stimulus) and fatigue (measure as exhaustion-induced completion of an endurance running task) that achieved statistical significance at the last recording session (corresponding to the fifth week of cisplatin administration).

Cisplatin-induced loss of bodyweight was likely secondary to anorexia [22–24]. The present study failed to assess food intake of the tested rats, as the group-housing condition selected with the aim of yielding less-stressed animals (a condition deemed necessary for a profitable conduction of the Von Frey test) impeded a reliable recording of daily or weekly food intake of each single rat. However, and in agreement with literature data [22–24], a supplementary experiment found that a cisplatin treatment identical to that employed in the present study produced, in male Wistar rats,

a progressive reduction in weekly food intake that paralleled bodyweight loss [Lobina C, Colombo G,

Unpublished Data].The results of the present experiment clearly

demonstrated that chronic treatment with Panax ginseng extract – given daily over the entire period of exposure to cisplatin – exerted a fully protec-tive effect on all cisplatin-induced alterations. All measured parameters (malaise score, body-weight, body temperature, pain sensitivity and running performance) scored indeed practically identical in control (cisplatin vehicle + Panax ginseng extract vehicle) and 50 mg/kg Panax ginseng extract-treated rat groups. Likewise, the 25 mg/kg Panax ginseng dose exerted a remark-able, and almost complete, protective effect on cisplatin-induced alterations. Additional studies should now be undertaken to better define the protective effect of this Panax ginseng extract on cachexia-like states, possibly testing wider dose ranges, different administration timings and its effect on food intake and appetite.

To our knowledge, these data constitute the first evidence of the protective effect of treat-ment with a ginseng preparation in a rat model

Figure 4. Protective effect of the repeated administration of Panax ginseng extract on cisplatin-induced decrease in motor performance (expressed as meters of total distance travelled) in rats exposed to the treadmill. Each bar is the mean ± standard error of the mean of 10–11 rats. *p < 0.05 with respect to cisplatin vehicle + Panax ginseng extract vehicle; **p < 0.05 with respect to cisplatin + Panax ginseng extract vehicle (Newman–Keuls test).

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of cachexia. Conversely, and in close agreement with the data collected in the present study, treat-ment with Panax ginseng extract has recently been reported to suppress cisplatin-induced con-sumption of kaolin in rats [28]; these data are of interest as cisplatin-stimulated pica (manifested by the abnormal intake of kaolin) represents a valid surrogate for emesis in rats, thus providing an important piece of evidence on the potential efficacy of ginseng against highly frequent and unpleasant side effects of chemotherapy such as nausea and vomiting.

The suppressing effect of Panax ginseng extract on cisplatin-induced sickness behaviors observed in the present study may represent one of the several ‘adaptogenic’ actions ascribed to prepa-rations containing ginseng. Ginseng is indeed believed to protect against several stressors via re-establishment of body homeostasis [2]. These effects should be secondary to the capacity of ginsenosides (one of the several classes of the active ingredients of ginseng) to stimulate the secretion of adrenal hormones and also to bind, behaving as partial agonists, to steroid hormone receptors [4,14]. The chemistry of ginseng is how-ever extremely complex, as different active ingre-dients have been identified (beside the already mentioned ginsenosides, this list includes poly-saccharides, peptides, polyacetylenic alcohols and fatty acids [29]) and more than 20 different ginsenosides, producing different effects in the same tissue, have been identified [30]; additionally, the content of active ingredients, and therefore of the pharmacological effects of the extract, may differ largely among plants cultivated in different locations [31]. Studies are thus needed to possibly identify the active ingredient(s) of Panax ginseng extract responsible for the suppressing effects on cisplatin-induced, cachexia-like ‘sickness behaviors’ observed in the present study.

In the present study, it could be also hypoth-esized that Panax ginseng extract interfered chemically with cisplatin, ablating its cytotoxic actions and impeding therefore development of the multiple cachexia-like effects observed. This hypothesis is however highly unlikely, as – to our knowledge – no study has ever reported that Panax ginseng extracts, or any of their ingredients, may chemically interfere with cisplatin, leading to its inactivation.

At the preclinical level, additional lines of experimental evidence have increased the interest shown in the field of oncology in Panax ginseng extracts: as an example, a recent study [32] found

that 2-year treatment with high doses of a Panax ginseng extract was devoid of genotoxic and car-cinogenic activity in rats and mice and protected female rats from mammary gland fibroadenomas and female mice from ovarian cystadenomas. Several other studies reported that Panax ginseng extracts extract had anticarcinogenic effects on lung, liver, mammary gland, ovary and uterus tumors in rodents [33–36].

At the clinical level, data on ginseng and cancer are rather heterogeneous. Qi and colleagues [17] mentioned several clinical studies, conducted in Asian countries, claiming the beneficial adjunc-tive effects of different medicinal herbs, including ginseng, in patients undergoing chemotherapy; unfortunately, these data are not available on general publishing database such as Medline or Embase. Mention of ginseng-induced enhance-ment of immune activity, appetite and quality of life in cancer patients under chemotherapy has also been made by Jia and colleagues [16]. Other studies reported that ginseng may have preventive effects on cancer development [1,37–41] or improve quality of life in disease-free cancer survivors [41]. Notably, a clinical trial (NCT01375114) is cur-rently recruiting patients in the USA to test the same Panax ginseng extract (Panax ginseng C.A. Meyer supplied by Indena S.p.A.) used in the present study for the reduction of cancer-related fatigue, depression, anxiety and mood changes in cancer patients, including those receiving chemotherapy. This study is expected to translate to humans the protective effect of Panax ginseng extract on the cachexia-like state observed in the present study.

conclusionThe results of the present study provide a pre-clinical contribution to the current debate on the utility of ginseng in cancer therapy [42], dem-onstrating that the repeated administration of a standardized extract of Panax ginseng completely abolished different, severe cachexia-like ‘sick-ness behaviors’ induced in rats by the repeated administration of the chemotherapeutic drug, cisplatin. Should these results be translated to human patients afflicted by cancer, this extract of Panax ginseng would represent an effective supportive care.

Future perspectiveThere is a pressing need for effective therapies capable of preventing and alleviating malaise, fatigue, nausea and cachexia, the distressing

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effects of antineoplastic drugs, in cancer patients from the onset of therapy and throughout treat-ment. The results of the present study suggest that an extract from Panax ginseng, one of the most popular herbal medicines worldwide, may represent a potentially effective therapeu-tic option. Data from the present study have been collected using a validated rodent model of cisplatin-induced cachexia: studies should now be undertaken in an attempt to possibly extend these data to humans. An initial study, using the same Panax ginseng tested in the pre-sent rat study, is currently ongoing in the USA; the expected outcome is a reduction of cancer-related fatigue, depression, anxiety and mood changes in cancer patients. Should this outcome be observed, it would be consistent with several claims – made by several Asian countries – of the beneficial adjunctive effects of ginseng in patients undergoing chemotherapy. These initial data would subsequently need to be replicated and extended in the forthcoming years, and stud-ies performed to further the understanding of the mechanism(s) of action and identification of

the active ingredient(s) of Panax ginseng extracts underlying these remarkable effects.

Financial and competing interests disclosureA Riva, W Cabri, G Petrangolini and P Morazzoni are employees at Indena S.p.A. CNR Neuroscience Institute, Section of Cagliari (for which MAM Carai, G Colombo, GL Gessa, C Lobina and B Loi work, or have worked at the time of the study), received a grant from Indena S.p.A. for designing and conducting the study. The authors have no other 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 apart from those disclosed.

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

ethical conduct of researchThe authors state that they have obtained appropriate insti-tutional review board approval or have followed the princi-ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for inves-tigations involving human subjects, informed consent has been obtained from the participants involved.

ReferencesPapers of special note have been highlighted as: • of interest

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executive summAryRepeated treatment with cisplatin: a rat model of cachexia

● According to multiple literature data, the repeated treatment with cisplatin produced a constellation of ‘sickness behaviors’ in rats; these ‘sickness behaviors’ represent a valid animal model of cachexia, useful to test new and potentially effective supportive therapies for cancer patients.

chronic treatment with Panax ginseng extract exerted a fully protective effect

● Chronic treatment with Panax ginseng extract fully protected from all cisplatin-induced cachexia-like signs in rats.

● These data constitute the first evidence of the protective effect of treatment with a ginseng preparation in a rat model of cachexia.

Panax ginseng as an ‘adaptogenic’ substance

● The suppressing effect of Panax ginseng extract on cisplatin-induced ‘sickness behaviors’ likely represents one of the several ‘adaptogenic’ actions ascribed to ginseng preparations.

Possible translation to humans of the protective effect of Panax ginseng extract on cachexia-like state

● Literature reports from several Asian Countries mention the capacity of ginseng to enhance immune activity, appetite and quality of life in cancer patients undergoing chemotherapy.

● A clinical trial is currently ongoing in the USA to test the capacity of the same Panax ginseng extract used in the present study to ameliorate cancer-related fatigue, depression, anxiety and mood changes in cancer patients, including those receiving chemotherapy.

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