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Paraquat induces redox imbalance and disrupts glutamate and energy metabolism in the hippocampus of prepubertal rats
Abstract
Paraquat (1,1′-dimethyl-4,4′-bipyridinium dichloride; PQ) is a widely used herbicide in Brazilian crops, despite its banishment in many other countries. The present study investigated the effects of repeated dose of PQ on glutamate system, energy metabolism and redox parameters in the hippocampus of prepubertal rats. Twenty-two-day-old rats received daily intraperitoneal injections of PQ (10 mg/Kg) during 5 consecutive days and the effects of the pesticide were assessed 24 h after the last injection. The PQ exposure provoked cytotoxicity associated to decreased cell viability and increased glutamate excitotoxicity, as demonstrated by decreased 14C-glutamate uptake and increased ⁴⁵Ca²⁺ uptake. Downregulated glutamine synthetase (GS) activity, further supports disrupted glutamate metabolism compromising the glutamate-glutamine cycle. Downregulated ¹⁴C-2-Deoxy-D-glucose indicates energy failure and upregulated lactate dehydrogenase (LDH) suggests the relevance of lactate as energy fuel. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) upregulation suggest Krebs cycle replenishment and piruvate production. In addition, PQ disturbed the redox status inducing lipid peroxidation, evaluated by increased TBARS and imbalanced antioxidant system. Downregulated glutathione reductase (GR), gamma-glutamyltransferase (GGT), glutathione-S-transferase (GST) and glucose-6-P-dehydrogenase (G6PD) activities together with upregulated superoxide dismutase (SOD) and catalase activities corroborate the oxidative imbalance. The mechanisms underlying PQ-induced neurotoxicity involves the modulation of GSK-3β, NF-κB and NMDA receptors. These neurochemical and oxidative events observed may contribute to neuroinflammation and neurotoxic effects of PQ on hippocampal cells.
... Studies conducted in mice found that exposures to paraquat or glyphosate-based herbicides led to cognitive impairments and neurobehavioral alterations, including depressive-like behavior (Ait- Bali et al., 2020;Ait Bali et al., 2017). Glutamate excitotoxicity, oxidative distress, and neuroinflammation were demonstrated as hallmarks of paraquat-induced toxicity during neurodevelopment in a rodent model (Naspolini et al., 2021). In addition, the association between neurotoxic effects of pesticides and neurodegenerative conditions has been demonstrated (Vellingiri et al., 2022). ...
... Redox imbalance, mitochondrial dysfunction and neuroinflammation were described as key factors on the mechanism underlying the neurotoxic impacts of pesticides (Naspolini et al., 2021;Vellingiri et al., 2022;Tu et al., 2022;Naughton and Terry, 2018;Cattani et al., 2023). In addition, inflammatory processes were ascribed as one of the putative biological pathways associated with the neurobiology of both depressive mood and suicidal behavior (Abou Chahla et al., 2023;Troubat et al., 2021). ...
... The brain's high lipid content and oxygen consumption make it particularly susceptible to oxidative damage. Furthermore, through stimulation of cholinergic and glutamatergic receptors, pesticides increase mitochondrial permeability, calcium influx, and nitric oxide production, enhancing the generation of reactive oxygen species (ROS) and leading to cell death (Patel et al., 1996;Naughton and Terry, 2018;Karami-Mohajeri and Abdollahi, 2011;Naspolini et al., 2021). ...
... A exposição dos trabalhadores rurais a herbicidas tem sido associada à ocorrência de diversos problemas de saúde nesses indivíduos (Tsai, 2013;Mazlan et al., 2016;Myers et al., 2016;Islam et al., 2018;Naspolini et al., 2021). Os trabalhadores rurais que manuseiam e conduzem as operações de aplicação de herbicidas e outros defensivos agrícolas geralmente estão expostos a altos níveis de contaminação por esses produtos, e essa exposição se dá principalmente durante a preparação, mistura e carregamento e aplicações em spray (Yarpuz-Bozdogan e Bozdogan, 2016; Pinto et al., 2020). ...
... Efeitos deletérios da exposição de trabalhadores à herbicidas são bem reportados na literatura para diferentes princípios ativos, como Paraquat (Tsai, 2013) A toxidade do Paraquat em humanos e mamíferos está associada ao seu potencial redox, mesmo mecanismo que confere a ele atividade herbicida. O mecanismo de ação tóxica do Paraquat envolve reações de redução-oxidação cíclicas, no qual são produzidas espécies reativas de oxigênio e a depleção de NADPH reduzido (Tsai, 2013), o que confere alta toxidade a humanos (Naspolini et al., 2021). Se ingerido, o Paraquat produz uma sensação de queimação na boca e garganta, levando a náuseas, vômitos, diarreia etc. Mesmo que não seja absorvido de forma significativa pela pele humana se intacta, o contato direto com soluções ou aerossóis de Paraquat pode causar queimaduras na pele e dermatite. ...
... Estudos experimentais em animais e evidências epidemiológicas também indicam que a exposição crônica a esse herbicida pode estar associada ao desenvolvimento da doença de Parkinson (Tsai, 2013). Esse histórico de danos à saúde humana levaram o Paraquat a ser banido ou severamente restringido em mais de 20 países ao redor do mundo; porém somente em setembro de 2020 o Brasil entrou na lista de países que o baniram, muito embora seu uso em algumas lavouras brasileiras ainda era permitido até julho de 2021 (Naspolini et al., 2021). ...
O Brasil se destaca internacionalmente como o maior produtor de cana-de-açúcar, uma cultura chave para o agronegócio nacional. Nessa cultura, a ocorrência de plantas daninhas pode ocasionar graves prejuízos, motivo pelo qual seu controle se faz necessário. Para isso, se faz uso principalmente do controle químico à base de herbicidas. Entretanto, a exposição dos trabalhadores rurais a herbicidas tem sido associada à ocorrência de diversos problemas de saúde nesses indivíduos. Nesse sentido, este trabalho busca levantar, por meio de levantamento bibliográfico, a importância da cultura da cana-de-açúcar e o uso de herbicidas nessas culturas, os riscos aos quais os trabalhadores rurais estão expostos e quais agravos à saúde estão sujeitos pelo manuseio e aplicação desse produtos, bem como qual é a legislação que ampara esses trabalhadores e quais os desafios para garantir a efetividade dessa legislação. Para tanto, conduziu-se uma pesquisa bibliográfica utilizando o método de revisão integrativa. Os efeitos deletérios da exposição de trabalhadores à herbicidas são bem reportados na literatura para diferentes princípios ativos. O Brasil tem uma densa legislação vigente voltada para segurança do trabalho, o que, teoricamente, tornaria o manuseio e a aplicação de herbicidas e outros defensivos agrícolas uma atividade de baixo risco para a saúde do trabalhador rural. Todavia, infelizmente, esse não é o panorama visto em muitas regiões agrícolas do país, principalmente pelo não uso de Equipamentos de Proteção Individual (EPIs). Ações como treinamentos periódicos para esses profissionais se fazem necessárias e um maior rigor na fiscalização de uso também deve ser implementado. **Palavras-Chave**: Contaminação; Equipamentos de proteção individual; Exposição.
... Chronic exposure to pesticides such as glyphosate and paraquat impairs mitochondrial function and contributes to the pathogenesis of both Parkinson's and Alzheimer's diseases. Research by Wang et al. (2011) links Paraquat exposure to Parkinson's Disease and other study highlights its detrimental effects on the neuroendocrine axis (Naspolini et al. 2021). Similarly, Atrazine has been shown to have detrimental effects on monoaminergic brain pathways, increasing the expression of characteristic molecular markers of Parkinsonism (Zhao et al. 2024). ...
... The decrease in percentage change in animal weight is implied to be due to the paraquat neurotoxicity, which was improved significantly by the eugenol treatment as a mark of its therapeutic property. The current findings run counter to those of Nathalia et al. [52] and Li et al. [53], who claimed that rats exposed to 10 mg/kg of PQ for five days did not experience any changes in body weight but instead displayed cognitive, learning, and memory impairments. The disparity recorded in weight loss could be due to the length of the study, as our study is a sub-chronic study, while the studies cited above-concerning weight are acute studies. ...
Background
The Microtubules-associated protein tau (MAPT), alpha-synuclein (SNCA), and leucine zipper tumor suppressor 3 (LZTS3) genes are implicated in neurodegeneration and tumor suppression, respectively. This study investigated the regulatory roles of eugenol on paraquat-altered genes.
Results
Forty male Wistar rats divided into five groups of eight rats were used. The control group received normal saline; the Paraquat (PQ)-untreated group received only Paraquat. The low dose of eugenol was 200 mg/kg, the medium dose of eugenol was 400 mg/kg, and the high dose of eugenol was 600 mg/kg. All groups except the control group received 10 mg/kg of PQ orally for 14 days at one-day intervals, allowing PQ in the rats for 28 days. Eugenol treatment started on the 29th and lasted 14 days. Motor impairments were determined using wire string and beam-walk; biomarkers were estimated using cerebellar homogenates, while frozen cerebellum was used to study LZTS3, MAPT, and SNCA gene expression. LZTS3 was significantly suppressed in the PQ-untreated group and highly expressed in the eugenol-treated group. The MAPT and SNCA genes were overexpressed in the PQ-untreated group compared to the control group. Eugenol significantly decreased the expression of these genes compared to that in the PQ-untreated group. Antioxidants were reduced considerably, and oxidative stress markers were increased significantly, which could have caused increased protein fibrillation and reduced limb functionality. Histology revealed that eugenol mitigated the alterations caused by Paraquat.
Conclusions
PQ can enhance tumor expression in addition to causing neurotoxicity, which decreases limb functionality, while eugenol, an antioxidant, can mitigate the effects of PQ.
... Paraquat disrupts the oxidation of NADPH to NADP + via ETC complex I by accepting electrons to form a charged form of paraquat (PQ + ). This charged form of PQ generates superoxide radicals which in turn lead to the formation of other ROS products [41,91]. ...
The widespread incidence of brain tumors presents a substantial obstacle to public health due to their debilitating and lethal outcomes. Although the etiology of brain tumors is still an enigma, emerging evidence indicates a strong correlation between pesticide exposure and the onset of brain cancer. The commonly used pesticides, including organophosphates, organochlorines and pyrethroids, exert their toxic effects by inducing oxidative stress that causes damage to nucleic acids, lipids, and proteins. Oxidative stress is a significant factor in the development of brain cancer mainly due to its elevated oxygen consumption and abundance of polyunsaturated fatty acids that make it more susceptible to oxidative harm. Pesticides induce oxidative stress through various pathways, such as JAK-STAT and Keap1/Nrf2/ARE, which regulate reactive oxygen species production and antioxidant responses. Despite extensive research linking pesticides to brain tumors, precise molecular mechanisms remain unclear. The present review attempts to discuss the molecular mechanisms by which pesticides induce oxidative stress and explores the interplay between various signaling pathways in regulating reactive oxygen species and reactive nitrogen species. It also highlights the complicated relationship between pesticide-induced oxidative stress and brain cancer development and emphasizes the need for further investigation into the genetic and epigenetic impacts of pesticides on xenobiotic detoxification systems and the production of oncometabolites. By providing a comprehensive overview of the molecular foundations of pesticide-mediated genetic damage, this paper aims to contribute significantly to the existing literature for developing regulatory measures and safer alternatives to mitigate the health risks associated with pesticide exposure.
... The citric acid cycle, glycolysis, alanine, aspartate, and glutamate metabolism are the primary related pathways. An imbalance in the redox state can also severely disrupt the metabolic pathways of alanine, aspartate, and glutamate [37]. Although we did not detect a direct link between compound treatment and this metabolic pathway, the enrichment results might be due to the disruption of energy metabolism. ...
Swietenia macrophylla fruit is a valuable and historically significant medicinal plant with anti-hypertension and anti-diabetes. We identified a toxic component, Febrifugin, from the edible part of the nut following zebrafish toxicity-guided isolation. Febrifugin is a mexicanolide-type limonoid compound. The toxic factor induced acute toxicity in zebrafish, including yolk sac edema and pericardial edema, reduced body length, decreased melanin deposition, and presented acute skeletal developmental issues. Further exploration of the acute toxicity mechanism through metabolomics revealed that Febrifugin caused significant changes in 13 metabolites in zebrafish larvae, which are involved in the pentose phosphate, tricarboxylic acid (TCA) cycle, and amino acid biosynthesis. The bioassay of oxidative stress capacity and qRT-PCR measurement showed that the compound significantly affected the h6pd gene in the pentose phosphate pathway and the mRNA expression of cs, idh3a, fh, and shda genes in the TCA cycle, leading to reactive oxygen species (ROS) accumulation and a notable decrease in glutathione (GSH) activity in zebrafish. These findings provide a basis for the rational use of S. macrophylla as a medicinal plant and raise awareness of the safety of medicinal plants.
... Regarding the effect of PQ Naspolini et al 30 showed that PQ exposure and the oxidative stress response resulted in decreased glucose transport into neural cells associated with a compensatory increase in lactate dehydrogenase (LDH) activity suggesting the importance of lactate as energy fuel. To address the question if EHMT1 haploinsu ciency impacts LDH expression we measured the transcript levels of the two subunits of LDH, LDHA which has higher a nity for pyruvate and, LDHB with higher a nity for lactate. ...
In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high CDKN1A expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression.
KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive dopaminergic neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was detected in the KS spheroid as well, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.
... Glyphosate and its metabolite aminomethylphosphonic acid induced oxidative stress and the caspase 3/7 activation in neuroblastoma cell line SH-SY5Y (Martínez et al., 2020). Paraquat and glyphosate-induced neurotoxicity leads to oxidative stress and glutamate excitotoxicity (Cattani et al., 2014;Cattani et al., 2017;Naspolini et al., 2021). Moreover, glyphosate herbicide causes neurodevelopmental impacts in the expression of the neuropeptide dynorphin and increased the number of progenitor cells in adult rat hippocampal cells . ...
Pesticide exposure and poisoning may rise the risk of mental health problems and suicidal tendencies. To explore the potential connection between chronic occupational exposure to pesticides and depression, anxiety, and suicide-related outcomes in farmers, a systematic review was performed. Systematic review protocol is available in PROSPERO registration number CRD42022316285. A total of fifty-seven studies met inclusion criteria: twenty-nine on depression or other mental disorders, twelve on suicide (two of them on both depression and suicide), and fourteen on pesticide poisoning or self-poisoning and death. Among the fifty-seven selected studies, eighteen were conducted in Asia, seventeen in North America, fourteen in South America, seven in European Union, one in Africa, and one in Australia/Oceania. Selected studies demonstrated an increased prevalence of depressive disorders in farmworkers exposed to pesticides as well as an increased self-reported prevalence of depression in this population. Moreover, previous pesticide poisoning increased the risk estimates for depression or other mental disorders as compared with chronic pesticide exposure. Severe pesticide poisoning and multiple poisoning showed increased risks of depressive symptoms compared with milder cases. In addition, financial difficulties and poor health were positively correlated with depression. Among studies on suicide, nine of them found that suicide rates increased in areas devoted to agriculture with intensive pesticide consumption. Moreover, studies demonstrate a higher suicide risk among farmers. The present review suggests more attention to the farmer's mental health and more detailed studies on occupational exposure to the mixture of these compounds.
... Moreover, PQ activates NMDA receptors, leading to increased intracellular calcium concentrations and disrupting mitochondrial function. Disturbances in cell signal pathways such as such as Jun N-terminal kinase (JNK), protein kinase Cδ (PKCδ) and the cystein-3 signaling cascades are also responsible for PQ neurotoxicity (Bastías-Candia et al., 2019;Naspolini et al. 2021). It is still unknown how PQ exposure affects lipid metabolism and elicits neuroinflammation in the midbrain. ...
Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson’s disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.
... The study by Dwyer et al. [81] revealed the induction of nigrostriatal pathology, inflammatory changes, and stress and trophic effects. Naspolini et al. [82] reported glutamate neurotoxicity in rats. Amin et al. [83] confirmed the occurrence of systemic and pulmonary inflammation in rats after inhalation for 16 days. ...
The present review analyzed papers using adsorption that explore the removal of paraquat herbicide from aqueous effluents. Contamination and toxicology aspects of the paraquat are tackled as well. Analysis regarding the effects of process variables and textural proprieties on the paraquat adsorption is presented. The reported works found that the best adsorbent was those of silicate and carbon nature, which presented adsorption capacities above 400 mg g − 1. Unfortunately, most works do not report the paraquat solution's pH or perform adsorption conditions optimization. Regarding the adsorption kinetics, it was found that the pseudo-second-order is the proper model to represent several paraquat systems; however, mass transfer investigations are not presented. Classical isotherm models are the most employed, such as Langmuir and Freundlich. In addition, the paraquat adsorption systems are of any thermic nature (endothermic/exothermic), with the paraquat molecules binding due to physisorption. Last, common mistakes in the reports, knowledge gaps, and future perspectives are discussed, focusing on improving the adsorption works.
The preventative effects of a hydroalcoholic extract of Zataria multiflora (ZM) on hippocampal oxidative stress and memory alterations caused by inhaled paraquat (PQ) in rats were investigated.
The study included a control group of male Wistar rats administered saline (Ctrl) and PQ groups (54 mg/m3) aerosol eight times in alternate days. PQ groups were treated with two ZM extract doses (ZM-L and ZM-H), pioglitazone (Pio), combination of ZM-L + Pio and dexamethasone (Dexa) during PQ exposure (for 16 days). The doses and procedures were selected based on previous studies. Morris Water Maze (MWM) and shuttle box tests, as well as measurements of oxidative stress markers in the hippocampus, total and differential white blood cell (WBC) counts were performed.
PQ significantly increased total and differential WBC, MDA levels, escape latency and travelled distance in MWM test, but it reduced CAT, SOD, thiol levels, and time latency 24–72 h post-electric shock. Compared to the PQ group, ZM-L, ZM-H, Pio + ZM-L, and Dexa treatments significantly reverse the alterations of total and differential WBC, MDA, CAT, SOD, and thiol levels. ZM-H, Pio + ZM-L, and Dexa treatments decreased the escape latency on days 2–5, travelled distance on day 3, and time latency at 24–72 h post-electric shock. ZM-H had more preventive effects on most measured variables than ZM-L. The Pio + ZM-L group showed significantly greater effect than Pio on some measured variable than ZM-L (from p < 0.05 to p < 0.001 for all).
The study found that ZM similar to Dexa reduced PQ-induced hippocampal oxidative injury and memory alterations in a preventative manner. Additionally, Pio + ZM-L showed a synergistic effect, indicating that PPARγ-mediated processes play a role in preventive advantages of ZM.
NAFLD is gaining recognition as a complex, multifactorial condition with suspected associations with endocrine disorders. This investigation employed MR analysis to explore the potential causality linking NAFLD to a spectrum of endocrine diseases, encompassing T1D, T2D, obesity, graves’ disease, and acromegaly.
Our methodology leveraged a stringent IV selection process, adhering to the STROBE-MR guidelines. The MR analysis was conducted utilizing three distinct methods: IVW, WM, and MR-Egger. The IVW method was prioritized as the primary analytical approach. We conducted MR analyses to analyze the causal relationship between NAFLD and metabolic disorders. We also examined 1400 metabolites implicated in NAFLD. Metabolic pathway analysis was performed using the MetaboAnalyst database.
The findings indicated that T2D (OR = 1.211, 95%CI: 0.836–1.585) and obesity (OR = 1.245, 95%CI: 0.816–1.674) are associated with an increased risk of NAFLD development. Further exploration into the the 1400 metabolites revealed that cys-gly and diacetylornithine are predictive of NAFLD, T2D, and obesity, whereas isovalerylcarnitine exhibited an inverse association, potentially inhibiting disease development. Metabolic pathways involving alanine, aspartate, and glutamate metabolism were identified as pivotal regulators in the pathophysiology of NAFLD, T2D, and obesity.
The present study generated innovative viewpoints on the etiology of NAFLD. Our findings underscore the significant role of T2D and obesity in NAFLD pathogenesis through metabolic pathways, presenting opportunities for targeted therapeutic strategies and warranting further investigation.
In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.
Background
After hypovolemic shock caused by severe burns, lipid peroxidation is an important factor in tissue edema and multiorgan dysfunction syndrome (MODS). Many studies have shown that valproic acid (VPA) inhibits lipid peroxidation and reduces tissue and organ injury.
Objectives
This study investigated whether the VPA treatment of scalded rats reduced tissue edema by inhibiting lipid peroxidation, thereby improving organ function and survival rate.
Materials and Methods
A total of 60 male Sprague-Dawley rats (weighing: 280–300 g) with a 50% total body surface area (TBSA) full-thickness dermal burn were randomly assigned to the following 3 groups (with 20 rats per group): (I) the no infusion resuscitation (NR) group; (II) the sodium lactate Ringer’s solution (LR) group; and (III) the sodium valproate Ringer’s solution (VR) group. After scalding, the following hemodynamic parameters were measured: Copper ²⁺ -Zinc ²⁺ -superoxide dismutase (Cu ²⁺ -Zn ²⁺ -SOD) activity, thiobarbituric acid reactive substances (TBARSs), oxidized glutathione (GSSG), reduced glutathione (GSH), and antioxidant enzyme activities. Organ function parameters and water content were also measured. Another 60 male Sprague-Dawley rats were used to observe the 24-h survival rate of the rats using the same scald model and fluid resuscitation.
Results
VPA significantly increased the mean arterial pressure (MAP) and cardiac output (CO), and significantly decreased the pulmonary vascular permeability index (PVPI) and extravascular lung water index (ELWI). VPA also increased plasma Cu ²⁺ -Zn ²⁺ -SOD activity and decreased the plasma TBARS level. VPA reduced the TBARS level and GSSG in various tissues and increased the concentration of GSH. VPA decreased glutathione peroxidase (GPx) and catalase (CAT) activity, but significantly increased glutathione reductase (GR) activity in various tissues. VPA significantly improved organ functions and decreased water content. VPA significantly improved the survival rate, and the 24-h survival rate of the VR group was double that of the LR group.
Conclusion
Resuscitation with VPA reduced tissue edema, protected visceral functions, and improved the survival rate of rats with severe burn shock (BS) by alleviating lipid peroxidation.
The organ systems are specialized tissues that perform discrete functions. They are vital and thus have interdependencies. For instance, the heart and renal system both need and influence each other. When deficiency requirements of health and damaging factors lead to a weakened state, then the beginning of disease commences. This is at first hypofunction, then disordered circulation and communication in that tissue or organ. This further leads to inflammation, immune involvement, and eventually, fibrosis and drastic decline of function. Therapy involves addressing deficient requirements of health. More specific therapy involves supporting biochemical function, hormetic stimulation in the low-dose zone, and whole person therapy. These all help to increase adaptive responses of the body. Alternatively and often in combination, there are ways to dampen maladaptive responses and even to introduce some measure of homeostasis by external means. This is why standard medical therapy can often be successful, as it can externally create a balance or at least dampen maladaptive responses. But this may not lead to healing if the body is severely depleted and dysregulated.KeywordsDysfunctionNaturopathic treatmentDiagnosisWhole person approaches
The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) in offspring's liver. Pregnant Wistar rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 to postnatal day 15. The perinatal exposure to GBH increased 45Ca2+ influx in offspring's liver. Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca2+ channel modulation on GBH-induced Ca2+ influx in offspring's liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH-induced hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats perinatally exposed to GBH, which were associated with. Increased phospho-p65NFκB immunocontent. Therefore, we propose that excessive amounts of iron in offspring's liver, blood and bone marrow induced by perinatal exposure to GBH may account for iron-driven hepatotoxicity, which was associated with Ca2+ influx, oxidative damage and inflammation. Further studies will clarify whether these events can ultimately impact on liver function.
The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) on liver of immature Wistar rats. Female rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 and continually up to lactation day 15. The perinatal exposure to GBH increased ⁴⁵ Ca ²⁺ influx in offspring’s liver Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca ²⁺ channel modulation to GBH-induced Ca ²⁺ influx in liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats exposed to GBH. We also detected increased phospho-p65NFκB immunocontent, corresponding to the active form of this transcription factor. Therefore, we propose that excessive amounts of iron induced by perinatal exposure to GBH in offspring’s liver, blood and bone marrow may account for iron-driven hepatotoxicity, which was associated with Ca ²⁺ influx, oxidative damage and inflammation in immature rats. Further studies will clarify whether these events can ultimately impact on liver function.
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP⁺) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•–) production by acting on complex I. In RAW264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•– and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca²⁺/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.
Background:
Multiple studies have suggested that various pesticides are associated with a higher risk of developing Parkinson's disease (PD) and may influence the progression of the disease. However, the evidence regarding the impact of pesticide exposure on mortality among patients with PD is equivocal. This study examines whether pesticide exposure influences the risk of mortality among patients with PD in Southern Brazil.
Methods:
A total of 150 patients with idiopathic PD were enrolled from 2008 to 2013 and followed until 2019. In addition to undergoing a detailed neurologic evaluation, patients completed surveys regarding socioeconomic status and environmental exposures.
Results:
Twenty patients (13.3%) reported a history of occupational pesticide exposure with a median duration of exposure of 10 years (mean = 13.1, SD = 11.2). Patients with a history of occupational pesticide exposure had higher UPDRS-III scores, though there were no significant differences in regards to age, sex, disease duration, Charlson Comorbidity Index, and age at symptom onset. Patients with occupational pesticide exposure were more than twice as likely to die than their unexposed PD counterparts (HR = 2.32, 95% CI [1.15, 4.66], p = 0.018). Occupational pesticide exposure was also a significant predictor of death in a cox-proportional hazards model which included smoking and caffeine intake history (HR = 2.23, 95% CI [1.09, 4.59], p = 0.03)) and another which included several measures of socioeconomic status (HR = 3.91, 95% CI [1.32, 11.58], p = 0.01).
Conclusion:
In this prospective cohort study, we found an increased all-cause mortality risk in PD patients with occupational exposure to pesticides. More studies are needed to further analyze this topic with longer follow-up periods, more detailed exposure information, and more specific causes of mortality.
Living organisms are surrounded with heavy metals such as methylmercury, manganese, cobalt, cadmium, arsenic, as well as pesticides such as deltamethrin and paraquat, or atmospheric pollutants such as quinone. Extensive studies have demonstrated a strong link between environmental pollutants and human health. Redox toxicity is proposed as one of the main mechanisms of chemical-induced pathology in humans. Acting as both a sensor of oxidative stress and a positive regulator of antioxidants, the nuclear factor erythroid 2-related factor 2 (NRF2) has attracted recent attention. However, the role NRF2 plays in environmental pollutant-induced toxicity has not been systematically addressed. Here, we characterize NRF2 function in response to various pollutants, such as metals, pesticides and atmospheric quinones. NRF2 related signaling pathways and epigenetic regulations are also reviewed.
Parkinson’s disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish, Caenorhabditis (C.) elegans, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as α-Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes.
Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5′ monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.
Neurotoxin exposure of zebrafish larvae has been used to mimic a Parkinson’s disease (PD) phenotype and to facilitate high-throughput drug screening. However, the vulnerability of zebrafish to various neurotoxins was shown to be variable. Here, we provide a direct comparison of ablative effectiveness in order to identify the optimal neurotoxin-mediated dopaminergic (DAnergic) neuronal death in larval zebrafish. Transgenic zebrafish, Tg(dat:eGFP), were exposed to different concentrations of the neurotoxins MPTP, MPP+, paraquat, 6-OHDA, and rotenone for four days, starting at three days post-fertilization. The LC50 of each respective neurotoxin concentration was determined. Confocal live imaging on Tg(dat:eGFP) showed that MPTP, MPP+, and rotenone caused comparable DAnergic cell loss in the ventral diencephalon (vDC) region while, paraquat and 6-OHDA caused fewer losses of DAnergic cells. These results were further supported by respective gene expression analyses of dat, th, and p53. Importantly, the loss of DAnergic cells from exposure to MPTP, MPP+, and rotenone impacted larval locomotor function. MPTP induced the largest motor deficit, but this was accompanied by the most severe morphological impairment. We conclude that, of the tested neurotoxins, MPP+ recapitulates a substantial degree of DAnergic ablation and slight locomotor perturbations without systemic defects indicative of a Parkinsonian phenotype.
The rate of autoxidation of epinephrine and the sensitivity of this autoxidation to inhibition by superoxide dismutase were both augmented, as the pH was raised from 7.8 → 10.2. O2⁻, generated by the xanthine oxidase reaction, caused the oxidation of epinephrine to adrenochrome and the yield of adrenochrome produced per O2⁻ introduced, increased with increasing pH in the range 7.8 → 10.2 and also increased with increasing concentration of epinephrine. These results, in conjunction with complexities in the kinetics of adrenochrome accumulation, lead to the proposal that the autoxidation of epinephrine proceeds by at least two distinct pathways, only one of which is a free radical chain reaction involving O2⁻ and hence inhibitable by superoxide dismutase. This chain reaction accounted for a progressively greater fraction of the total oxidation as the pH was raised. The ability of superoxide dismutase to inhibit the autoxidation of epinephrine at pH 10.2 has been used as the basis of a convenient and sensitive assay for this enzyme.
The NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways, providing a mechanism for the cells in response to a wide variety of stimuli linking to inflammation. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-κB pathways. To initiate both of these pathways, IκB-degradation triggers NF-κB release and the nuclear translocated-heterodimer (or homodimer) can associate with the κB sites of promoter to regulate the gene transcriptions. NF-κB ubiquitously expresses in neurons and the constitutive NF-κB activation is associated with processing of neuronal information. NF-κB can regulate the transcription of genes such as chemokines, cytokines, proinflammatory enzymes, adhesion molecules, proinflammatory transcription factors, and other factors to modulate the neuronal survival. In neuronal insult, NF-κB constitutively active in neuron cell bodies can protect neurons against different injuries and regulate the neuronal inflammatory reactions. Besides neurons, NF-κB transcription factors are abundant in glial cells and cerebral blood vessels and the diverse functions of NF-κB also regulate the inflammatory reaction around the neuronal environment. NF-κB transcription factors are abundant in the brain and exhibit diverse functions. Several central nerve system (CNS) diseases are linked to NF-κB activated by inflammatory mediators. The RelA and c-Rel expression produce opposite effects on neuronal survival. Importantly, c-Rel expression in CNS plays a critical role in anti-apoptosis and reduces the age-related behaviors. Moreover, the different subunits of NF-κB dimer formation can modulate the neuroninflammation, neuronal protection, or neurotoxicity. The diverse functions of NF-κB depend on the subunits of the NF-κB dimer-formation which enable us to develop a therapeutic approach to neuroinflammation based on a new concept of inflammation as a strategic tool in neuronal cells. However, the detail role of NF-κB in neuroinflammation, remains to be clarified. In the present article, we provide an updated review of the current state of our knowledge about relationship between NF-κB and neuroinflammation.
Background
Alcohol abuse during pregnancy leads to intellectual disability and morphological defects in the offspring. The aim of this study was to determine the effect of chronic maternal ethanol (EtOH) consumption during pregnancy and lactation on glutamatergic transmission regulation, energy deficit, and oxidative stress in the hippocampus of the offspring.
Methods
EtOH was administered to dams in drinking water at increasing doses (2 to 20%) from the gestation day 5 to lactation day 21. EtOH and tap water intake by treated and control groups, respectively, were measured daily.
Results
Results showed that EtOH exposure does not affect fluid intake over the course of pregnancy and lactation. The toxicity of maternal exposure to EtOH was demonstrated by decreased offspring body weight at experimental age, on postnatal day 21. Moreover, maternal EtOH exposure decreased ⁴⁵Ca²⁺ influx in the offspring's hippocampus. Corroborating this finding, EtOH increased both Na⁺‐dependent and Na⁺‐independent glial [¹⁴C]‐glutamate uptake in hippocampus of immature rats. Also, maternal EtOH exposure decreased glutamine synthetase activity and induced aspartate aminotransferase enzymatic activity, suggesting that in EtOH‐exposed offspring hippocampus, glutamate is preferentially used as a fuel in tricarboxylic acid cycle instead of being converted into glutamine. In addition, EtOH exposure decreased [U‐14C]‐2‐deoxy‐D‐glucose uptake in offspring hippocampus.
Conclusions
The decline in glucose transport coincided with increased lactate dehydrogenase activity, suggesting an adaptative response in EtOH‐exposed offspring hippocampus, using lactate as an alternative fuel. These events were associated with oxidative damage, as demonstrated by changes in the enzymatic antioxidant defense system and lipid peroxidation. Taken together, the results demonstrate that maternal exposure to EtOH during pregnancy and lactation impairs glutamatergic transmission, as well as inducing oxidative stress and energy deficit in immature rat hippocampus.
Laboratory studies involving repeated exposure to paraquat (PQ) in different animal models can induce many of the pathological features of Parkinson’s disease (PD), such as the loss of dopaminergic neurons in the nigrostriatal dopamine system. Epidemiological studies identify an increased risk of developing PD in human populations living in areas where PQ exposure is likely to occur and among workers lacking appropriate protective equipment. The mechanisms involved in these phenomena may not be due to any single cause, but rather a multifactorial situation may exist where PQ exposure may cause PD in some circumstances. A multifactorial theory is adopted as we review a number of sub-cellular mechanisms that can explain the observations. The pathogenesis of PD in relation to PQ requires chronic low-dose exposure where PQ acts as an oxidative stress inducer. This paper reviews the consequence PQ oxidative stress and the metabolic processes of PQ inducing excitotoxicity, α-synuclein aggregate formation, autophagy, alteration of dopamine catabolism, and inactivation of tyrosine hydroxylase, which could ultimately cause the loss of dopaminergic cells. The environmental context and biochemistry of PQ in soils, water, and organisms is reviewed to consider potential routes and rates of exposure that might elicit the type of response that is observed in animal models and other types of laboratory research involving PQ exposure. The purpose of this review is to synthesize key relations and summarize hypotheses linking PD to PQ exposure by using multifactorial approach. Recommendations are given to integrate laboratory methods to the environmental context as a means to improve on experimental design. The multifactorial approach is a necessary step for conducting valid tests of causal relations and understanding of potential relations between PD and PQ exposure. This approach may prevent further delay in solving what has proven to be an evasive aetiological problem.
Mitochondria are essential for survival. Their primary function is to support aerobic respiration and to provide energy for intracellular metabolic pathways. Paraquat is a redox cycling agent capable of generating reactive oxygen species. The aim of the present study was to evaluate changes in cortical and striatal mitochondrial function in an experimental model of acute paraquat toxicity and to compare if the brain areas and the molecular mechanisms involved were similar to those observed after chronic exposure. Sprague-Dawley rats received paraquat (25 mg/Kg i.p.) or saline and were sacrificed after 24 h. Paraquat treatment decreased complex I and IV activity by 37 and 21 % respectively in striatal mitochondria. Paraquat inhibited striatal state 4 and state 3 KCN-sensitive respiration by 80 % and 62 % respectively, indicating a direct effect on respiratory chain. An increase of 2.2 fold in state 4 and 2.3 fold in state 3 in KCN-insensitive respiration was observed in striatal mitochondria from paraquat animals, suggesting that paraquat redox cycling also consumed oxygen. Paraquat treatment increased hydrogen peroxide production (150 %), TBARS production (42 %) and cardiolipin oxidation/depletion (12 %) in striatal mitochondria. Also, changes in mitochondrial polarization was induced after paraquat treatment. However, no changes were observed in any of these parameters in cortical mitochondria from paraquat treated-animals. These results suggest that paraquat treatment induced a clear striatal mitochondrial dysfunction due to both paraquat redox cycling reactions and impairment of the mitochondrial electron transport, causing oxidative damage. As a consequence, mitochondrial dysfunction could probably lead to alterations in cellular bioenergetics.
Publisher Summary Glutathione reductase is a flavoprotein catalyzing the NADPH-dependent reduction of glutathione disulfide (GSSG) to glutathione (GSH). The reaction is essential for the maintenance of glutathione levels. Glutathione has a major role as a reductant in oxidation–reduction processes, and serves in detoxication and several other cellular functions of great importance. A purification method of this enzyme from calf liver and rat liver is described in this chapter. Similar methods are used for the purification of the enzyme from yeast, porcine, and human erythrocytes. All the steps are carried out at about 5 ° . The purification method from calf liver consists of various steps including preparation of cytosol fraction, chromatography on DEAE-sephadex, precipitation with ammonium sulfate, and chromatography on hydroxyapatite. The purification of glutathione reductase from rat liver is usually combined with the preparation of glutathione transferases, thioltransferase, and glyoxalase I.
Lung injury is the main manifestation of paraquat poisoning. Few studies have addressed brain damage after paraquat poisoning. Ulinastatin is a protease inhibitor that can effectively stabilize lysosomal membranes, prevent cell damage, and reduce the production of free radicals. This study assumed that ulinastatin would exert these effects on brain tissues that had been poisoned with paraquat. Rat models of paraquat poisoning were intraperitoneally injected with ulinastatin. Simultaneously, rats in the control group were administered normal saline. Hematoxylin-eosin staining showed that most hippocampal cells were contracted and nucleoli had disappeared in the paraquat group. Fewer cells in the hippocampus were concentrated and nucleoli had disappeared in the ulinastatin group. Western blot assay showed that expressions of GRP78 and cleaved-caspase-3 were significantly lower in the ulinastatin group than in the paraquat group. Immunohistochemical findings showed that CHOP immunoreactivity was significantly lower in the ulinastatin group than in the paraquat group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining showed that the number of apoptotic cells was reduced in the paraquat and ulinastatin groups. These data confirmed that endoplasmic reticular stress can be induced by acute paraquat poisoning. Ulinastatin can effectively inhibit this stress as well as cell apoptosis, thereby exerting a neuroprotective effect.
Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as "excitotoxicity". This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood-brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate-glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.
Unlabelled:
We have previously shown that paraquat (PQ)-induced oxidative stress causes dramatic damage in various human cell lines. Naringenin (NG) is an active flavanone, which has been reported to have beneficial bioactivities, including antioxidative, anti-inflammatory, and antitumorigenic activities, with a relatively low toxicity to normal cells. In this study, we intended to assess the cytoprotective effect of NG against PQ-induced toxicity in the human bronchial epithelial BEAS-2B cell line. Co-treatment with NG in PQ-treated BEAS-2B cells can reduce PQ-induced cellular toxicity. NG can also decrease the generation of intracellular ROS caused by PQ treatment. We also observed that treatment with NG in PQ-exposed BEAS-2B cells can significantly induce the expression of antioxidant-related genes, including GPX2, GPX3, GPX5, and GPX7. NG co-treatment can also activate the NRF2 transcription factor and promote its nuclear translocation. In addition, NG co-treatment can induce the expression of NRF2-downstream target genes such as that of heme oxygenase-1 (HO-1) and
Nad(p)h:
quinone oxidoreductase 1 (NQO1). A small interfering RNA study revealed that the knockdown of NRF2 can abrogate NG-mediated protection of the cells from PQ-induced cellular toxicity. We propose that NG effectively alleviates PQ-induced cytotoxicity in human bronchial epithelial BEAS-2B cells through the NRF2-regulated antioxidant defense pathway, and NG might be a good therapeutic candidate molecule in oxidative stress-related diseases.
Background
Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis.
Results
We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues.
Conclusions
We report that adult neurogenesis is highly susceptible to multiple “risk factors” for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.
Previous systematic reviews have indicated that pesticide exposure is possibly associated with Parkinson disease (PD). However, considerable heterogeneity has been observed in study results.
We aimed at providing an update of the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis. In addition, we investigated whether methodological differences between studies could explain the heterogeneity in study results.
We identified studies through a systematic literature search. We calculated summary risk ratios (sRRs) for pesticide exposure and subcategories using random effects meta-analyses and investigated sources of heterogeneity by meta-regression and stratified analyses.
Thirty-nine case-control studies, four cohort studies, and three cross-sectional studies were identified. An sRR of 1.62 [95% confidence interval (CI): 1.40, 1.88] for pesticide exposure (ever vs. never) was found. Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. Heterogeneity in individual study results was not related to study design, source of control population, adjustment of results for potential confounders, or geographical area. However, results were suggestive for heterogeneity related to differences in the exposure assessment. Job title-based exposure assignment resulted in a higher sRR (2.5; 95% CI: 1.5, 4.1) than did assignment based on self-reported exposure (e.g., for self-reported ever/never exposure, sRR = 1.5; 95% CI: 1.3, 1.8).
This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.
Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. RECENT ADVANCES: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology.
Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD.
Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide disease-modifying therapeutics for human PD patients.
Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans.
Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans.
We assessed lifetime use of pesticides selected by mechanism in a case-control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls:one case.
In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR)=1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR=2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR=2.5; 95% CI, 1.4-4.7).
PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally-those that impair mitochondrial function and those that increase oxidative stress-supporting a role for these mechanisms in PD pathophysiology.
Deciphering the mechanisms that modulate the inflammatory response induced by microglial activation not only improves our insight into neuroinflammation but also provides avenues for designing novel therapies that could halt inflammation-induced neuronal degeneration. Decreasing glycogen synthase kinase-3β (GSK-3β) activity has therapeutic benefits in inflammatory diseases. However, the exact molecular mechanisms underlying GSK-3β inactivation-mediated suppression of the inflammatory response induced by microglial activation have not been completely clarified. Tumor necrosis factor-α (TNF-α) plays a central role in injury caused by neuroinflammation. We investigated the regulatory effect of GSK-3β on TNF-α production by microglia to discern the molecular mechanisms of this modulation.
Lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured primary microglia or murine BV-2 microglial cells. Release of TNF-α was measured by ELISA. Signaling molecules were analyzed by western blotting, and activation of NF-κB and AP-1 was measured by ELISA-based DNA binding analysis and luciferase reporter assay. Protein interaction was examined by coimmunoprecipitation.
Inhibition of GSK-3β by selective GSK-3β inhibitors or by RNA interference attenuated LPS-induced TNF-α production in cultured microglia. Exploration of the mechanisms by which GSK-3β positively regulates inflammatory response showed that LPS-induced IκB-α degradation, NF-κBp65 nuclear translocation, and p65 DNA binding activity were not affected by inhibition of GSK-3β activity. However, GSK-3β inactivation inhibited transactivation activity of p65 by deacetylating p65 at lysine 310. Furthermore, we also demonstrated a functional interaction between mixed lineage kinase 3 (MLK3) and GSK-3β during LPS-induced TNF-α production in microglia. The phosphorylated levels of MLK3, MKK4, and JNK were increased upon LPS treatment. Decreasing GSK-3β activity blocked MLK3 signaling cascades through disruption of MLK3 dimerization-induced autophosphorylation, ultimately leading to a decrease in TNF-α secretion.
These results suggest that inactivation of GSK-3β might represent a potential strategy to downregulate microglia-mediated inflammatory processes.
Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and subsequent death of dopaminergic neurons of the substantia nigra pars compacta (SNpc). More recently, the multisystem effects of the disease have been investigated, with the immune system being implicated in a number of these processes in the brain, the blood, and the gut. In this review, we highlight the dysfunctional immune system found in both human PD and animal models of the disease, and discuss how genetic risk factors and risk modifiers are associated with pro-inflammatory immune responses. Finally, we emphasize evidence that the immune response drives the pathogenesis and progression of PD, and discuss key questions that remain to be investigated in order to identify immunomodulatory therapies in PD.
To reconcile and unify available results regarding paraquat exposure and Parkinson’s disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27–2.13; I² = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson’s disease are warranted.
We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[(14)C]-glutamate uptake and increased (45)Ca(2+) influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring.
Paraquat is a rather toxic pro-oxidant herbicide, prompting to multi-organ failure, including the heart, brain, and lung injuries, although the precise underlying mechanism(s) remains poorly understood. Up-to-date, a number of signaling machineries have been postulated for paraquat toxicity, such as accumulation of free radical species and development of oxidative stress. Paraquat is believed to serve as a potent ROS generator, resulting in detrimental biological effects through oxidative stress injury and mitochondrial dysfunction. In this mini-review we will recapitulate some aspects of paraquat toxicity in main body organs, including the lungs, brain, and heart. Cellular mechanisms behind paraquat toxicity will be discussed with a focus on oxidative stress, mitochondrial injury, and autophagy. Special attention will be given to the direct stress signaling and pro-inflammatory signaling cascades triggered by paraquat exposure in the herbicide-induced organ damage.
Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
Environmental agents have been implicated in Parkinson's disease (PD) based on epidemiological studies and the ability of toxicants to replicate features of PD. However, the precise mechanisms by which toxicants induce dopaminergic toxicity observed in the idiopathic form of PD remain to be fully understood. The roles of ROS and mitochondria are strongly suggested in the mechanisms by which these toxicants exert dopaminergic toxicity. There are marked differences and similarities shared by the toxicants in increasing steady-state levels of mitochondrial ROS. Furthermore, toxicants increase steady-state mitochondrial ROS levels by stimulating the production, inhibiting the antioxidant pathways of both. This review will focus on the role of mitochondria and ROS in PD associated with environmental exposures to redox-based toxicants.
Significance:
Glutamate serves multi-faceted (patho)physiological functions in the central nervous system as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Regarding the latter, elevated extracellular glutamate is known to play a central role in ischemic stroke brain injury.
Recent advances:
Glutamate oxaloacetate transaminase (GOT) has emerged as a new therapeutic target in protecting against ischemic stroke injury. Oxygen-sensitive induction of GOT expression and activity during ischemic stroke lowers glutamate levels at the stroke site while sustaining adenosine triphosphate levels in brain. The energy demands of the brain are among the highest of all organs underscoring the need to quickly mobilize alternative carbon skeletons for metabolism in the absence of glucose during ischemic stroke. Recent work builds on the important observation of Hans Krebs that GOT-mediated metabolism of glutamate generates tri-carboxylic acid (TCA) cycle intermediates in brain tissue. Taken together, outcomes suggest GOT may enable the transformative switch of otherwise excitotoxic glutamate into life-sustaining TCA cycle intermediates during ischemic stroke.
Critical issues:
Neuroprotective strategies that focus solely on blocking mechanisms of glutamate-mediated excitotoxicity have historically failed in clinical trials. That GOT can enable glutamate to assume the role of a survival factor represents a paradigm shift necessary to develop the overall significance of glutamate in stroke biology.
Future directions:
Ongoing efforts are focused to develop the therapeutic significance of GOT in stroke-affected brain. Small molecules that target induction of GOT expression and activity in the ischemic penumbra are the focus of ongoing studies.
The central process in energy production is the oxidation of acetyl‐CoA to CO 2 by the tricarboxylic acid ( TCA , Krebs, citric acid) cycle. However, this cycle functions also as a biosynthetic pathway from which intermediates leave to be converted primarily to glutamate, GABA , glutamine and aspartate and to a smaller extent to glucose derivatives and fatty acids in the brain. When TCA cycle ketoacids are removed, they must be replaced to permit the continued function of this essential pathway, by a process termed anaplerosis . Since the TCA cycle cannot act as a carbon sink, anaplerosis must be coupled with cataplerosis ; the exit of intermediates from the TCA cycle. The role of anaplerotic reactions for cellular metabolism in the brain has been studied extensively. However, the coupling of this process with cataplerosis and the roles that both pathways play in the regulation of amino acid, glucose, and fatty acid homeostasis have not been emphasized. The concept of a linkage between anaplerosis and cataplerosis should be underscored, because the balance between these two processes is essential. The hypothesis that cataplerosis in the brain is achieved by exporting the lactate generated from the TCA cycle intermediates into the blood and perivascular area is presented. This shifts the generally accepted paradigm of lactate generation as simply derived from glycolysis to that of oxidation and might present an alternative explanation for aerobic glycolysis. image
Intermediates leave the tricarboxylic acid cycle and must be replaced by a process termed anaplerosis that must be coupled to cataplerosis. We hypothesize that cataplerosis is achieved by exporting the lactate generated from the cycle into the blood and perivascular area. This shifts the paradigm of lactate generation as solely derived from glycolysis to that of oxidation and might present an alternative explanation for aerobic glycolysis.
Parkinson's disease (PD) is a multi-factorial disorder with a complex etiology including genetic risk factors, environmental exposures and aging. While energy failure and oxidative stress have largely been associated with the loss of dopaminergic cells in PD and the toxicity induced by mitochondrial/environmental toxins, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. In this study, we investigated the alterations in the energy/redox-metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, 1-methyl-4-phenylpyridinium [MPP+] and 6-hydroxydopamine [6-OHDA]) in order to identify common and/or different mechanisms of toxicity. A combined metabolomics approach using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (DI-ESI-MS) was used to identify unique metabolic profile changes in response to these neurotoxins. Paraquat exposure induced the most profound alterations in the pentose phosphate pathway (PPP) metabolome. 13C-glucose flux analysis corroborated that PPP metabolites such as glucose 6-phosphate, fructose 6-phosphate, glucono-1,5-lactone and erythrose 4-phosphate were increased by paraquat treatment, which was paralleled by inhibition of glycolysis and the TCA cycle. Proteomic analysis also found an increase in the expression of glucose 6-phosphate dehydrogenase (G6PD), which supplies reducing equivalents by regenerating nicotinamide adenine dinucleotide phosphate (NADPH) levels. Overexpression of G6PD selectively increased paraquat toxicity, while its inhibition with 6-aminonicotinamide inhibited paraquat- induced oxidative stress and cell death. These results suggest that paraquat "hijacks" the PPP to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress and cell death. Our study clearly demonstrates that alterations in energy metabolism, which are specific for distinct environmental toxins, are not bystanders to energy failure, but also contribute significant to cell death progression.
Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup(®) (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup(®) (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup(®) (0.00005 to 0.1%) during 30min and experiments were carried out to determine whether glyphosate affects (45)Ca(2+) influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup(®) (30min) increases (45)Ca(2+) influx by activating NMDA receptors and voltage-dependent Ca(2+) channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup(®)-induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup(®) increased (3)H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup(®) decreased (3)H-glutamate uptake and metabolism, while induced (45)Ca(2+) uptake and (14)C-MeAIB accumulation in immature rat hippocampus. Taken together, these results demonstrated that Roundup(®) might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus.
1. Oxygen is a toxic gas - an introductionto oxygen toxicity and reactive species 2. The chemistry of free radicals and related 'reactive species' 3. Antioxidant defences Endogenous and Diet Derived 4. Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death 5. Measurement of reactive species 6. Reactive species can pose special problems needing special solutions. Some examples. 7. Reactive species can be useful some more examples 8. Reactive species can be poisonous: their role in toxicology 9. Reactive species and disease: fact, fiction or filibuster? 10. Ageing, nutrition, disease, and therapy: A role for antioxidants?
Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively. Moreover, hyperphosphorylation of the cytoskeletal proteins was not reversed by T3 and poorly reversed by T4. In addition, congenital hypothyroidism is associated with downregulation of astrocyte glutamate transporters (GLAST and GLT-1) leading to decreased glutamate uptake and subsequent influx of Ca(2)(+)through N-methyl-D-aspartate (NMDA) receptors. The Na(+)-coupled (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation into hippocampal cells also might cause an increase in the intracellular Ca(2+) concentration by opening voltage-dependent calcium channels (VDCC). The excessive influx of Ca(2)(+)through NMDA receptors and VDCCs might lead to an overload of Ca(2)(+)within the cells, which set off glutamate excitotoxicity and oxidative stress. The inhibited acetylcholinesterase (AChE) activity might also induce Ca(2)(+) influx. The inhibited glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyl transferase (GGT) activities, associated with altered glutamate and neutral amino acids uptake could somehow affect the GSH turnover, the antioxidant defense system, as well as the glutamate-glutamine cycle. Reduced levels of S100B and glial fibrillary acidic protein (GFAP) take part of the hypothyroid condition, suggesting a compromised astroglial/neuronal neurometabolic coupling which is probably related to the neurotoxic damage in hypothyroid brain.
Recent advances in the field of brain energy metabolism strongly suggest that glutamate receptor-mediated neurotransmission is coupled with molecular signals that switch-on glucose utilization pathways to meet the high energetic requirements of neurons. Failure to adequately coordinate energy supply for neurotransmission ultimately results in a positive amplifying loop of receptor over-activation leading to neuronal death, a process known as excitotoxicity. In this review, we revisited current concepts in excitotoxic mechanisms, their involvement in energy substrate utilization, and the signaling pathways that coordinate both processes. In particular, we have focused on the novel role played by the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1, in cell metabolism. Our laboratory identified 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) -a key glycolytic-promoting enzyme- as an APC/C-Cdh1 substrate. Interestingly, APC/C-Cdh1 activity is inhibited by over-activation of glutamate receptors through a Ca(2+)-mediated mechanism. Furthermore, by inhibiting APC/C-Cdh1 activity, glutamate-receptors activation promotes PFKFB3 stabilization, leading to increased glycolysis and decreased pentose-phosphate pathway activity. This causes a loss in neuronal ability to regenerate glutathione, triggering oxidative stress and delayed excitotoxicity. Further investigation is critical to identify novel molecules responsible for the coupling of energy metabolism with glutamatergic neurotransmission and excitotoxicity, as well as to help developing new therapeutic strategies against neurodegeneration.
Glutamate concentration at the synaptic level must be kept low in order to prevent excitotoxicity. Astrocytes play a key role in brain energetics, and also astrocytic glutamate transporters are responsible for the vast majority of glutamate uptake in CNS. Experiments with primary astrocytic cultures suggest that increased influx of glutamate cotransported with sodium at astrocytes favors its flux to the tricarboxylic acid cycle instead of the glutamate-glutamine cycle. Although metabolic coupling can be considered an emergent field of research with important recent discoveries, some basic aspects of glutamate metabolism still have not been characterized in brain tissue. Therefore, the aim of this study was to investigate whether the presence of extracellular glutamate is able to modulate the use of glutamate and glucose as energetic substrates. For this purpose, isolated hippocampi of mice were incubated with radiolabeled substrates, and CO(2) radioactivity and extracellular lactate were measured. Our results point to a diminished oxidation of glucose with increasing extracellular glutamate concentration, glutamate presumably being the fuel, and might suggest that oxidation of glutamate could buffer excitotoxic conditions by high glutamate concentrations. In addition, these findings were reversed when glutamate uptake by astrocytes was impaired by the presence of (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA). Taken together, our findings argue against the lactate shuttle theory, because glutamate did not cause any detectable increase in extracellular lactate content (or, presumably, in glycolysis), because the glutamate is being used as fuel instead of going to glutamine and back to neurons. © 2013 Wiley Periodicals, Inc.
Paraquat (PQ) is a common herbicide and PQ poisoning is a major medical problem in Asia. However, few studies have focused on the acute neurotoxic changes caused by PQ. Here we report the acute neurotoxicological findings of rats treated with lethal dose of PQ. In substantia nigra (SN) and striatum we found obvious microglia (labeled by Iba-1) activation within one week. In SN and hippocampus, we detected increased oxidative stress in the neurons based on NeuN/8-OHdG immunofluorescence double labeling and laser cofocal microscopy. Moreover, we provided ultrastructural evidences of astrocyte edema and neurons apoptosis in rat brain by electron microscopy. Further studies will be needed with non-lethal dose of PQ to confirm these results and demonstrate the direct CNS toxicity of PQ.
Primary cultures of fetal rat cortical neurons and astrocytes were used to test the hypothesis that astrocyte-mediated control of neuronal glutathione (GSH) is a potent factor in neuroprotection against rotenone and paraquat. In neurons, rotenone (0.025-1 μM) for 4 and 24 h decreased viability as did paraquat (2-100 μM). Rotenone (30 nM) decreased neuronal viability and GSH by 24% and 30%, while ROS were increased by 56%. Paraquat (30 μM) decreased neuronal viability and GSH by 36% and 70%, while ROS were increased by 23%. When neurons were co-cultured with astrocytes, their GSH increased 1.5 fold and 5 fold at 12 and 24 h. Co-culturing with astrocytes blocked neuronal death and damage by rotenone and paraquat. Astrocyte-mediated neuroprotection was dependent on the activity of components of the γ-glutamyl cycle. These studies illustrate the importance of astrocyte-mediated glutathione homeostasis for protection of neurons from rotenone and paraquat and the role of the γ-glutamyl cycle in this neuroprotection.
Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway.
The energy requirements of the brain are very high, and tight regulatory mechanisms operate to ensure adequate spatial and temporal delivery of energy substrates in register with neuronal activity. Astrocytes-a type of glial cell-have emerged as active players in brain energy delivery, production, utilization, and storage. Our understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving an intense cooperativity between astrocytes and neurons. This review focuses on the cellular aspects of brain energy metabolism, with a particular emphasis on the metabolic interactions between neurons and astrocytes.
Accumulating evidence implicates pesticides such as paraquat in the development of Parkinson's disease (PD). Indeed, paraquat exposure is associated with an increased risk of PD and when administered to rodents the pesticide recapitulates many of the neuropathological and behavioural features of the disease. However, it is unclear whether any sexual dimorphism exists in the in vivo murine response to paraquat intoxication, since most studies have used exclusively males. Accordingly, we sought to determine the impact of repeated paraquat exposure on a range of neural and behavioural outcomes in female C57BL/6J mice. The present investigation revealed that the female mice were largely resistant to the paraquat-induced nigrostriatal dopamine changes and locomotor deficits that were reported previously in males. Similarly, in contrast to the reductions of hippocamapal brain-derived neurotrophic factor (BDNF) previously reported in paraquat treated male mice, the herbicide actually increased levels of the trophic factor in females. Yet, similar to our previous findings in males, paraquat increased norepinephrine utilization within the hippocampus and prefrontal cortex of the female mice. However, these changes did not translate into anxiety- or- depression-like behaviours in the open field test, as the females actually seemed to show enhanced exploration. Consistent with reports of a greater incidence of PD in males, these data suggest that female mice may be less susceptible than males to the nigrostriatal dopaminergic and motor effects of environmental toxins. The augmented hippocampal BDNF and noradrenergic changes observed could conceivably act to buffer female mice against some of the deleterious behavioural effects of parquat.
Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
Pesticides are widely used in agricultural and other settings, resulting in continued human exposure. Pesticide toxicity has been clearly demonstrated to alter a variety of neurological functions. Particularly, there is strong evidence suggesting that pesticide exposure predisposes to neurodegenerative diseases. Epidemiological data have suggested a relationship between pesticide exposure and brain neurodegeneration. However, an increasing debate has aroused regarding this issue. Paraquat is a highly toxic quaternary nitrogen herbicide which has been largely studied as a model for Parkinson's disease providing valuable insight into the molecular mechanisms involved in the toxic effects of pesticides and their role in the progression of neurodegenerative diseases. In this work, we review the molecular mechanisms involved in the neurotoxic action of pesticides, with emphasis on the mechanisms associated with the induction of neuronal cell death by paraquat as a model for Parkinsonian neurodegeneration.
Environmental paraquat (PQ) exposure has been suggested to be a potential risk factor for neurodegenerative disorders such as Parkinson's disease (PD). The hippocampus plays an important role in the learning and memory abilities of the brain. This study aims to demonstrate the effect and mechanism of paraquat toxicity on the hippocampus of mice. Kunming mice were randomly divided into four groups (one control and three treatment groups) and the dosage levels were defined as 0, 0.89, 2.67 and 8mg/kg body weight. Paraquat was given orally, once a day and for 28 consecutive days. After treatment with paraquat, the hippocampus cells were found to be irregular and the cytoplasm was found to be condensed. The nissl bodies were reduced and apoptotic or necrotic neuron was observed. Morris water maze tests showed that the response latency increased significantly in animals that were administered paraquat. The level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus of mice increased significantly. The activities of total superoxide dismutase (SOD) in the hippocampus of mice decreased significantly after treatment with paraquat. An analysis of the energy metabolism of hippocampus showed that the concentration of adenosine-triphosphate (ATP) decreased significantly in the hippocampus after treatment with paraquat, which implied that the energy synthesis of mitochondria with hippocampal neurocytes declined. The level of 8-OHdG in mitochondrial DNA (mtDNA) increased significantly after treatment with paraquat, which indicated that the oxidative damage of mtDNA increased. This suggests that paraquat had a toxic influence on the hippocampus of mice, and that the mechanism of toxicity might be associated with the mitochondrial injury of hippocampal neurocytes induced by oxidative stress.
As evidence emerges that complex gene alterations are involved in the onset of Parkinson's disease (PD), the role of environmental chemicals in the pathogenesis of this disease becomes intensely debated. Although it is undisputed that acute exposure to certain chemicals such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is sufficient to cause human parkinsonism, the evidence that the risk for PD increases because of environmental exposure is generally weaker. Several studies have suggested that pesticide exposure and life in rural areas are significant risks factors for PD. Among other pesticides, paraquat (PQ) has been linked to PD by epidemiological studies and experimental work in rodents, in which it causes lesions in the substantia nigra, pars compacta. However, the evidence that human exposure to the chemical results in an increased risk for PD is rather limited and based on insufficient epidemiological data. This review critically analyses the evidence that implicates PQ in parkinsonism and discusses the limitations of chemical modelling of PD.
Environmental factors have long been thought to have a role in the etiology of idiopathic Parkinson's disease (PD). Since the discovery of the selective neurotoxicity of MPTP to dopamine cells, suspicion has focused on paraquat, a common herbicide with chemical structure similar to 1-methyl-4-phenylpyridinium (MPP+), the MPTP metabolite responsible for its neurotoxicity. Although in vitro evidence for paraquat neurotoxicity to dopamine cells is well established, its in vivo effects have been ambiguous because paraquat is di-cationic in plasma, which raises questions about its ability to cross the blood brain barrier. This study assessed the brain uptake of [(11)C]-paraquat in adult male rhesus macaques using quantitative PET imaging. Results showed minimal uptake of [(11)C]-paraquat in the macaque brain. The highest concentrations of paraquat were seen in the pineal gland and the lateral ventricles. Global brain concentrations including those in known dopamine areas were consistent with the blood volume in those structures. This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinson's disease.