Omega-3 polyunsaturated fatty acids and Parkinson's disease: A systematic review of animal studies.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The primary pathological features of PD include the presence of α-synuclein aggregates and Lewy bodies, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Recently, omega-3 fatty acids (ω-3 PUFAs) have been under investigation as a preventive and/or therapeutic strategy for PD, primarily owing to their antioxidant and anti-inflammatory properties. Therefore, the objective of this study was to conduct a systematic review of the literature, focusing on studies that assessed the effects of ω-3 PUFAs in rodent models mimicking human PD. The search was performed using the terms "Parkinson's disease," "fish oil," "omega 3," "docosahexaenoic acid," and "eicosapentaenoic acid" across databases PUBMED, Web of Science, Science Direct, Scielo, and Google Scholar. Following analysis based on predefined inclusion and exclusion criteria, 39 studies were included. Considering behavioral parameters, pathological markers of the disease, quantification of ω-3 PUFAs in the brain, as well as anti-inflammatory, antioxidant, and anti-apoptotic effects, it can be observed that ω-3 PUFAs exhibit a potential neuroprotective effect in PD. In summary, this systematic review presents significant scientific evidence regarding the effects and mechanisms underlying the neuroprotective properties of ω-3 PUFAs, offering valuable insights for the development of future clinical investigations.

Preclinical toxicological assessment of polydatin in zebrafish model.

Polydatin (3,4',5-trihydroxystilbene-3-ß-D-glucoside, piceid), a natural stilbenoid found in different plant sources, has gained increasing attention for its potential health benefits. However, prior to its widespread adoption in human therapeutics and consumer products, a comprehensive investigation of its toxicological effects is crucial. In this study, the toxicity of polydatin was investigated in a developmental toxicity test using zebrafish (Danio rerio) as a valuable model for preclinical assessments. We employed the Fish Embryo Test (FET test - OECD n°236) to investigate the effects of polydatin on survival, hatchability, development, and behavior of zebrafish embryo-larval stage. Remarkably, the results demonstrated that polydatin up to 435 µM showed no toxicity. Throughout the exposure period, zebrafish embryos exposed to polydatin exhibited normal development, with no significant mortality observed. Furthermore, hatching success and heartbeat rate were unaffected, and no morphological abnormalities were identified, signifying a lack of teratogenic effects and cardiotoxicity. Locomotion activity assessment revealed normal swimming patterns and response to stimuli, indicating no neurotoxic effects. Our study provides valuable insights into the toxicological profile of polydatin, suggesting that it may offer potential therapeutic benefits under a considerable concentration range. In addition, zebrafish model proves to be an efficient system for early-stage toxicological screening, guiding further investigations into the secure utilization of polydatin for human health and wellness.

Experimental models of chemically induced Parkinson's disease in zebrafish at the embryonic larval stage: a systematic review.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that results in a decrease in dopamine levels, resulting in motor-type disturbances. Different vertebrate models, such as rodents and fish, have been used to study PD. In recent decades, Danio rerio (zebrafish) has emerged as a potential model for the investigation of neurodegenerative diseases due to its homology to the nervous system of humans. In this context, this systematic review aimed to identify publications that reported the utilization of neurotoxins as an experimental model of parkinsonism in zebrafish embryos and larvae. Ultimately, 56 articles were identified by searching three databases (PubMed, Web of Science, and Google Scholar). Seventeen studies using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 4 1-methyl-4-phenylpyridinium (MPP+), 24 6-hydroxydopamine (6-OHDA), 6 paraquat/diquat, 2 rotenone, and 6 articles using other types of unusual neurotoxins to induce PD were selected. Neurobehavioral function, such as motor activity, dopaminergic neuron markers, oxidative stress biomarkers, and other relevant parameters in the zebrafish embryo-larval model were examined. In summary, this review provides information to help researchers determine which chemical model is suitable to study experimental parkinsonism, according to the effects induced by neurotoxins in zebrafish embryos and larvae.

Effects of curcumin to counteract levodopa-induced toxicity in zebrafish.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction due to the death of dopaminergic neurons in the substantia nigra pars compacta. Currently, treatment of PD has focused on increasing dopamine levels, using a dopamine precursor, levodopa (L-DOPA) or stimulation of dopaminergic receptors. Prolonged use of L-DOPA is associated with the occurrence of motor complications and dyskinesia, attributed to neurotoxic effects of this drug. The aim of this study was to investigate the effects of curcumin (CUR), a lipophilic polyphenol, to counteract L-DOPA induced toxicity. Zebrafish larvae were pre-treated with CUR (0.05 µM) or vehicle dimethyl sulfoxide (DMSO) for 24 hr and subsequently exposed to L-DOPA (1 mM) or vehicle. Immediately and 24 hr after L-DOPA exposure, spontaneous swimming and dark/light behavioral tests were performed. In addition, levels of reactive oxygen species (ROS) and lipid peroxidation products were determined at the end of treatment. CUR significantly improved the motor impairment induced by 24 hr L-DOPA treatment, and reduced levels of ROS and lipoperoxidation products in zebrafish larvae. In conclusion, our results suggest that CUR acts as a neuroprotector against toxicity initiated by L-DOPA. Evidence suggests the observed effects of CUR are associated with its antioxidant properties.

Toxicity evaluation of traditional and organic yerba mate (Ilex paraguariensis A. St.-Hil.) extracts.

Yerba mate (Ilex paraguariensis A. St.-Hil.) is an important source of biologically active compounds with pharmacological potential. The aim of this study was to examine the toxicity of different extracts obtained from either traditional or organic cultivated yerba mate in vitro and in vivo. Aqueous, ethanolic and methanolic extracts were obtained from commercial samples of yerba mate and total phenolic content was determined employing Folin-Ciocalteau reagent. The aqueous extracts presented higher content of total phenols, compared to ethanolic and methanolic extracts, and also demonstrated lower cytotoxicity, which is the basis for testing were carried out only using aqueous extracts. The main phenolic acids found in traditional aqueous (TA) extract were chlorogenic, gallic and protocatechuic acids. Gallic and hydroxybenzoic acids were detected in aqueous cultivated organic (OA) extract. Pretreatment with OA extract (100 µg/ml, 1 hr) was cytoprotective against rotenone-induced toxicity (1 µM). For in vivo toxicity assay, zebrafish embryos were exposed to OA or TA extracts (10-160 µg/ml) at 4 hr post fertilization. TA extract decreased embryos survival in a concentration-dependent manner, reduced the hatching rate at 40 µg/ml, increased edema frequency at 80 µg/ml and altered body curvature at 120 µg/ml. Further, TA extract produced locomotor disorders at concentrations equal to or greater than 10 µg/ml. In contrast, OA extract exhibited no apparent toxic effect on organogenesis and behavior up to 100 µg/ml. In summary, the OA cultivated extract showed the lowest cytotoxicity in vitro, enhanced reduction in rotenone-induced toxicity, and produced less toxicity in zebrafish embryos compared to the TA extract.

Phenolic compounds and antioxidant capacity of Pediastrum boryanum (Chlorococcales) biomass.

Bioactive compounds, synthesized by photosynthetic microorganisms, have drawn the attention of the pharmaceutical field. This study aimed at evaluating synthesis and in vitro antioxidant capacity of phenolic compounds produced by a microalgae species P. boryanum, which was grown in six different culture media (standard BG11, modified BG11/MBG11, standard WC, modified WC, WC*2 and basal). The highest concentrations of biomass (1.75 ± 0.01 g.L-1) and phenolic content (3.18 ± 0.00 mg.g-1) were obtained when P. boryanum was grown in MBG11 and phenolic acids were identified: gallic, protocatechuic, chlorogenic, hydroxybenzoic and vanillic ones. All extracts exhibited scavenger activity in the ABTS assay and inhibited peroxidase. However, phenolic compounds from P. boryanum grown in BG11 and MBG11 had the most potent scavenger activity in the DPPH assay. In sum, P. boryanum can be a new source of free phenolic compounds with potential antioxidant activity when grown in MBG11, since it yields high amounts of biomass and phenolic compounds.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

In vivo toxicity evaluation of nanoemulsions for drug delivery.

Lipid nanocarriers (LNs), for example nanoemulsions (NE), are an emerging tool for drug delivery due to their ability to incorporate drugs, protect the drug from degradation, improve bioavailability, and control release. Although LNs are widely studied and applied, especially in the pharmaceutical field, knowledge about their toxicity is scarce. Moreover, the majority of studies focus on their efficiency rather than safety. Thus, the aim of this study was to evaluate the possible toxic effects of NE in vivo. Male Wistar rats (2 months old, 250 g) were treated once daily for 21 days with NE via oral or intraperitoneal delivery at 200, 400 or 800 mg lipid/kg body weight. At the end of the experiment, biochemical, hematological, oxidative stress, and genotoxicity parameters were analyzed. Our results showed that treatment with NE did not modify organ weight or biochemical parameters when compared to controls. The highest NE dose (800 mg/kg) via intraperitoneal injection caused changes in hematological parameters, namely increased plasma proteins, platelets, total leukocytes, and neutrophils, findings that suggest an inflammatory reaction. Further, the same dose evoked lipid peroxidation in the liver. Taken together, the results from this study suggest that NEs can be considered safe for oral administration, but high doses via the parenteral route can cause toxic effects. This study contributes to knowledge about NE toxicity and provides important data about their safe use in the pharmaceutical field.

Long-term and low-dose malathion exposure causes cognitive impairment in adult mice: evidence of hippocampal mitochondrial dysfunction, astrogliosis and apoptotic events.

The organophosphorus (OP) pesticide malathion is a neurotoxic compound whose acute toxicity is primarily caused by the inhibition of acetylcholinesterase (AChE), leading to cholinergic syndrome-related symptoms. Some lines of evidence indicate that long-term exposure to low levels of OP may produce neuropsychiatric and/or neurobehavioral signs that do not necessarily involve the AChE inhibition. This study evaluated the effects of a repeated (15-day period) and low-dose malathion exposure on spatial memory and discrimination (object location task), as well as on biochemical parameters in the hippocampus of mice [AChE and mitochondrial chain complexes activities; levels of proapoptotic proteins (Bax and Bak) and cholinergic neuronal and astroglial markers (ChAT and GFAP, respectively)]. Malathion treatments (30 and 100 mg/kg, s.c.) did not affect the body weight of animals and caused no evident signs of cholinergic toxicity throughout the treatment, although the highest dose (100 mg/kg) was associated with inhibition of AChE activity. Malathion-exposed animals showed a significant impairment on spatial memory and discrimination, which was correlated with a decrease in the mitochondrial complex I activity in the hippocampus. Moreover, malathion increased the levels of proapoptotic proteins and induced astroglial activation. The results show that long-term malathion exposure, at a dose that does not affect hippocampal AChE activity (30 mg/kg), caused impaired spatial memory and discrimination in mice that was related to hippocampal mitochondrial dysfunctional, astrogliosis and apoptosis. When extrapolated to humans, such results shed light on noncholinergic mechanisms likely related to the neurobehavioral and cognitive deficits observed in individuals chronically exposed to this pesticide.

Effects of quercetin in preclinical models of Parkinson's disease: A systematic review.

Parkinson's disease (PD) is a neurodegenerative disease that affects dopaminergic neurons, thus impairing dopaminergic signalling. Quercetin (QUE) has antioxidant and neuroprotective properties that are promising for the treatment of PD. This systematic review aimed to investigate the therapeutic effects of QUE against PD in preclinical models. The systematic search was performed in PubMed, Scopus and Web of Science. At the final screening stage, 26 articles were selected according to pre-established criteria. Selected studies used different methods for PD induction, as well as animal models. Most studies used rats (73.08%) and mice (23.08%), with 6-OHDA as the main strategy for PD induction (38.6%), followed by rotenone (30.8%). QUE was tested immersed in oil, nanosystems or in free formulations, in varied routes of administration and doses, ranging from 10 to 400 mg/kg and from 5 to 200 mg/kg in oral and intraperitoneal administrations, respectively. Overall, evidence from published data suggests a potential use of QUE as a treatment for PD, mainly through the inhibition of oxidative stress, neuroinflammatory response and apoptotic pathways.

Diphenyl diselenide prevents cortico-cerebral mitochondrial dysfunction and oxidative stress induced by hypercholesterolemia in LDL receptor knockout mice.

Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr(-/-)) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)2 (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr(-/-) mice. (PhSe)2 effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr(-/-) mice. Overall, (PhSe)2 may be a promising molecule to protect against hypercholesterolemia-induced effects on the central nervous system, in addition to its already demonstrated antiatherogenic effects.

Toward a Platform for the Treatment of Burns: An Assessment of Nanoemulsions vs. Nanostructured Lipid Carriers Loaded with Curcumin.

Curcumin is a highly promising substance for treating burns, owing to its anti-inflammatory, antioxidant, antimicrobial, and wound-healing properties. However, its therapeutic use is restricted due to its hydrophobic nature and low bioavailability. This study was conducted to address these limitations; it developed and tested two types of lipid nanocarriers, namely nanoemulsions (NE-CUR) and nanostructured lipid carriers (NLC-CUR) loaded with curcumin, and aimed to identify the most suitable nanocarrier for skin burn treatment. The study evaluated various parameters, including physicochemical characteristics, stability, encapsulation efficiency, release, skin permeation, retention, cell viability, and antimicrobial activity. The results showed that both nanocarriers showed adequate size (~200 nm), polydispersity index (~0.25), and zeta potential (~>-20 mV). They also showed good encapsulation efficiency (>90%) and remained stable for 120 days at different temperatures. In the release test, NE-CUR and NCL-CUR released 57.14% and 51.64% of curcumin, respectively, in 72 h. NE-CUR demonstrated better cutaneous permeation/retention in intact or scalded skin epidermis and dermis than NLC-CUR. The cell viability test showed no toxicity after treatment with NE-CUR and NLC-CUR up to 125 µg/mL. Regarding microbial activity assays, free curcumin has activity against P. aeruginosa, reducing bacterial growth by 75% in 3 h. NE-CUR inhibited bacterial growth by 65% after 24 h, and the association with gentamicin had favorable results, while NLC-CUR showed a lower inhibition. The results demonstrated that NE-CUR is probably the most promising nanocarrier for treating burns.

Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation.

Neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by the progressive loss of neuronal cells, resulting in different clinical symptoms according to the affected brain region. Although there are drugs available for the treatment of these diseases, they present relatively low efficacy and are not capable of modifying the course of the disease or stopping its progression. In the field of drug development, drug repurposing could be an interesting strategy to search new therapeutic options against neurodegenerative diseases, since it involves lower costs and time for development. In this review, we discuss the search of new treatments for Alzheimer's and Parkinson's disease through drug repurposing. A focus was given to drugs that modulate neuroinflammation, since it represents a common point among neurodegenerative diseases and has been explored as a target for drug action.

Neuroprotective Effects of Resveratrol in In vivo and In vitro Experimental Models of Parkinson's Disease: a Systematic Review.

Parkinson's disease (PD) is currently the second most common neurodegenerative disease, being characterized by motor and non-motor symptoms. The therapeutic options available for its treatment are limited, do not slow the progression of the disease, and have serious side effects. For this reason, many studies have sought to find compounds with neuroprotective properties that bring additional benefits to current therapy. In this context, resveratrol is a phenolic compound, found in many plant species, capable of crossing the blood-brain barrier and having multiple biological properties. Experimental studies in vitro and in vivo have shown that it can prevent or slow the progression of a variety of diseases, including PD. In this systematic review, we summarize the effects of resveratrol in experimental in vivo and in vitro models of PD and discuss the molecular mechanisms involved in its action. The bibliographic search was performed in the databases of PubMed, Web of Science, SciELO, and Google Scholar, and based on the inclusion criteria, 41 articles were selected and discussed. Most of the included studies have demonstrated neuroprotective effects of resveratrol. In general, resveratrol prevented behavioral and/or neurological disorders, improved antioxidant defenses, reduced neuroinflammatory processes, and inhibited apoptosis. In summary, this systematic review offers important scientific evidence of neuroprotective effects of resveratrol in PD and also provide valuable information about its mechanism of action that can support future clinical studies.

Effects of Progesterone on Preclinical Animal Models of Traumatic Brain Injury: Systematic Review and Meta-analysis.

Since the publication of two phase III clinical trials not supporting the use of progesterone in patients with traumatic brain injury (TBI), several possible explanations have been postulated, including limitations in the analysis of results from preclinical evidence. Therefore, to address this question, a systematic review and meta-analysis was performed to evaluate the effects of progesterone as a neuroprotective agent in preclinical animal models of TBI. A total of 48 studies were included for review: 29 evaluated brain edema, 21 evaluated lesion size, and 0 studies reported the survival rate. In the meta-analysis, it was found that progesterone reduced brain edema (effect size - 1.73 [- 2.02, - 1.44], p < 0.0001) and lesion volume (effect size - 0.40 [- 0.65, - 0.14], p = 0.002). Lack of details in the studies hindered the assessment of risk of bias (through the SYRCLE tool). A funnel plot asymmetry was detected, suggesting a possible publication bias. In conclusion, preclinical studies show that progesterone has an anti-edema effect in animal models of TBI, decreasing lesion volume or increasing remaining tissue. However, more studies are needed using assessing methods with lower risk of histological artifacts.

Development of a Novel Lipid-Based Nanosystem Functionalized with WGA for Enhanced Intracellular Drug Delivery.

Despite a considerable number of new antibiotics under going clinical trials, treatment of intracellular pathogens still represents a major pharmaceutical challenge. The use of lipid nanocarriers provides several advantages such as protection from compound degradation, increased bioavailability, and controlled and targeted drug release. Wheat germ agglutinin (WGA) is known to have its receptors on the alveolar epithelium and increase phagocytosis. The present study aimed to produce nanostructured lipid carriers with novel glycosylated amphiphilic employed to attach WGA on the surface of the nanocarriers to improve intracellular drug delivery. High-pressure homogenization was employed to prepare the lipid nanocarriers. In vitro, high-content analysis and flow cytometry assay was employed to study the increased uptake by macrophages when the nanocarriers were grafted with WGA. A lipid nanocarrier with surface-functionalized WGA protein (~200 nm, PDI > 0.3) was successfully produced and characterized. The system was loaded with a lipophilic model compound (quercetin; QU), demonstrating the ability to encapsulate a high amount of compound and release it in a controlled manner. The nanocarrier surface functionalization with the WGA protein increased the phagocytosis by macrophages. The system proposed here has characteristics to be further explored to treat intracellular pathogens.

Diphenyl diselenide effectively reduces atherosclerotic lesions in LDLr -/- mice by attenuation of oxidative stress and inflammation.

Glutathione peroxidase (GPx) plays an important role in the antioxidant defense of the vascular wall, and its deficiency has been implicated in the development of atherosclerotic lesions. This study analyzed the potential of diphenyl diselenide (DD), a simple organoselenium compound with GPx-like activity, to reduce atherosclerosis. Herein, we demonstrate that oral treatment with low doses of DD potently reduced the formation of atherosclerotic lesion in hypercholesterolemic low-density lipoprotein (LDL) receptor knockout (LDLr -/-) mice. This reduction was accompanied by significantly improved endothelium-dependent vasorelaxation, lower nitrotyrosine and malondialdehyde levels, decrease in vessel-wall infiltration by inflammatory cells, and prevention of upregulation of the proatherogenic monocyte chemoattractant protein-1. Studies in J774 macrophage-like cells show that DD significantly decreased oxLDL-induced formation of foam cells and the generation of reactive oxygen species and inflammatory mediators. Our results reveal the antiatherogenic actions of DD by modulating intracellular signaling pathways related to antioxidant and anti-inflammatory responses.

Nanoemulsion Improves the Neuroprotective Effects of Curcumin in an Experimental Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction. Recent studies have shown that curcumin (CUR) has neuroprotective effects in PD experimental models. However, its efficacy is limited due to low water solubility, bioavailability, and access to the central nervous system. In this study, we compared the effects of new curcumin-loaded nanoemulsions (NC) and free CUR in an experimental model of PD. Adult Swiss mice received NC or CUR (25 and 50 mg/kg) or vehicle orally for 30 days. Starting on the eighth day, they were administered rotenone (1 mg/kg) intraperitoneally until the 30th day. At the end of the treatment, motor assessment was evaluated by open field, pole test, and beam walking tests. Oxidative stress markers and mitochondrial complex I activity were measured in the brain tissue. Both NC and CUR treatment significantly improved motor impairment, reduced lipoperoxidation, modified antioxidant defenses, and prevented inhibition of complex I. However, NC was more effective in preventing motor impairment and inhibition of complex I when compared to CUR in the free form. In conclusion, our results suggest that NC effectively enhances the neuroprotective potential of CUR and is a promising nanomedical application for PD.

Mechanisms involved in the endothelium-dependent vasodilatory effect of an ethyl acetate fraction of Cyathea phalerata Mart. in isolated rats' aorta rings.

The species Cyathea phalerata Mart. is a tree fern, commonly known as "xaxim", which is found in tropical and subtropical areas of Brazil. The present study investigated the mechanisms related with the vasorelaxant effects of an Ethyl Acetate Fraction (EAF) obtained from C. phalerata in rats' thoracic aorta rings. In pre-contracted vessels, EAF (0.1-1000 µg/mL) caused a concentration-dependent relaxation. The endothelium denudation, the nitric oxide (NO) synthase and guanylyl cyclase inhibitor reduced the vasodilation, indicating the participation of NO/cGMP pathway in its effect. The relaxation of EAF was abolished in the absence of extracellular Ca2+ and was significantly decreased in the presence of Ca2+ entry blocker, suggesting that Ca2+ influx plays an important role in EAF effect and probably in eNOS activity. However, the PI3K/Akt pathway is not responsible for eNOS phosphorylation/activation. The vasodilator effect of EAF was partially inhibited by KCl 40 mM and almost totally abolished with L-NOARG + KCl 40 mM, indicating also the role of hyperpolarization in its effect. Calcium activated K+ channels are not involved in the EAF-induced hyperpolarization. The COX inhibitor, indomethacin, slightly reduced the vasodilation induced by EAF. In addition, EAF did not alter the relaxant effects of NO-donor, indicating that the relaxant activity cannot be attributed to free radical-scavenging properties. In conclusion, the present study showed that the EAF, causes an endothelium-dependent vasorelaxant effect in aorta that mainly involves the NO-cGMP pathway, hyperpolarization and prostanoids. The vasorelaxant activity of EAF can be attributed to the occurrence of polyphenol compounds.

Early Postnatal Exposure to Paraquat and Maneb in Mice Increases Nigrostriatal Dopaminergic Susceptibility to a Re-challenge with the Same Pesticides at Adulthood: Implications for Parkinson's Disease.

Exposure to environmental contaminants represents an important etiological factor in sporadic Parkinson's disease (PD). It has been reported that PD could arise from events that occur early in development and that lead to delayed adverse consequences in the nigrostriatal dopaminergic system at adult life. We investigated the occurrence of late nigrostriatal dopaminergic neurotoxicity induced by exposures to the pesticides paraquat (PQ) and maneb (MB) during the early postnatal period in mice, as well as whether the exposure to pesticides during development could enhance mice vulnerability to subsequent challenges. Male Swiss mice were exposed to a combination of 0.3 mg/kg PQ and 1.0 mg/kg MB (PQ + MB) from postnatal (PN) day 5 to 19. PN exposure to pesticides neither induced mortally nor modified motor-related parameters. However, PN pesticides exposure decreased the number of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-positive neurons in the substantia nigra pars compacta (SNpc), as well as reduced TH and DAT immunoreactivity in the striatum. A parallel group of animals developmentally exposed to the pesticides was re-challenged at 3 months of age with 10 mg/kg PQ plus 30 mg/kg MB (twice a week, 6 weeks). Mice exposed to pesticides at both periods (PN + adulthood) presented motor deficits and reductions in the number of TH- and DAT-positive neurons in the SNpc. These findings indicate that the exposure to PQ + MB during the early PN period can cause neurotoxicity in the mouse nigrostriatal dopaminergic system, rendering it more susceptible to a subsequent adult re-challenge with the same pesticides.