Jean-François Bisson

Effects of long-term administration of a cocoa polyphenolic extract (Acticoa powder) on cognitive performances in aged rats

Numerous studies have indicated that increased vulnerability to oxidative stress may be the main factor involved in functional declines during normal and pathological ageing, and that antioxidant agents, such as polyphenols, may improve or prevent these deficits. We examined whether 1-year administration of a cocoa polyphenolic extract (Acticoa powder), orally delivered at the dose of 24 mg/kg per d between 15 and 27 months of age, affects the onset of age-related cognitive deficits, urinary free dopamine levels and lifespan in old Wistar-Unilever rats. Acticoa powder improved cognitive performances in light extinction and water maze paradigms, increased lifespan and preserved high urinary free dopamine levels. These results suggest that Acticoa powder may be beneficial in retarding age-related brain impairments, including cognitive deficits in normal ageing and perhaps neurodegenerative diseases. Further studies are required to elucidate the mechanisms of cocoa polyphenols in neuroprotection and to explore their effects in man.

Antidepressant-like effects of a cocoa polyphenolic extract in Wistar-Unilever rats.

Abstract Depression is a major public health problem affecting about 12% of the world population. Drugs exist but they have many side effects. In the last few years, natural substances (e.g. flavonoids) have been tested to cure such disorders. Cocoa polyphenolic extract is a complex compound prepared from non-roasted cocoa beans containing high levels of flavonoids. The antidepressant-like effect of cocoa polyphenolic extract was evaluated using the forced swimming test in rats. Cocoa polyphenolic extract significantly reduced the duration of immobility at both doses of 24 mg/kg/14 days and 48 mg/kg/14 days, although no change of motor dysfunction was observed with the two doses tested in the open field. The results of the forced swimming test after a subchronic treatment and after an additional locomotor activity test confirm the assumption that the antidepressant-like effect of cocoa polyphenolic extract in the forced swimming test model is specific. Further, it can be speculated that this effect might be related to its content of active polyphenols.

Effects of lifelong intervention with an oligofructose-enriched inulin in rats on general health and lifespan.

Ageing is associated with changes in physiology and morphology; nutritional strategies to decrease morbidity and to prolong life are of high interest. The aim of the study was to investigate the effects of lifelong supplementation with an oligofructose-enriched inulin on morphological and biological markers and lifespan in male and female rats. Male and female rats, age 3 months, were randomised into two groups to receive either a diet with 10 % of an oligofructose-enriched inulin (Synergy 1) or a standard diet (control) for 27 months. The rats were weighed every 2 weeks and their food intake was evaluated on four successive days every 4-6 weeks. Samples were taken at 12, 18 and 24 months of age. During the whole intervention period, male rats receiving Synergy 1 (SYN1-M) displayed lower body weight, cholesterol and plasma triacylglycerolaemia compared with the controls (Cont-M). The survival rate at 24 months of age of SYN1-M rats was 35.3 % greater than that of Cont-M rats. In female rats, the Synergy 1 supplementation (SYN1-F) group also reduced body weight, cholesterol and triacylglycerolaemia levels, but results were less consistent over the experiment. The survival rate at 24 months of age in SYN1-F rats was 33.3 % greater compared with that of the control (Cont-F) group. To conclude, lifelong intervention with Synergy 1 improved biological markers during ageing and survival rate (lifespan) of rats.

Protective effect of Acticoa powder, a cocoa polyphenolic extract, on prostate carcinogenesis in Wistar–unilever rats

The effects of Acticoa powder on prostate carcinogenesis were investigated using the N-methylnitrosourea and testosterone propionate prostate tumor model. Sixty male Wistar–Unilever rats were randomly divided in four groups of 15 rats: one control group not induced but treated with vehicle (not induced+vehicle) and three chemo-induced groups. Two weeks before prostate tumor induction and then throughout the experiment, chemo-induced rats were orally treated with Acticoa powder at 24 (chemo-induced+Acticoa powder24) or 48 (chemo-induced+Acticoa powder48) mg/kg or with vehicle (chemo-induced+vehicle), daily from Monday to Friday. Survival, body weight, food and water consumption were recorded throughout the experiment. Six rats per group were randomly killed 9 months after the prostate tumor induction for histopathological analysis of prostates. A reduction in the incidence of prostate tumors was observed for the chemo-induced+Acticoa powder48-treated group in comparison with the chemo-induced+vehicle-treated group and no tumors were observed in the chemo-induced+Acticoa powder24-treated group as in the not induced+vehicle-treated group after 9 months. The nine remaining rats per group were maintained in a long-term survival study. The life span of the chemo-induced+Acticoa powder24-treated group was significantly increased in comparison with the chemo-induced+Acticoa powder48 and the chemo-induced+vehicle-treated groups, close to the one of the not induced+vehicle-treated group. A significant reduction in the incidence of prostate tumors was also observed for the chemo-induced+Acticoa powder24 and chemo-induced+Acticoa powder48-treated groups in comparison with the chemo-induced+vehicle-treated group. In conclusion, Acticoa powder at 24 mg/kg protected rats from prostate carcinogenesis when chronically given before the initiation and promotion phases of induction.

Neurobehavioral and physiological effects of low doses of polybrominated diphenyl ether (PBDE)-99 in male adult rats

Polybrominated diphenyl ethers (PBDEs) are flame retardants. Because of their high lipophilicity and persistence, PBDEs bioaccumulate in all abiotic and biological matrices. The aim of this study was to investigate the long-term neurobehavioral and physiological effects of exposure to environmental doses of PBDE-99 in adult rats. Rats received a daily administration of PBDE-99 for 90 days by oral gavage at 0.15, 1.5 and 15μg/kg, doses which are relevant of human exposure. Before and after the 90 days of exposure, behavioral tests including the open-field and the elevated plus-maze tests for locomotor activity and anxiety, and the Morris water maze for spatial learning were conducted. Physiological measures such as body weight, food and water consumption, organs weight, hepatic enzymes levels and PBDE-99 concentration in adipose tissue were also evaluated at the end of exposure. There was no effect on body weight, food and water consumption, organs weight, hepatic enzymes levels despite rising PBDE-99 concentration in adipose tissue with the doses tested. Moreover, there was no effect on locomotor activity and exploration, and spatial learning. Deleterious effects of PBDE-99 at high doses have often been highlighted in many studies after an acute dose whereas exposure during 90 days at realistic doses would have no significant effect in adult rats.

Diuretic and antioxidant effects of Cacti-Nea®, a dehydrated water extract from prickly pear fruit, in rats.

Dehydrated extract of the prickly pear fruit Opuntia ficus indica, Cacti‐Nea®, was evaluated for its chronic diuretic and antioxidant effects in Wistar rats. Cacti‐Nea® was orally administered daily for seven days at the dose of 240 mg/kg/day. A positive group was orally treated with hydrochlorothiazide at the dose of 10 mg/kg/day and a control group with vehicle. Daily measurements of body weight, urine volume, and concentration of sodium, potassium and uric acid in urine were performed for each rat. At the end of the study, the blood globular level of glutathione peroxidase was determined. Cacti‐Nea® significantly increased the urine volumes excreted by rats in comparison with the control group and it showed a trend to reduce significantly the body weight gain of rats. No significant differences were observed in the urine concentration of sodium, potassium and uric acid in comparison with the control group. The chronic diuretic effects of Cacti‐Nea® were comparable with that of the standard drug hydrochlorothiazide. Chronic oral administration of Cacti‐Nea® significantly increased the blood globular levels of glutathione peroxidase in comparison with control and hydrochlorothiazide groups. The prickly pear fruit extract Cacti‐Nea® demonstrated chronic diuretic and antioxidant effects in Wistar rats with respect to the excretion of the metabolites. Copyright

Structure- Activity Relationship Study and Function-Based Petidomimetic Design of Human Opiorphin with Improved Bioavailability Property and Unaltered Analgesic Activity

Human opiorphin inhibits enkephalin-inactivating ectopeptidases to produce analgesic and antidepressant-like effects in standard murine models via activation of μ and/or δ opioid pathways. It is an endogenous peptide regulator of enkephalin bioavailability. Opiorphin molecule, a QRFSR-peptide, is thus a promising prototype for the design of an improved class of analgesics. The major limitation on the clinical use of peptide drugs is their rapid degradation by circulating peptidases. Our goal was, therefore, to search for functional derivatives of opiorphin with improved metabolic stability. In order to identify the functional amino acid groups required for opiorphin inhibitory potency toward both AP-N and NEP human ectopeptidases, we used the Structure-Activity Relationship (SAR) method. From this data, a series of opiorphin derivatives was designed and selected. The best performing compound then underwent a complete metabolic profile using in vitro kinetic models. Finally, its safety profile relative to the native peptide as well as its efficacy in an in vivo rat model was evaluated. We demonstrated a tight structural selectivity in the functional interaction of opiorphin with both human NEP and AP-N targets by SAR studies. Nevertheless, we found that the addition of an N-terminal Zn-chelating group, a Cys-thiol group and the replacement of the first labile peptide bond by a polyethylene surrogate, a [CH2]6 linker,and, finally, the substitution of Ser4 by Ser-O-[CH2]8, results in a high performing C-[(CH2)6]-QRF[S-O-[CH2]8]-R peptidomimetic product. This designed opiorphin analog shows reinforced inhibitory potency toward human AP-N activity (more than 10-fold increase) and NEP activities (more than 40-fold increase) relative to the QRFSR native peptide. It also has increased metabolic stability in human plasma and yet retains full analgesic activity in the behavioral formalin-induced rat pain model. C-[(CH2)6]-QRF[S-O-[CH2]8]-R thus represents a very attractive and promising analgesic drug-candidate.

Effects of ID-alG™ on weight management and body fat mass in high-fat-fed rats.

Seaweed extract of Ascophyllum nodosum, ID‐alG™, was evaluated for its chronic effects on weight management in high‐fat‐fed Sprague‐Dawley rats. ID‐alG™ was orally administered daily during 9 weeks at doses of 40 and 400 mg/kg/day with fat‐enriched diet (FED) in comparison with two control groups consuming standard diet (negative control) or FED (positive control) and orally treated with vehicle. Body weight, percentage of body fat mass and lipid parameters were measured. After 9 weeks, the oral administration of ID‐alG™ at both doses decreased significantly the mean body weight gains (MBWG) of rats submitted to the FED in comparison to the positive control (−6.8% and −11.8%). ID‐alG™ at both doses improved significantly the MBWG of rats and decreased significantly the percentage of body fat mass of rats (−9.8% and −19.0%), in comparison to the positive control. In the same way, the triglyceride blood level was also significantly improved for the dose of 400 mg/kg/day (−30.6% vs. +49.9% for the positive control); and the dose of 40 mg/kg/day just lead to a trend. Moreover, in both controls and ID‐alG™‐treated groups, total cholesterol, LDL and HDL blood levels were not modified. The seaweed extract of Ascophyllum nodosum, ID‐alG™, demonstrated beneficial effects on weight management of rats submitted to a high‐fat diet. Copyright

Behavioral toxicity and physiological changes from repeated exposure to fluorene administered orally or intraperitoneally to adult male Wistar rats: A dose-response study.

Fluorene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in the environment by reason of its high volatility. Demonstrated to be a neurotoxicant through inhalation, it was also identified as a contributive PAH to food contamination. Since no data are available on its oral neurotoxicity, the purpose of the present study was to assess the behavioral and physiological toxicity of repeated oral administration of fluorene to adult Wistar male rats. Animals were daily treated with fluorene at 1, 10 or 100mg/kg/day for 28 consecutive days. Administration was intraperitoneal (i.p.) or oral (p.o.) to evaluate the influence of the route of exposure on fluorene toxicity. Following this period of treatment, animals in both groups were subjected to similar cognitive evaluations, namely anxiety (elevated-plus maze), locomotor activity (open-field) and learning and memory abilities (eight-arm maze and avoidance test of an aversive light stimulus), as well as physiological measurements. The behavioral testing occurred from the 28th to the 60th day of the experiment during which fluorene treatment continued uninterrupted. At the end of this period, the concentration levels of fluorene and of three of its monohydroxylated metabolites in blood and brain were determined using a GC-MS/MS method. The results demonstrated a reduction in rat anxiety level at the lowest doses administered (1 and 10mg/kg/day) regardless of the treatment route, whereas locomotor activity and learning abilities remained unchanged. Moreover, a less significant weight gain was noticed in animals i.p.- and p.o.-treated with 100mg/kg/day during the 28-day period of treatment, which, upon comparison with the three other groups, induced a body weight gap that was maintained throughout the experiment. Significant increases in relative liver weight were also observed in a dose-dependent manner in orally treated rats and only in animal treated i.p. with 100mg/kg/day. According to the dose, higher concentration levels of fluorene and its monohydroxylated metabolites were measured in blood and brain compartments of i.p.-treated rats compared to p.o.-treated animals. In conclusion, fluorene reduced the anxiety level of rats related to dose, treatment route, duration of exposure and blood concentration levels of metabolites.

p-Coumaric Acid Activates the GABA-A Receptor In Vitro and is Orally Anxiolytic In Vivo

The increasing prevalence and social burden of subclinical anxiety in the western world represents a significant psychosocial and financial cost. Consumers are favouring a more natural and nonpharmacological approach for alleviating the effects of everyday stress and anxiety. The gamma‐aminobutyric acid (GABA) receptor is the primary mediator of central inhibitory neurotransmission, and GABA‐receptor agonists are well known to convey anxiolytic effects. Using an in vitro screening approach to identify naturally occurring phytochemical GABA agonists, we discovered the plant secondary metabolite p‐coumaric acid to have significant GABAergic activity, an effect that could be blocked by co‐administration of the specific GABA‐receptor antagonist, picrotoxin. Oral administration of p‐coumaric acid to rodents induced a significant anxiolytic effect in vivo as measured using the elevated plus paradigm, in line with the effects of oral diazepam. Given that p‐coumaric acid is reasonably well absorbed following oral consumption in man and is relatively nontoxic, it may be suitable for the formulation of a safe and effective anxiolytic functional food. Copyright