Anti-Stress Effects of d-Limonene and Its Metabolite Perillyl Alcohol

Abstract

Stress is closely linked by its biological mechanisms to inflammation and by its consequences to accelerated aging. Stress triggers a hormonal response along the hypothalamus-pituitary-adrenal (HPA) axis, which can disrupt the ortho/parasympathetic balance essential for a harmonious life. Proper nutrition, adequate physical activity, and limiting the harmful influence of stress play important roles in avoiding the development of disease and promoting healthy aging. d-Limonene, a monoterpene shown to reduce inflammatory parameters in several pre-clinical and clinical models, could also produce an anti-stress action by altering ortho/parasympathetic parameters as well as central neurotransmitter functions. Here we report on a rat model, where a functional observational battery (FOB) was performed by submitting animals to non-pathological stress. d-Limonene or its metabolite perillyl alcohol (POH) were administered per os at a dose of 10 mg/kg. FOB tests were performed 1 hr before gavage and then at 60, 120, and 180 min. These tests confirmed the stressed status of control rats fed vehicle. Conversely, a series of parameters were significantly less disturbed in treated rats, who retained a better activity and displayed less signs of stress. These effects were more pronounced and sustained after ingestion of d-limonene than POH, suggesting the role of endogeneous metabolization of the terpene. These studies show that d-limonene exerts, through its metabolite POH, a significant anti-stress action measurable by behavioral and physiologic parameters under the influence of the nervous system. In addition to its anti-inflammatory effects, a beneficial role as an anti-stress substance could thus be claimed for d-limonene used as a dietary supplement.

Limonene: Aroma of innovation in health and disease

“…The authors consider this study as a promising field for the discovery of new anti-hyperalgesic and/or antidepressant agents. Limonene also showed a potential anti-stress effect in a study performed by d'Alessio et al [71]. The aim of this study was to evaluate the effect of oral treatment with limonene and its metabolite perillyl alcohol in a rat model submitted to non-pathologic mild stress conditions.…”

D‐limonene: A multifunctional compound with potent therapeutic effects

“…The anti‐stress effects of D‐limonene and its metabolite perillyl alcohol has been studied in HsdBrlHan rats (d'Alessio et al., 2014). Parameters that were studied for assessing the stress effects in rats include temperature, vocalization, toe pinch, startles, approach, irritability, interest, inversion, and cases.…”

“…The anti-stress effects of D-limonene and its metabolite perillyl alcohol has been studied in HsdBrlHan rats (d'Alessio et al, 2014).…”

Terpenoids as Potential Geroprotectors

“…Esters of terpene alcohols (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) are described as highly potent, reversible, and low toxic skin penetration enhancers [ 36 ]. D-limonene reduces overall stress levels and improves markers of inflammation [ 37 , 38 , 39 ]. D-limonene in Wistar rats caused the intense and persistent bradycardia associated with hypotension.…”