Mitochondrial DNA methylation and copy number predict body composition in a young female population.

BACKGROUND: Since both genomic and environmental factors are involved in obesity etiology, several studies about the influence of adiposity on both nuclear DNA and mitochondrial DNA methylation patterns have been carried out. Nevertheless, few evidences exploring the usage of buccal swab samples to study mitochondrial DNA epigenetics can be found in literature. METHODS: In this study, mitochondrial DNA from buccal swabs collected from a young Caucasian population (n = 69) have been used to examine potential correlation between mitochondrial DNA copy number and methylation with body composition (BMI, WHtR and bioimpedance measurements). RESULTS: A negative correlation between mitochondrial DNA copy number and BMI was measured in females (p = 0.028), but not in males. The mean percentage of D-loop methylation is significantly higher in overweight than in lean female subjects (p = 0.003), and a specific CpG located in the D-loop shows per se an association with impaired body composition (p = 0.004). Body composition impairment is predicted by a combined variable including mtDNA copy number and the D-loop methylation (AUC = 0.785; p = 0.009). CONCLUSIONS: This study corroborates the hypothesis that mitochondrial DNA carries relevant information about body composition. However, wider investigations able to validate the usage of mtDNA methylation from buccal swabs as a biomarker are warranted.

Imbalance in redox system of rat liver following permethrin treatment in adolescence and neonatal age.

The effect of different permethrin treatments on the redox system of rat liver, is presented. Two types of oral administration were chosen: (i) sub-chronic treatment (1/10 of LD50 for 60 days) during adolescence (5 weeks old) and (ii) sub-acute treatment (1/44 of LD50 for 15 days) during early life (from postnatal days 6-21). The results show that adolescent permethrin treatment induces damage to the liver redox system, increasing lipid and protein peroxidation and reducing membrane fluidity in the hydrophilic--hydrophobic region of the bilayer. In addition, glutathione peroxidase (GPx) and GSH levels resulted decreased, while glutathione transferase (GST) and catalase (CAT) levels increased. The rats treated in early life with permethrin and sacrificed in adult age, showed less signs of damage compared to those exposed during adolescence in which lipid peroxidation was increased by 32%, whereas for the first group the raise was only 11%. Moreover, fluidity improved in the deeper hydrophobic membrane region of the treated group, while the level of CAT was significantly lower compared to the control one. Although sub-chronic treatment increased CAT and GST and decreased GPx and GSH levels, the present data suggest that a shorter exposure to permethrin during neonatal age decreased CAT level and it could represent an important risk factor for the onset of long-term liver damage.

Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer's disease rat model.

BACKGROUND: Alzheimer's disease (AD) is a frequent form of senile dementia. Neuroglobin (Ngb) has a neuroprotective role and decreases Aß peptide levels. Ngb, promoting Akt phosphorylation, activates cell survival involving cyclic-nucleotide response element-binding protein (CREB). A new molecule (IBU-LA) was synthetized and administered to an AD rat model to counteract AD progression. OBJECTIVE: The aim of this study was to investigate the IBU-LA-mediated induction of Ngb neuroprotective and antiapoptotic activities. METHODS: Brain morphology was analyzed through Bielschowsky staining, Aß(1-40) and Ngb expression by immunohistochemistry. Akt, p-Akt, CREB and p-CREB expression was evaluated by Western blot, apoptosis through cytochrome C/Apaf 1 immunocomplex formation, and TUNEL analysis. RESULTS: Bielschowsky staining and Aß(1-40) expression show few nerve connections and Aß(1-40) expression in an Aß sample, preserved neuronal cells and Aß(1-40) expression lowering in an IBU sample, mostly in IBU-LA. The Ngb level decreases in Aß samples, compared to control and IBU-LA samples. p-Akt/Akt and p-CREB/CREB ratios reveal a reduction in Aß sample, going back to the basal level in control and IBU-LA samples. Cytochrome C/Apaf 1 co-immunoprecipitate occurs and TUNEL-positive nuclei percentage decreases in Aß sample. Probe test performance shows an increased spatial reference memory in the IBU-LA compared to the Aß sample; no significant differences were seen between the IBU-LA and IBU samples. CONCLUSION: This evidence reveals that IBU-LA administration has the capability to maintain a high Ngb level allowing Ngb to perform a neuroprotective and antiapoptotic role, representing a valid tool in the therapeutic strategy of AD progression.

Early life permethrin exposure leads to hypervitaminosis D, nitric oxide and catecholamines impairment.

The aim of this study is to gain more knowledge on the impact of early life pesticide exposure on premature aging. The effect of a low dose of the insecticide permethrin administered to rats during early life (1/50 LD50, from 6th to 21st day of life) was analyzed by measuring some metabolites in plasma and urine of 500-day-old animals. Significant differences in early life treated rats compared to the control group were found in the plasma levels of Ca(++), Na(+), 25-hydroxy-vitamin D, adrenaline, noradrenaline, nitric oxide, cholesterol and urea while in urine only Na(+) content was different. These results add information on the impact of permethrin during the neonatal period, supporting the evidence that early life environmental exposure to xenobiotics has long-term effects, inducing modifications in adulthood that can be revealed by the analysis of some macroelements, metabolites and catecholamines in plasma, when rats are 500 days old.

Early-Life Exposure to Commercial Formulation Containing Deltamethrin and Cypermethrin Insecticides Impacts Redox System and Induces Unexpected Regional Effects in Rat Offspring Brain.

Several studies have shown that the oxidative impact of pesticides is most prevalent in rural environments where they are intensively used. At different levels, pyrethroids are reported to promote neurodegeneration; they share the ability to promote oxidative stress, and to induce mitochondrial impairments, α-synuclein overexpression and neuronal cell loss. The present study evaluates the impact of early-life exposure to a commercial formulation containing deltamethrin (DM) and cypermethrin (CYP) at a dose of 1/100 LD50 (1.28 and 2.5 mg/kg, respectively). Rats aged 30 days old, treated from the 6th to the 21st day of life, were tested for brain antioxidant activity and α-synuclein levels. Four regions of the brain were analyzed: the striatum, cerebellum, cortex and hippocampus. Our data demonstrated a significant increase in catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) antioxidant levels in the brain regions compared to the controls. Pups exhibited no significant changes in protein carbonyl levels and lipid peroxidation. Striatal α-synuclein expression was significantly reduced in the rats exposed to DM + CYP, while the treatment resulted in a non-significant increase in the other brain areas. These findings indicate unexpected effects of postnatal treatment with the commercial formulation containing DM and CYP on brain redox state and α-synuclein expression, suggesting an adaptive response.

CNS delivery of L-dopa by a new hybrid glutathione-methionine peptidomimetic prodrug.

Parkinson's disease (PD) is a neurodegenerative disorder associated primarily with loss of dopamine (DA) neurons in the nigrostriatal system. With the aim of increasing the bioavailability of L: -dopa (LD) after oral administration and of overcoming the pro-oxidant effect associated with LD therapy, we designed a peptidomimetic LD prodrug (1) able to release the active agent by enzyme catalyzed hydrolysis. The physicochemical properties, as well as the chemical and enzymatic stabilities of the new compound, were evaluated in order to check both its stability in aqueous medium and its sensitivity towards enzymatic cleavage, providing the parent LD drug, in rat and human plasma. The radical scavenging activities of prodrug 1 was tested by using both the DPPH-HPLC and the DMSO competition methods. The results indicate that the replacement of cysteine GSH portion by methionine confers resistance to oxidative degradation in gastric fluid. Prodrug 1 demonstrated to induce sustained delivery of DA in rat striatal tissue with respect to equimolar LD dosages. These results are of significance for prospective therapeutic application of prodrug 1 in pathological events associated with free radical damage and decreasing DA concentration in the brain.

Leukocyte Nurr1 as peripheral biomarker of early-life environmental exposure to permethrin insecticide.

The effect of a low dose of the insecticide permethrin administered during early-life was evaluated on leukocytes inflammation mediators on 300- and 500-day-old rats. Nurr1, NF-κB-p65, Nrf2, lipid peroxidation and GSH levels increased with age but compared to the control group, treatment with permethrin induced a significant increase only of Nurr1 and lipid peroxidation in oldest rats. TNF-α and Rantes increased, while IL-1ß, IL-2, IL-13 decreased in oldest treated rats. The results propose Nurr1, TNF-α, Rantes, GSH and plasma lipid peroxidation as peripheral biomarkers for monitoring the impact of early-life environmental exposure to xenobiotics in old age.

Ibuprofen and glutathione conjugate as a potential therapeutic agent for treating Alzheimer's disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, we synthesized a molecular combination of glutathione (GSH) and ibuprofen (IBU) via an amide bond and investigated its potential for targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation are related to AD. Evaluation of its physicochemical and in-vitro antioxidant properties indicated that compound 1 exhibits good stability toward human plasma enzymatic activity, and, like GSH, displays in-vitro free radical scavenging activity in a time and concentration-dependent manner. The new compound was also assessed by infusion in a rat model for Alzheimer's disease for its potential to antagonize the deleterious structural and cognitive effects of ß-amyloid(1-40). In behavioral tests of long-term spatial memory, animals treated with codrug 1 performed significantly better than those treated with ß-amyloid (Aß) peptide. Histochemical findings confirmed the behavioral data, revealing that Aß protein was less expressed in cerebral cortex treated with 1 than that treated with IBU. Taken together, the present findings suggest that conjugate 1 treatment may protect against the oxidative stress generated by reactive oxygen species (ROS) and the cognitive dysfunction induced by intracerebroventricular (i.c.v.) infusion of Aß(1-40) in rats, and thus that codrug 1 could prove useful as a tool for controlling AD induced cerebral amyloid deposits and behavioral deterioration.

Novel imidazoline compounds as partial or full agonists of D2-like dopamine receptors inspired by I2-imidazoline binding sites ligand 2-BFI.

Based on the well known biological versatility of the imidazoline nucleus, we prepared the novel derivatives 3a-k inspired by 2-BFI scaffold to assess imidazoline molecules as D(2)-like dopamine receptor ligands. Conservative chemical modifications of the lead structure, such as the introduction of an hydroxy group in the aromatic ring alone or associated with N-benzyl substitution, provided partial (3f) or nearly full (3e and 3h) agonists, all endowed with D(2)-like potency comparable to that of dopamine.

Ibuprofen and lipoic acid diamides as potential codrugs with neuroprotective activity.

Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-alpha-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-alpha-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1-3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-alpha-lipoic acid. Codrugs 1-3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of Abeta (1-40) protein showed that Abeta-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, Abeta (1-40) protein was less expressed in codrug-1-treated than in ibuprofen-treated cerebral cortex.

Permethrin induces lymphocyte DNA lesions at both Endo III and Fpg sites and changes in monocyte respiratory burst in rats.

Pyrethroids are widely used insecticides of low acute toxicity in mammals but the consequences of long-term exposure are of concern. Their insecticidal action is related to neurotoxicity and, in addition, there are indications of mammalian immuno-toxicity. In this work the effect of 60 days permethrin (150 mg kg(-1) body weight/day) exposure on two types of leukocytes (monocytes and lymphocytes) in adolescent rats was investigated. In particular, the monocyte respiratory burst response was first investigated, followed by studies on the degree and type of lymphocyte DNA damage induced by permethrin at this stage of life. Permethrin treatment reduces the monocyte respiratory burst response to phorbol myristate acetate, thereby decreasing superoxide anion (65%) and hydrogen peroxide (37%) production. Moreover an increase [correction made here after initial online publication] in monocyte plasma membrane fluidity in the hydrophilic-hydrophobic interface of the lipid bilayer was measured. Data obtained from the comet assay show that permethrin induces lymphocyte DNA lesions at both formamido pyrimidine glycosylase (Fpg) and endonuclease III (Endo III) sites in adolescent rats. Our results indicate the key role of permethrin in oxidative stress whose consequences lead to biochemical and functional changes. The reduced phagocyte respiratory burst induced by permethrin treatment and the type of DNA damage measured could represent new relevant aspects of pyrethroid toxicity which should be considered for human health.

Epigenetic Memory of Early-Life Parental Perturbation: Dopamine Decrease and DNA Methylation Changes in Offspring.

Early-life exposure (from postnatal day 6 to postnatal day 21) to permethrin has been associated with long-term development of dopaminergic neurodegeneration in rats. Here, we first investigated if the dopamine decrease observed following early postnatal exposure to permethrin, an oxidative stressor, can impair the dopamine level in the brain of their untreated offspring. Secondly, we evaluated whether this adverse event affects the epigenome of both directly exposed rats (F0) and their untreated offspring (F1). The results show that early-life exposure to the stressor is associated with changes in global DNA methylation and hydroxymethylation in adult age. Furthermore, parental exposure leads to a significant reduction in dopamine level in the offspring (F1) born from parents or just mothers early-life treated (72.72% and 47.35%, respectively). About 2/3 of pups from exposed mothers showed a significant reduction in dopamine level compared to controls. Global DNA methylation and hydroxymethylation impairment was associated with the F1 pups that showed reduced dopamine. This study provides pivotal evidences on intergenerational effects of postnatal exposure to permethrin emphasizing that this xenobiotic can influence the epigenetic memory of early-life parental perturbations disturbing offspring health.

NOP Receptor Agonist Ro 64-6198 Decreases Escalation of Cocaine Self-Administration in Rats Genetically Selected for Alcohol Preference.

Cocaine dependence is a psychiatric condition for which effective medications are still lacking. Published data indicate that an increase in nociceptin/orphanin FQ (N/OFQ) transmission by NOP receptor activation attenuates cocaine-induced place conditioning and the locomotor sensitization effects of cocaine. This suggests that the activation of the N/OFQ receptor (NOP) may attenuate the motivation for psychostimulants. To further explore this possibility, we investigated the effect of the potent and selective NOP receptor agonist Ro 64-6198 on cocaine intake under 1 h short access (ShA) and 6 h long access (LgA) operant self-administration conditions in rats. We used Marchigian Sardinian alcohol-preferring (msP) rats and Wistar control rats. msP rats were used because we recently found that this rat line, originally selected for excessive alcohol drinking and preference, exhibits a greater propensity to escalate cocaine self-administration following LgA training. msP rats are also characterized by innate overexpression of the N/OFQ-NOP system compared with Wistar rats. Wistar and msP rats both exhibited an increase in cocaine self-administration under LgA conditions, with a higher trend toward escalation in msP rats. In Wistar rats, the intraperitoneal administration of Ro 64-6198 (0. 1 and 3 mg/kg) significantly decreased ShA cocaine self-administration. In Wistar rats that underwent LgA cocaine self-administration training, Ro 64-6198 induced no significant effect either during the first hour of self-administration or after the entire 6 h session. In msP rats, Ro 64-6198 significantly reduced cocaine self-administration both under ShA conditions and in the first hour of the LgA session. At the end of the 6 h session, the effect of Ro 64-6198 was no longer observed in msP rats. The highest dose of Ro 64-6198 (3 mg/kg) did not affect saccharin self-administration in msP rats but reduced saccharin self-administration in Wistar rats. Altogether, these data suggest that NOP receptor activation attenuates cocaine self-administration, and this effect tends to be more pronounced in a rat line with innately higher NOP receptor expression and that more robustly escalates cocaine intake.

Anti-Inflammatory, Anti-Arthritic and Anti-Nociceptive Activities of Nigella sativa Oil in a Rat Model of Arthritis.

This study investigated the preventive efficacy of the crude oil extracted from Nigella sativa seeds in a rat model of arthritis induced by using complete Freund's adjuvant (CFA). Nigella sativa oil at 1.82 mL/kg or 0.91 mL/kg (corresponding to 1596 and 798 mg/kg, respectively) was orally administered for 25 days from the day of immunization. One immunized group was treated orally with indomethacin (3 mg/kg) as a reference drug. Body weight growth rate, paw swelling, arthritis score, mechanical allodynia, locomotor activity and anxiety-like behavior were observed, and the levels of Interleukin 6 (IL-6), C-reactive protein, albumin and total cholesterol in plasma were measured on days 15 and 25. Nigella sativa oil showed anti-inflammatory, anti-arthritic and anti-nociceptive activities that were significant as compared to untreated arthritic rats but less than indomethacin. These results indicated that Nigella sativa oil significantly attenuated adjuvant-arthritis in rats and the higher dose (1.82 mL/kg) prevented the development of arthritis with an inhibition of 56%.

Positive effect of an electrolyzed reduced water on gut permeability, fecal microbiota and liver in an animal model of Parkinson's disease.

There is growing awareness within the scientific community of the strong connection between the inflammation in the intestine and the pathogenesis of Parkinson's disease (PD). In previous studies we developed a PD animal model exposing pup rats to permethrin (PERM) pesticide. Here, we intended to explore whether in our animal model there were changes in gut permeability, fecal microbiota and hepatic injury. Moreover, we tested if the co-treatment with an electrolyzed reduced (ERW) was effective to protect against alterations induced by PERM. Rats (from postnatal day 6 to 21) were gavaged daily with PERM, PERM+ERW or vehicle and gut, liver and feces were analyzed in 2-months-old rats. Increased gut permeability, measured by FITC-dextran assay, was detected in PERM group compared to control and PERM+ERW groups. In duodenum and ileum, concentration of occludin was higher in control group than those measured in PERM group, whereas only in duodenum ZO-1 was higher in control than those measured in PERM and PERM+ERW groups. Number of inflammatory focis and neutrophils as well as iNOS protein levels were higher in livers of PERM-treated rats than in those of PERM+ERW and control rats. Fecal microbiota analysis revealed that Lachnospira was less abundant and Defluviitaleaceae more abundant in the PERM group, whereas the co-treatment with ERW was protective against PERM treatment since the abundances in Lachnospira and Defluviitaleaceae were similar to those in the control group. Higher abundances of butyrate- producing bacteria such as Blautia, U.m. of Lachnospiraceae family, U.m. of Ruminococcaceae family, Papillibacter, Roseburia, Intestinimonas, Shuttleworthia together with higher butyric acid levels were detected in PERM+ERW group compared to the other groups. In conclusion, the PD animal model showed increased intestinal permeability together with hepatic inflammation correlated with altered gut microbiota. The positive effects of ERW co-treatment observed in gut, liver and brain of rats were linked to changes on gut microbiota.

Antioxidant and Anti-Inflammatory Properties of Nigella sativa Oil in Human Pre-Adipocytes.

The oil obtained from the seeds of Nigella sativa L. (N. sativa), also known as black cumin, is frequently used in the Mediterranean area for its anti-inflammatory, anti-oxidant, and anti-cancer activities. The aim of the present study was to evaluate the antioxidant and anti-inflammatory properties of the oil extracted from seeds of a N. sativa cultivar produced in the Marche region of Italy, and to determine if the thymoquinone content, antioxidant properties, and biological activity would decay during storage. Cytotoxicity and anti-inflammatory properties of N. sativa oil were tested in an in vitro model of low-grade inflammation in Simpson⁻Golabi⁻Behmel syndrome human pre-adipocytes. The fresh extracted oil (FEO) contained 33% more thymoquinone than stored extracted oil (SEO), demonstrating that storage affects its overall quality. In addition, the thymoquinone content in the N. sativa oil from the Marche region cultivar was higher compared with other N. sativa oils produced in the Middle East and in other Mediterranean regions. Pro-inflammatory cytokines (e.g., Interleukin (IL)-1alpha, IL-1beta, IL-6) were differently modulated by fresh and stored extracts from N. sativa oils: FEO, containing more thymoquinone reduced IL-6 levels significantly, while SEO inhibited IL-1beta and had a higher antioxidant activity. Total antioxidant activity, reported as µM of Trolox, was 11.273 ± 0.935 and 6.103 ± 0.446 for SEO and FEO (p = 1.255 × 10-7), respectively, while mean values of 9.895 ± 0.817 (SEO) and 4.727 ± 0.324 (FEO) were obtained with the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay (p = 2.891 × 10-14). In conclusion, the oil capacity to counteract proinflammatory cytokine production does not strictly depend on the thymoquinone content, but also on other antioxidant components of the oil.

Early impairment of epigenetic pattern in neurodegeneration: Additional mechanisms behind pyrethroid toxicity.

Permethrin is a synthetic pyrethroid extensively used as anti-woodworm agent and for indoor and outdoor pest control. The main route of human exposure is through fruit, vegetable and milk intake. Low dosage exposure to permethrin during neonatal brain development (from postnatal day 6 to postnatal day 21) leads to dopamine decrease in rat striatum nucleus, oxidative stress and behavioural changes linked to the development of Parkinson's like neurodegeneration later in life. The aim of this study was to evaluate the expression of genes involved in the dopaminergic pathway and epigenetic regulatory mechanisms in adolescent rats treated with permethrin during neonatal brain development. Furthermore, in order to shed light on the mechanisms associated with molecular impairments, in silico studies were performed. The outcomes show increased expression of genes related to the dopamine-synthesis pathway (Nurr1, Th, Snca), epigenetics (TET proteins and Mecp2) and exposure to toxicants (Pon1 and Pon2) in adolescent rats compared with control group. Furthermore, increased global 5mC and 5hmC levels were observed in the DNA extracted from striatum of early-life treated rats in comparison with controls. FAIRE-qPCR analysis shows that permethrin induces an enrichment of chromatin-free DNA at the level of Th and Nurr1 promoters, and ChIP-qPCR reveals a significant reduction in methylation levels at H3K9me3 position at both Th and Nurr1 promoter regions. In silico studies show that permethrin competes for the same two binding sites of known NURR1 agonists, with a lower binding free energy for permethrin, suggesting an important durable association of permethrin with the orphan receptor. Moreover, alpha-synuclein shows a strong affinity for NURR1, corroborating previous experimental outcomes on the interactions between them. This study focuses on an emerging role of early-life exposure to environmental pollutants in the regulation of late onset diseases through intriguing mechanisms that change crucial epigenetic patterns starting from adolescent age.

Effect of permethrin plus antioxidants on locomotor activity and striatum in adolescent rats.

Pyrethroids are important insecticides used largely because of their high activity as an insecticide and their low mammalian toxicity. Some studies have demonstrated that these products show neurotoxic effects on the mammalian central nervous system. The aim of the present study was to investigate the propensity of permethrin to induce oxidative stress in adolescent rats and its possible attenuation by Vitamin E alone or+Coenzyme Q(10). Data indicated that adolescent rats exposed to permethrin exhibited alteration in the locomotor activity and plasma membrane fluidity of striatum. Vitamin E+Q(10) and Vitamin E alone supplementation reversed the negative effect on central nervous system. Permethrin alteration of striatum plasma membrane fluidity was restored by Vitamin E+Q(10). Data obtained from red blood cells showed that permethrin did not induce any modification of plasma membrane fluidity in adolescent rats, whereas antioxidants supplementation induced pro-oxidant effect. In summary some differences between antioxidant treatments were observed at striatum level: Coenzyme Q(10)+Vitamin E maintains plasma membrane fluidity, while Vitamin E is more effective to preserve GSH level.

Synthesis and study of L-dopa-glutathione codrugs as new anti-Parkinson agents with free radical scavenging properties.

A series of novel molecular combinations (1-4), in which L-dopa (LD) is linked covalently via an amide bond with glutathione (GSH), were synthesized and evaluated as potential anti-Parkinson agents with antioxidant properties. These conjugates were characterized by evaluating solubility, chemical and enzymatic stabilities, and apparent partition coefficient (log P). Derivatives 2 and 4 were tested for their radical scavenging activities, by use of a test involving the Fe(II)/H2O2-induced degradation of deoxyribose. In this study, the antioxidant efficacy of codrugs 1 and 3 was also assessed through the evaluation of plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Furthermore, the central nervous effects and rat striatal concentration of LD and dopamine (DA) have been evaluated after oral administration of codrugs 1 and 3. Tested compounds prolonged the plasma LD levels and were able to induce sustained delivery of DA in rat striatum with respect to an equimolar dose of LD. The results suggest that compounds 1 and 3 could represent useful new anti-Parkinson agents devoid of the pro-oxidant effects associated with LD therapy and potentially able to restore the GSH depletion evidenced in the substantia nigra pars compacta (SNpc) of PD patients.

Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids.

Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.