A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers.

OBJECTIVE: To identify possible electroencephalographic (EEG) markers of donepezil's effect on cortical activity in young, healthy adult volunteers at the group level. METHODS: Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS: The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION: Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil's effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE: Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer's disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice.

Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22 weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidone-induced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidone-induced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human.

Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease.

BACKGROUND: Growing body of evidence suggests that Parkinson's disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). Low ceruloplasmin (CP)-ferroxidase activity has been identified in the SN and the cerebrospinal fluid (CSF) of patients with PD. The iron chelator, deferiprone, reduces the abnormally high levels of iron in the SN. In order to determine CP's involvement in iron accumulation in SN and PD progression, we aim to compare the ability of iron chelation treatment to reducing both SN iron levels and motor handicap in PD patients according to the level of ceruloplasmin activity. METHODS: We used a moderate chelation protocol with deferiprone (DFP) based on a, 6-month delayed-start paradigm, randomized placebo controlled clinical trial in 40 PD patients. CP-ferroxidase activity was determined in blood and CSF together with the D544E gene polymorphism (rs701753). Iron levels were determined by R2* MRI sequence and the motor handicap by the UPDRS motor score. RESULTS: After 6 to 12 months of DFP treatment, greater reductions in SN iron levels and UPDRS motor scores were obtained in patients with higher serum and CSF levels of CP-ferroxidase activity. After 6 months of DFP treatment, the AT genotype group displayed greater reduction of iron level in the SN with greater CSF and serum levels of CP activity than the AA genotype group. CONCLUSION: Although most of the DFP-treated patients displayed clinical and radiological improvements, those with the lower CP activity appeared to respond better to iron chelation. Larger RCTs are now needed to establish whether pharmacological modulation of CP activity could be an innovative neuroprotective strategy in PD. TRIAL REGISTRATION: FAIR-PARK study (ClinicalTrials.gov reference: NCT00943748 ; French national reference number: 2008-006842-25). This study was approved by the French Drug Agency (ANSM) and the local institutional review board ("Comité de Protection des Personnes of Lille").

Therapeutic prospects of PPARs in psychiatric disorders: a comprehensive review.

Peroxisome Proliferator-Activated Receptors (PPARs) are a family of nuclear receptors whose activation modulates the gene expression that underlies both the glucid-lipid and the inflammation pathways. While many PPARs agonists have been used for years as medication for metabolic disorders, an increasing attention is being currently dedicated to these drugs for inflammation-related pathologies. Within the psychiatric field, it has recently appeared that inflammatory processes are highly suspected in the pathophysiology of several important disorders, such as schizophrenia and mood disorders. By their anti-inflammatory properties, PPARs might have a disease-modifying action that could help in improving the outcome of patients. Furthermore, recent data suggest that PPARs could also modulate the expression of some neurotransmission factors. Therefore, PPARs may directly modify the information processing, and have a potential symptomatic action on several psychiatric disorders. At last, PPARs action of metabolic regulation could have a role on corrective or even preventive strategies against the metabolic adverse events that are commonly observed with some current psychiatric medications, notably antipsychotics. This triple potential action profile of PPARs modulators is investigated in this article, successively for schizophrenia spectrum disorders and mood disorders. Theoretical involvements of PPARs are also discussed for the treatment of Post- Traumatic Stress Disorder and Personality Disorders. At the time of the emerging concept of psychoneuroimmunology, PPARs open original therapeutic prospects for the psychiatric research.

Oral administration of docosahexaenoic acid/eicosapentaeinoic acids is not anticonvulsant in rats: implications for translational research.

Omega-3 and omega-6 poly-unsaturated fatty acids (PUFAs) are dietary fatty acids that are involved in a myriad of physiological processes in the brain. Although experimental data have shown that PUFAs have anticonvulsant properties, the outcomes of clinical trials have been controversial. Docosahexaenoic acid (DHA) is a PUFA which has been reported to exert anticonvulsant effects. Here we studied anticonvulsant potential of a mixture of enriched n-3 PUFA upon their oral administration in rats. We did not observe an anticonvulsant effect of n-3 PUFA in the i.v. pentylentetrazol threshold test. n-3 PUFA component was increased in the plasma of rats treated with the eicosapentaenoic acid (EPA)/DHA mix (275 mg/kg/d/400 mg/kg/d) due to the increase of both DHA and EPA. We also found modification of PUFA composition in the brain. Despite PUFA profiles modified both in plasma and in the brain, we did not find any anticonvulsant effect of orally administered DHA. Further studies are needed to define the type and the amount of fatty acids that would possess anticonvulsant properties. As the existing literature suggests that the route of administration of PUFA may be crucial, future studies should involve oral administration to provide relevant clinical information.

PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus.

Epidemiological data suggest that omega-3 polyunsaturated fatty acids (PUFA) consumption may be inversely correlated to the prevalence and severity of depression but little is known about the underlying mechanisms. In this study, we experimentally investigated whether a chronic supplementation with PUFA may induce antidepressant-like effects in mice in parallel to brain structural and molecular changes. Six weeks feeding with a PUFA-enriched diet induced behavioral changes in the Forced Swim Test (FST), the Tail Suspension Test and the Novelty-Suppressed Feeding Test. Moreover, more than 5 weeks supplementation with a PUFA blend containing 70% alpha-linolenic acid induced antidepressant-like effects in the FST with an increase in both swimming and climbing behaviors. The combination of a shorter duration of PUFA supplementation with a low dose of imipramine also induced an additive effect in the FST. Finally, PUFA supplementation was associated with an increase in the hippocampal volume, an over-expression of both synaptophysin and BDNF, and a raise in the number of newborn cells. Besides the possible modulation of brain plasticity, present results highlight the effectiveness of PUFA given alone or in combination with antidepressant drug as potential treatment of depressive disorders.

Anticonvulsant effects of linolenic acid are unrelated to brain phospholipid cell membrane compositions.

PURPOSE: Recent studies have revealed that polyunsaturated fatty acids (PUFAs) have anticonvulsive properties. Clinical trials using PUFAs reported conflicting results. It was suggested that PUFAs have anticonvulsant effects via modifications of brain phospholipids. Moreover, some authors suggested that the effect of the ketogenic diet (KD) leads to a high PUFA content. The aim of the study was to evaluate the anticonvulsant properties of a mixture containing alpha-linolenic acid (ALA) and linolenic acid (LA). METHODS: Four-week-old male Wistar rats were fed one of the following diets for 30 days: KD, standard diet, and standard diet with daily LA/ALA oral supplementation. Pentylenetetrazol (PTZ) threshold was used to assess the anticonvulsive effects of the diets. Nutritional status was monitored by body composition evaluation. Fatty acids composition of both plasma and brain phospholipids were also assessed. RESULTS: Animals fed the KD and those who had the daily LA/ALA supplementation exhibited an increase in PTZ threshold. The animals did not show any modification of body composition or brain phospholipid composition. The plasma fatty acids composition was modified by KD and LA/ALA. A decrease in arachidonic acid (AA) concentrations was observed in both the KD and LA/ALA groups, while an increase in eicosapentanoic acid (EPA) and ALA concentrations was only observed in the LA/ALA group. CONCLUSIONS: Our study shows that LA/ALA supplementation exerts anticonvulsive properties comparable to KD. Nutritional status can not explain the anticonvulsive effects of PUFAs supplementation. Brain phospholipids were not different within groups. The anticonvulsive effects of LA supplementation seem to be unrelated to brain phospholipid composition.

Effects of Microdesmis keayana alkaloids on vascular parameters of erectile dysfunction.

Microdesmis keayana (Pandaceae) is an African tropical plant whose roots are used in traditional medicine for erection impairment but the compounds responsible for its action are unknown. Two major alkaloids recently isolated from the roots of M. keayana, keayanidine B and keayanine, were tested for vasorelaxing properties using isolated rat aortic rings precontracted by phenylephrine to confirm its traditional use. Influence of the alkaloids on the endothelial production of endothelial nitric oxide synthase (eNOS) was measured by quantitative polymerase chain reaction (QPCR) analysis. Scavenging activities were assessed versus 1,1-diphenyl-2-picrylhydrazyle (DPPH) and reactive oxygen species (ROS) such as superoxide anion (O(2)(*-) and hydrogen peroxide (H(2)O(2)) in cell-free and cellular systems. The results showed that keayanidine B and keayanine had significant vasorelaxing properties. This effect could be due to their strong antioxidant activity versus O(2)(*-) and H(2)O(2) and to their stimulation of eNOS mRNA expression. Therefore these alkaloids could indirectly stimulate NO production in the vascular bed and would explain the traditional use of M. keayana in erectile dysfunction.

Vasoactivity, antioxidant and aphrodisiac properties of Caesalpinia benthamiana roots.

AIMS OF THE STUDY: Caesalpinia benthamiana (=Mezoneuron benthamianum) (Fabaceae) is an African tropical plant whose roots are used in traditional medicine as an aqueous decoction for many purposes, especially for erection impairment but its action mechanism is unknown. The action of Caesalpinia benthamiana on sexual behaviour and some assays on potential modes of action were performed. MATERIALS AND METHODS: The aqueous extract of Caesalpinia benthamiana (AECB) was tested for vasorelaxing properties using isolated rat aortic rings precontracted by phenylephrine. Influence of AECB in the production of endothelial isoform of nitric oxide synthase (eNOS) was measured by quantitative polymerase chain reaction (QPCR) analysis. Scavenging activities versus reactive oxygen species (ROS), such as superoxide anion (O(2).(-)), hydrogen peroxide (H(2)O(2)), and hypochlorous acid (HOCl) were assessed. Action of AECB on the cellular generation of O(2).(-) was also tested in a physiopathology model of oxidative burst using human polymorphonuclear neutrophils stimulated by phorbol myristate acetate. The aphrodisiac properties of AECB administered orally by gavage (50 mg/kg body weight) to male rats were evaluated by observing the sexual behaviour of animals. Finally, a short-term toxicity study was undertaken to establish the therapeutic index of AECB administered orally to rats at high dose (2 g/kg body weight). RESULTS: C. benthamiana roots are rich in phenolic compounds (gallic acid, resveratrol and tannins). The results showed that AECB had significant vasorelaxing properties. The extract also had a strong radical activity against ROS in cell-free and cellular systems and stimulated eNOS mRNA expression. As for the aphrodisiac activity of AECB in male rats, results have shown that sexual parameters are stimulated. Furthermore, after oral administration at high dose, AECB causes no mortality or changes in rats' behaviour. CONCLUSION: AECB enhanced the sexual activity of male rats. This could be partly explained by its vasorelaxant properties, which may be caused by an increase in NO production in vascular bed and a decrease in its destruction.

Neuroprotection: Present and future.

The treatment of brain diseases (regardless of the latter's neurological or psychiatric expression) is based on either preventive, symptomatic or etiopathogenic approaches. The frequent observation of neuronal death during brain disease initially prompted researchers to favour neuroprotection for the etiopathogenic approach. The repeated failure to develop reliable neuroprotective agents has prompted emergence of the concept of "disease modifyer". The disease modifyer concept (based essentially on clinical endpoints) enables us to envisage the broader application of etiopathogenic treatments by freeing ourselves of the need to demonstrate a cellular mechanism of action. The formalization of disease modification prompts several lines of thought, which are developed in the present article.

Paullinia pinnata extracts rich in polyphenols promote vascular relaxation via endothelium-dependent mechanisms.

Paullinia pinnata L. (Sapindaceae) is an African tropical plant whose roots and leaves are used in traditional medicine for many purposes, especially for erectile dysfunction, but its action mechanism is unknown. P. pinnata root and leaf methanolic extracts are rich in phenolic compounds. This study shows that both extracts are highly antioxidative and induce a slight transcriptional activity of peroxisome proliferator activated receptor-alpha. They also increased and decreased endothelial nitric oxide synthase and endothelin-1 mRNA levels in bovine aortic endothelial cells, respectively. In this study P. pinnata methanolic extracts in cumulative doses elicited in a dose-dependent manner the relaxation of phenylephrine precontracted isolated rat aortic rings. N-nitro-L-arginine methyl ester significantly attenuated the capacity of both extracts to induce arterial relaxation, indicating that this arterial relaxation was mediated by endothelial nitric oxide release. It could be suggested that the arterial relaxation induced by both extracts could be mainly linked to their capacities to inhibit nitric oxide oxidation through their antioxidant properties.

Vasoactivity and antioxidant properties of Microdesmis keayana roots.

Endothelial isoform of nitric oxide synthase (eNOS) mRNA expression increases in the corpora cavernosum, penile arteries and arterioles during erection. But eNOS expression and nitric oxide (NO), the product of its catalytic action, are inactivated by reactive oxygen species (ROS), especially by superoxide anion. ROS are involved in the impairment of endothelium-dependent relaxation and are responsible for some of the pathologies linked to erectile dysfunction (i.e. hypertension, atherosclerosis, etc.). While investigating Microdesmis keayana J. Léonard (Pandaceae) (syn. Microdesmis puberula Hook.f. ex. Planch.), used in African traditional medicine for erectile dysfunction, the hypotensive and the vasorelaxing properties of the aqueous extract of Microdesmis keayana (AEMK) were, respectively, tested using normotensive rabbits and aorta strips of guinea pigs in an organ bath experience. Interaction of AEMK in endothelial production of eNOS was measured by the quantitative polymerase chain reaction (QPCR) analysis. The scavenging activities versus ROS, such as superoxide anion (O(2)(.-)), hydrogen peroxide (H(2)O(2)), hypochlorous acid (HOCl) and hydroxyl radical (HO.) were evaluated. Action of AEMK on cellular generation of superoxide anion was also tested in a physiopathology model of oxidative burst using human polymorphonuclear neutrophils (PMNs) stimulated by phorbol myristate acetate. The results showed that Microdesmis keayana roots had significant hypotensive and vasorelaxing properties. These properties are due to both antioxidant activities and stimulation of eNOS mRNA expression. Therefore, AEMK stimulated indirectly NO production in the vascular bed.

Increased susceptibility of low-density lipoprotein to ex vivo oxidation in mice transgenic for human apolipoprotein B treated with 1 melatonin-related compound is not associated with atherosclerosis progression.

Considerable evidence supports the hypothesis that LDL oxidation has an important role in atherosclerosis. It has been demonstrated that the feeding of hypercholesterolemic mice on an atherogenic diet supplemented with melatonin highly increases the surface of atherosclerotic lesions in aorta and the sensitivity of atherogenic lipoprotein to ex vivo oxidation even though high melatonin doses inhibit lipoprotein oxidation in vitro. A melatonin-related compound (DTBHB: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3,5-di-tert-butyl-4-hydroxybenzamide) has been reported to strongly inhibit lipid peroxidation in vitro. In the present study, DTBHB treatment considerably increased the sensitivity of atherogenic lipoproteins to ex vivo oxidation but did not modify atherosclerotic lesion development in mice. Moreover, DTBHB treatment did not induce detectable lipidic alteration. These data confirm that the capacity of molecules to inhibit atherogenic lipoprotein oxidation in vitro offers no prediction of their capacity to inhibit in vivo atherosclerosis development.