ArticleLiterature Review

Toxin-Induced Models of Parkinson's Disease

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Abstract

Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.

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... Among several toxins, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxy-dopamine (6-OHDA) have been extensively studied for their toxicity on dopaminergic neurons in vivo and in vitro; however, their effect on β-cells viability has not been properly considered [20]. These compounds, though structurally different, are grouped as the most common toxins used to induce PD in animal model experiments for altering the bioenergetics and viability of dopaminergic cells [21]. ...
... The cellular toxicity is caused by inhibition of mitochondrial complex I and IV. In addition, it rapidly autoxidizes to para-quinone and H 2 O 2 [21]. Though it has no use as a chemical compound for human activities, it is utilized as a prototypic pro-oxidant neurotoxin in PD models. ...
... Taken together, these data confirm the inhibitory action of rotenone on β-cells mitochondria, involving complex I, altering cellular bioenergetics and increasing ROS production that is responsible for cell death. For MPP + , we can postulate a similar mechanism as it is a potent inhibitor of the mitochondrial complex I [29], whereas for 6-OHDA the generation of H 2 O 2 and other oxidative species through its chemical transformation should be responsible for its toxicity together with the inhibition of mitochondrial complex I and IV [21] (Figure 6). The connection between mitochondrial inhibition, determined by redox activity or ATP production and cell death is not simple [45]. ...
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Neurotoxins such as rotenone, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) are well known for their high toxicity on dopaminergic neurons and are associated with Parkinson’s disease (PD) in murine models and humans. In addition, PD patients often have glucose intolerance and may develop type 2 diabetes (T2D), whereas T2D patients have higher risk of PD compared to general population. Based on these premises, we evaluated the toxicity of these three toxins on pancreatic β-cell lines (INS-1 832/13 and MIN6) and we showed that rotenone is the most potent for reducing β-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration. Importantly, rotenone-induced toxicity was counteracted by α-tocopherol and partially by metformin, which are endowed with strong antioxidative and cytoprotective properties. These data show similarities between dopaminergic neurons and β-cells in terms of vulnerability to toxins and pharmacological agents capable to protect both cell types.
... The typical PD models ( Table 1) induce nigrostriatal dopaminergic cell loss, frequently with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), rotenone or paraquat [4,[6][7][8][9]. It is known that these models induce mitochondrial dysfunction and/or reactive oxygen species, but none completely simulate the pathology and symptoms seen in humans [7,9]. ...
... The typical PD models ( Table 1) induce nigrostriatal dopaminergic cell loss, frequently with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), rotenone or paraquat [4,[6][7][8][9]. It is known that these models induce mitochondrial dysfunction and/or reactive oxygen species, but none completely simulate the pathology and symptoms seen in humans [7,9]. 6-OHDA and MPTP are neurotoxins that rapidly and selectively destroy the dopaminergic neurons (within 1-3 days), while PD pathogenesis obeys a progressive progression over decades [4,10]. ...
... These models were aimed to induce nigrostriatal dopaminergic depletion. Selective neurotoxins such as 6-OHDA, MPTP, paraquat, or rotenone are generally used [4,7,9]. These models induce neuronal death by inhibiting mitochondrial function and producing ROS. ...
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The knowledge about the biochemical and behavioral changes in humans with PD has allowed proposing animal models for its study; however, the results obtained so far have been heterogeneous. Recently, we established a novel PD model in rodents by manganese chloride (MnCl2) and manganese acetate (Mn (OAc)3) mixture inhalation. After inhaling, the rodents presented bilateral loss of SNc dopaminergic neurons. Later, we conclude that the alterations are of dopamine origin since L-DOPA reverted the alterations. After six months, SNc significantly reduced the number of cells, and striatal dopamine content decreased by 71%. The animals had postural instability, action tremor, and akinesia; these symptoms improved with L-DOPA, providing evidence that Mn mixture inhalation induces comparable alterations that those in PD patients. Thus, this study aimed to compare the alterations in two different PD experimental models: 6-OHDA unilateral lesion and Mn mixture inhalation through open field test, rotarod performance and the number of SNc dopaminergic neurons. The results show that the Mn-exposed animals have motor alterations and bilateral and progressive SNc neurons degeneration; in contrast, in the 6-OHDA model, the neuronal loss is unilateral and acute, demonstrating that the Mn exposure model better recreates the characteristics observed in PD patients.
... The neurotoxic properties of PQ are primarily mediated by its effect on the redox cycle and the functioning of the nitric oxide synthase enzyme in neuronal cells. This, in turn, induces the increased production of reactive oxygen species (ROS) and increases the levels of α-synuclein and tau protein, α-tubulin hyperacetylation, inhibition of proteasomes, and dysfunction of axonal autophagy, which result in symptoms of PD [3]. 6-Hydroxydopamine (6-OHDA) is another neurotoxic compound that is often used as an inducer of neurodegenerative changes in an in vitro model of PD. ...
... It is a structural analogue of dopamine, which explains its selective uptake into dopaminergic and noradrenergic neurons via a membrane dopamine transporter and a norepinephrine transporter, respectively. In neurons, 6-OHDA accumulates in the cytosol, where, with the participation of the enzyme monoamine oxidase (MAO), it is metabolized into dihydrophenylacetic acid or oxidized to form hydrogen peroxide and para-quinone, which results in ROS formation and oxidative stress in neurons with their subsequent death [3]. ...
... •− (Scheme 1). The superoxide radicals formed by PQ play a decisive role in the manifestation of its cytotoxicity and neurototoxicity [3,16]. Due to its structural similarity with dopamine and norepinephrine, the neurotoxin 6-OHDA penetrates dopaminergic and noradrenergic neurons and causes the destruction of the catecholaminergic pathways of the nervous system. ...
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Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson’s disease. As a result, 10 compounds were selected that could protect neuronal cells from the cytotoxic effects of both paraquat and 6-hydroxydopamine. The five most active compounds at low concentrations were found to significantly protect the activity of nonspecific esterase from the inhibitory effects of neurotoxins, defend cell biomembranes from lytic destruction in the presence of paraquat and 6-hydroxydopamine, and normalize the cell cycle. The protective effects of these compounds are associated with the suppression of oxidative stress, decreased expression of reactive oxygen species and nitric oxide formation in cells and normalization of mitochondrial function, and restoration of the mitochondrial membrane potential altered by neurotoxins. It was suggested that the neuroprotective activity of the studied 1,4-NQs is attributable to their pronounced antioxidant and free radical scavenging activity and their ability to reduce the amount of reactive oxygen species formed by paraquat and 6-hydroxydopamine action on neuronal cells. The significant correlation between the neuroprotective properties of 1,4-naphthoquinones and Quantitative Structure–Activity Relationship descriptors describing the physicochemical properties of these compounds means that the hydrophobicity, polarity, charge, and shape of the molecules can be of decisive importance in determining the biological activity of studied substances.
... The etiology of PD can be associated not only with aging but also with adverse environmental influences and neurotoxins. 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were shown to cause PD symptoms [3]. Several pesticides and herbicides (rotenone, paraquat (PQ), maneb (MB), and mancozeb (MZ)) are also neurotoxins and cause pathologies similar to PD [3]. ...
... 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were shown to cause PD symptoms [3]. Several pesticides and herbicides (rotenone, paraquat (PQ), maneb (MB), and mancozeb (MZ)) are also neurotoxins and cause pathologies similar to PD [3]. The neurotoxic properties of these compounds are primarily due to their ability to generate toxic free radicals and reactive oxygen species in cells. ...
Article
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Pterocarpans and related polyphenolics are known as promising neuroprotective agents. We used models of rotenone-, paraquat-, and 6-hydroxydopamine-induced neurotoxicity to study the neuroprotective activity of polyphenolic compounds from Lespedeza bicolor and their effects on mitochondrial membrane potential. We isolated 11 polyphenolic compounds: a novel coumestan lespebicoumestan A (10) and a novel stilbenoid 5’-isoprenylbicoloketon (11) as well as three previously known pterocarpans, two pterocarpens, one coumestan, one stilbenoid, and a dimeric flavonoid. Pterocarpans 3 and 6, stilbenoid 5, and dimeric flavonoid 8 significantly increased the percentage of living cells after treatment with paraquat (PQ), but only pterocarpan 6 slightly decreased the ROS level in PQ-treated cells. Pterocarpan 3 and stilbenoid 5 were shown to effectively increase mitochondrial membrane potential in PQ-treated cells. We showed that pterocarpans 2 and 3, containing a 3’-methyl-3’-isohexenylpyran ring; pterocarpens 4 and 9, with a double bond between C-6a and C-11a; and coumestan 10 significantly increased the percentage of living cells by decreasing ROS levels in 6-OHDA-treated cells, which is in accordance with their rather high activity in DPPH• and FRAP tests. Compounds 9 and 10 effectively increased the percentage of living cells after treatment with rotenone but did not significantly decrease ROS levels.
... They are mostly genetic models of human mutant synuclein or knockouts of key Parkinson'sassociated genes such as Pink1 or Parkin [11][12][13][14]. Alternatively, local or systemic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin) or other dopaminergic neurotoxins have been widely used [15,16]. All of these models replicate parts of human PD pathology, but the behavioral manifestations are mostly subtle and the predictive nature for human PD is still limited. ...
... Since we did not observe differences in the treatment groups concerning health, RotaRod performance, and histology, we assessed plasma concentrations 2 h after the last rotenone dose to reveal a putative pharmacokinetic (PK) failure. Low bioavailability of oral rotenone has been described before [15]. Rotenone concentrations in the plasma of mice was determined by liquid chromatography combined with tandem mass spectrometry. ...
Article
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Oral rotenone has been proposed as a model for Parkinson’s disease (PD) in mice. To establish the model in our lab and study complex behavior we followed a published treatment regimen. C57BL/6 mice received 30 mg/kg body weight of rotenone once daily via oral administration for 4 and 8 weeks. Motor functions were assessed by RotaRod running. Immunofluorescence studies were used to analyze the morphology of dopaminergic neurons, the expression of alpha-Synuclein (α-Syn), and inflammatory gliosis or infiltration in the substantia nigra. Rotenone-treated mice did not gain body weight during treatment compared with about 4 g in vehicle-treated mice, which was however the only robust manifestation of drug treatment and suggested local gut damage. Rotenone-treated mice had no deficits in motor behavior, no loss or sign of degeneration of dopaminergic neurons, no α-Syn accumulation, and only mild microgliosis, the latter likely an indirect remote effect of rotenone-evoked gut dysbiosis. Searching for explanations for the model failure, we analyzed rotenone plasma concentrations via LC-MS/MS 2 h after administration of the last dose to assess bioavailability. Rotenone was not detectable in plasma at a lower limit of quantification of 2 ng/mL (5 nM), showing that oral rotenone had insufficient bioavailability to achieve sustained systemic drug levels in mice. Hence, oral rotenone caused local gastrointestinal toxicity evident as lack of weight gain but failed to evoke behavioral or biological correlates of PD within 8 weeks.
... Although none of the current animal models of PD could completely reproduce the disease progression. A few chemicals, i.e., rotenone, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP + ), and paraquat, have been well-characterized and utilized as PD animal models (Bové et al. 2005). These neurotoxicant-based animal models give us a chance to study both disease progression and explore possible treatments. ...
... Five complex I inhibitors, which are commonly used for PD animal model (rotenone, 6-OHDA, MPTP, MPP + , and paraquat) (Bové et al. 2005), were used for setting up the prediction threshold of the mitochondrial complex I molecular docking model and neuronal cytotoxicity model of the integrated model. The integrated model predicted a chemical with parkinsonian potential when positive predictions of both components were made. ...
Article
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Exposure to neurotoxicants has been associated with Parkinson's disease (PD). Limited by the clinical variation in the signs and symptoms as well as the slow disease progression, the identification of parkinsonian neurotoxicants relies on animal models. Here, we propose an innovative in silico model for the prediction of parkinsonian neurotoxicants. The model was designed based on a validated adverse outcome pathway (AOP) for parkinsonian motor deficits initiated from the inhibition of mitochondrial complex I. The model consists of a molecular docking model for mitochondrial complex I protein to predict the molecular initiating event and a neuronal cytotoxicity Quantitative Structure–Activity Relationships (QSAR) model to predict the cellular outcome of the AOP. Four known PD-related complex I inhibitors and four non-neurotoxic chemicals were utilized to develop the threshold of the models and to validate the model, respectively. The integrated model showed 100% specificity in ruling out the non-neurotoxic chemicals. The screening of 41 neurotoxicants and complex I inhibitors with the model resulted in 16 chemicals predicted to induce parkinsonian disorder through the molecular initiating event of mitochondrial complex I inhibition. Five of them, namely cyhalothrin, deguelin, deltamethrin, diazepam, and permethrin, are cases with direct evidence linking them to parkinsonian motor deficit-related signs and symptoms. The neurotoxicant prediction model for parkinsonian motor deficits based on the AOP concept may be useful in prioritizing chemicals for further evaluations on PD potential.
... 36 Toxin-induced models rely on the chemical ablation of DA neurons through nigrostriatal toxins, most commonly 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. 37,38 Although these can mimic many of the motor defects resulting from the loss of DA neurons, they do not recapitulate the full PD etiology and thus may obscure insights into PD pathogenesis. In contrast, genetic models, which can replicate autosomal dominant (SNCA, LRRK2) as well as recessive (PINK1, Parkin, DJ-1, and ATP13A2) forms of PD in mice, 39 provide the potential to gain more mechanistic insights 40 also for non-motor symptoms. ...
... Finally, we also challenged AMOs with nigrostriatal toxins, similar to the MPTP toxicity studies in midbrain organoids by Kim and colleagues. 112 Consistent with their results, treatment with the toxins 6-OHDA and MPP+ (the toxic metabolite of MPTP) preferentially induced a concentration-dependent loss of tyrosine hydroxylase (TH)-positive DA neurons relative to other neuronal subtypes, 133 recapitulating a commonly used model for PD 38 in a complex human tissue. ...
Article
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Parkinson's disease (PD) is the second most common neurodegenerative disease and primarily characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Despite decades of research and the development of various disease model systems, there is no curative treatment. This could be due to current model systems, including cell culture and animal models, not adequately recapitulating human PD etiology. More complex human disease models, including human midbrain organoids, are maturing technologies that increasingly enable the strategic incorporation of the missing components needed to model PD in vitro. The resulting organoid‐based biological complexity provides new opportunities and challenges in data analysis of rich multimodal data sets. Emerging artificial intelligence (AI) capabilities can take advantage of large, broad data sets and even correlate results across disciplines. Current organoid technologies no longer lack the prerequisites for large‐scale high‐throughput screening (HTS) and can generate complex yet reproducible data suitable for AI‐based data mining. We have recently developed a fully scalable and HTS‐compatible workflow for the generation, maintenance, and analysis of three‐dimensional (3D) microtissues mimicking key characteristics of the human midbrain (called “automated midbrain organoids,” AMOs). AMOs build a reproducible, scalable foundation for creating next‐generation 3D models of human neural disease that can fuel mechanism‐agnostic phenotypic drug discovery in human in vitro PD models and beyond. Here, we explore the opportunities and challenges resulting from the convergence of organoid HTS and AI‐driven data analytics and outline potential future avenues toward the discovery of novel mechanisms and drugs in PD research. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
... Chronic exposure to pesticides, including fungicides, piscicides, and herbicides, correlates with neurotoxic outcomes. Studies have associated pesticide exposure with sporadic Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and even autism [2][3][4][5][6][7][8]. The molecular underpinnings by which these xenotoxicants elicit neuronal injury and neuronal demise involve the production of reactive oxygen species, which decouples complex I along the oxidative phosphorylation pathway in mitochondria [4]. ...
... Environmental and idiopathic incidences are implicated in the rest of the observed cases. As previously discussed, the use of environmental pesticides, including herbicides, fungicides, and weedicides, provokes neurotoxic outcomes in vertebrates, including humans [2][3][4][5][6][7][8]. Therefore the laboratory use of agents such as rotenone and Paraquat to accelerate neurotoxicity and onset neuropathological outcomes is not only academically relevant but also of clinical importance. ...
Article
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The herbicide and viologen, N, N′-dimethyl-4,4′-bipyridinium dichloride (Paraquat) is known to be toxic to neuronal cells by a multifactorial process involving an elevation in the levels of reactive oxygen species (ROS), the triggering of amyloid-protein aggregation and their accumulation, collectively leading to neuronal dyshomeostasis. We demonstrate that green-chemistry-synthesized sustainable gelatin-derived carbon quantum dots (CQDs) mitigate paraquat-induced neurotoxic outcomes and resultant compromise in organismal mortality. Gelatin-derived CQDs were found to possess antioxidant properties and ameliorated ROS elevation in paraquat-insulted neuroblastoma-derived SHSY-5Y cells, protecting them from herbicide-induced cell death. These CQDs also increased lifespan in paraquat-compromised Caenorhabditis elegans and herbicide-mediated dopamine neuron ablation. Collectively, the data underscore the ability of this sustainably synthesized, environmentally friendly biocompatible nanomaterial to protect cell lines and organisms against neurotoxic outcomes. The study findings strategically position this relatively novel nanoscopic carbon quantum framework for further testing in vertebrate trials of neurotoxic insult.
... One function of DJ-1 is to protect cells from oxidative damage to the mitochondria. Oxidative modification leads to mitochondrial damage in cultured cells exposed to several compounds, such as paraquat, which inhibits the electron transport chain of mitochondrial complex I [10]. Paraquat enhances the production of reactive oxygen species (ROS) and reduces the production of ATP, resulting in mitochondrial dysfunction [11]. ...
... Antioxidants 2021, 10, 1970 ...
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The DJ-1 gene is highly conserved across a wide variety of organisms and it plays a role in anti-oxidative stress mechanisms in cells. The red flour beetle, Tribolium castaneum, is widely used as a model insect species because it is easy to evaluate gene function in this species using RNA interference (RNAi). The T. castaneum DJ-1 (TcDJ-1) sequence is annotated in the T. castaneum genome database; however, the function and characteristics of the TcDJ-1 gene have not been elucidated. Here, we investigated the cDNA sequence of TcDJ-1 and partially characterized its function. First, we examined the TcDJ-1 amino acid sequence and found that it was highly conserved with sequences from other species. TcDJ-1 mRNA expression was higher in the early pupal and adult developmental stages. We evaluated oxidant tolerance in TcDJ-1 knockdown adults using paraquat and found that adults with TcDJ-1 knockdown exhibited increased sensitivity to paraquat. Our findings show that TcDJ-1 has an antioxidant function, as observed for DJ-1 from other insects. Therefore, these results suggest that TcDJ-1 protects against oxidative stress during metamorphosis.
... The neurotoxic potential of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 6-OHDA (6-hydroxydopamine), and paraquat (N, N -dimethyl-4,4 -bipyridinium dichloride) as viable agents to generate PD-related symptoms is already well documented in the literature. Another compound that has gained increased interest with a toxicological profile and a broad spectrum of utility is ROT [1][2][3]. ...
... Presently, ROT is confirmed to be a dopaminergic antagonistic that crosses the blood-brain barrier (BBB) and directly enters the central nervous system (CNS) and accumulates in cellular organelles, predominantly in the mitochondria, due to its lipophilic structure [1][2][3]. ...
Article
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Background: Rotenone (ROT) is currently being used in various research fields, especially neuroscience. Separated from other neurotoxins, ROT induces a Parkinson's disease (PD)-related phenotype that mimics the associated clinical spectrum by directly entering the central nervous system (CNS). It easily crosses through the blood-brain barrier (BBB) and accumulates in mitochondria. Unfortunately, most of the existing data focus on locomotion. This is why the present study aimed to bring novel evidence on how ROT alone or in combination with different potential ant(agonists) might influence the social and aggressive behavior using the counterclockwise rotation as a neurological pointer. Material and methods: Thus, we exposed zebrafish to ROT-2.5 µg/L, valproic acid (VPA)-0.5 mg/mL, anti-parkinsonian drugs (LEV/CARB)-250 mg + 25 mg, and probiotics (PROBIO)-3 g for 32 days by assessing the anti-social profile and mirror tests and counterclockwise rotation every 4 days to avoid chronic stress. Results: We observed an abnormal pattern in the counterclockwise rotation only in the (a) CONTROL, (c) LEV/CARB, and (d) PROBIO groups, from both the top and side views, this indicating a reaction to medication and supplements administered or a normal intrinsic feature due to high levels of stress/anxiety (p < 0.05). Four out of eight studied groups-(b) VPA, (c) LEV/CARB, (e) ROT, and (f) ROT + VPA-displayed an impaired, often antithetical behavior demonstrated by long periods of time on distinct days spent on the right and the central arm (p < 0.05, 0.005, and 0.0005). Interestingly, groups (d) PROBIO, (g) ROT + LEV/CARB, and (h) ROT + PROBIO registered fluctuations but not significant ones in contrast with the above groups (p > 0.05). Except for groups (a) CONTROL and (d) PROBIO, where a normalized trend in terms of behavior was noted, the rest of the experimental groups exhibited exacerbated levels of aggression (p < 0.05, 0.005, and 0.001) not only near the mirror but as an overall reaction (p < 0.05, 0.005, and 0.001). Conclusions: The (d) PROBIO group showed a significant improvement compared with (b) VPA, (c) LEV/CARB, and ROT-treated zebrafish (e-h). Independently of the aggressive-like reactions and fluctuations among the testing day(s) and groups, ROT disrupted the social behavior, while VPA promoted a specific typology in contrast with LEV/CARB.
... 6-Hydroxydopamine (6-OHDA) is the first substance that has been identified as a dopaminergic neurotoxin. 6-OHDA is a DA analog with a high binding affinity to the DA transporter; therefore, it has a high potential to be selectively uptake into the catecholaminergic neurons, including the dopaminergic ones (Bové et al., 2005;Hernandez-Baltazar et al., 2017). Inside the neurons, the 6-OHDA undergoes enzymatic degradation facilitated by the monoamine oxidase-A (MAO-A) as well as the autoxidation. ...
... Because of structural similarity to endogenous catecholamines, 6-OHDA is recognized and uptaken by DA or noradrenaline membrane transporters. When 6-OHDA is absorbed and accumulated inside neurons, it undergoes both enzymatic breakdowns by MAO-A and autoxidation, resulting in the formation of multiple cytotoxic molecules that cause neuronal death through the production of oxidative damage and mitochondrial dysfunction (Glinka et al., 1997;Soto-Otero et al., 2000;Bové et al., 2005;Hernandez-Baltazar et al., 2017). This study revealed that exposure to 100 µM 6-OHDA could cause cell death, raise intracellular ROS levels, and induce LDH leakage. ...
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Parkinson's disease (PD) is considered one of the health problems in the aging society. Due to the limitations of currently available drugs in preventing disease progression, the discovery of novel neuroprotective agents has been challenged. Sulfonamide and its derivatives were reported for several biological activities. Herein, a series of 17 bis-sulfonamide derivatives were initially tested for their neuroprotective potential and cytotoxicity against the 6-hydroxydopamine (6-OHDA)-induced neuronal death in SH-SY5Y cells. Subsequently, six compounds (i.e., 2, 4, 11, 14, 15 , and 17 ) were selected for investigations on underlying mechanisms. The data demonstrated that the pretreatment of selected compounds (5 μM) can significantly restore the level of cell viability, protect against mitochondrial membrane dysfunction, decrease the activity of lactate dehydrogenase (LDH), decrease the intracellular oxidative stress, and enhance the activity of NAD-dependent deacetylase sirtuin-1 (SIRT1). Molecular docking was also performed to support that these compounds could act as SIRT1 activators. In addition, in silico pharmacokinetic and toxicity profile prediction was also conducted for guiding the potential development. Thus, the six neuroprotective bis-sulfonamides were highlighted as potential agents to be further developed for PD management.
... SNPs in OGG1, as well as APE1, have been associated with increased risk of PD upon exposure to pesticides [160]. Mice treated with the neurotoxins 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone develop a PD-like phenotype, likely via alterations in oxidative metabolism and generation of oxidative stress [161,162]. Interestingly, NEIL1 −/− mice were shown to display accelerated motor dysfunction and neuroinflammation compared to wild-type mice upon treatment with 6-OHDA and MPTP, respectively [115]. These results suggest that OGG1, MUTYH, and NEIL1 are associated with PD and may play distinct roles in the pathogenesis of the disease. ...
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The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.
... Various neurotoxin-based animal models are often raised in evaluating the therapeutic agent efficacy in PD. The sensory and motor impairment similar in PD patients can be observed in these animal models which experience a generation of DA neurons (Bové et al. 2005;Terzioglu and Galter 2008). ...
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Free radical or oxidative stress may be a fundamental mechanism underlying several human neurologic diseases. Therapy using free radical scavengers (antioxidants) has the potential to prevent, delay, or ameliorate many neurologic disorders. However, the biochemistry of oxidative pathobiology is complex, and optimum antioxidant therapeutic options may vary and need to be tailored to individual diseases. In vitro and animal model studies support the potential beneficial role of various antioxidant compounds in neurological disease. Antioxidants generally play an important role in reducing or preventing the cell damage and other changes which occur in the cells like mitochondrial dysfunction, DNA mutations, and lipid peroxidation in the cell membrane. Based on their mechanism of action, antioxidants can be used to treat various neurological disorders like Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease. Vitamin E has a scavenging action for reactive oxygen species (ROS) and also prevents the lipid peroxidation. Creatine generally reduces the mitochondrial dysfunction in Parkinson’s disease (PD) patients. Various metal chelators are used in PD for the prevention of accumulation of the metals. Superoxidase dismutase (SOD), lipases, and proteases act as repair enzymes in patients with AD. Accordingly, the antioxidant defense system is found to be most useful for treating various neurological disorders.
... Of note, most studies use unilateral injections due to the high mortality of bilateral administration. In addition, while direct injection provides for high selectivity, there is a concern that this protocol may cause increased inflammation and neuronal damage near the site of injection (Bové, et al., 2005). Due to the short temporal window between injection and neuronal loss, 6-OHDA striatal lesion models may be useful in studying the neuropathologic mechanisms J o u r n a l P r e -p r o o f underlying cell loss in PD as well as for the screening of potentially neuroprotective therapies (Bové and Perier 2012). ...
Article
Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are neurodegenerative disorders characterized by progressive structural and functional loss of specific neuronal populations, protein aggregation, an insidious adult onset, and chronic progression. Modeling AD, PD, and HD in animal models is useful for studying the relationship between neuronal dysfunction and abnormal behaviours. Animal models are also excellent tools to test therapeutic approaches. Numerous genetic and toxin-induced models have been generated to replicate these neurodegenerative disorders. These differ in the genetic manipulation employed or the toxin used and the brain region lesioned, and in the extent to which they mimic the neuropathological and behavioral deficits seen in the corresponding human condition. Each model exhibits unique advantages and drawbacks. Here we present a comprehensive overview of the numerous AD, PD, and HD animal models currently available, with a focus on their utilities and limitations. Differences among models might underlie some of the discrepancies encountered in the literature and should be taken into consideration when designing new studies and testing putative therapies.
... Indirubins are also found in human urine indicating that our body also synthesizes them [16]. Indirubins inhibit variety of kinases including CDK5 and the enzyme GSK3β and therefore recommended for the treatment of chronic bone marrow leukemia, cancer and neurodegenerative diseases [19][20][21]. 7-BIO is a derivative of indirubin-3-oxime improves the toxicity induced cognitive impairment by large amyloid-beta polymer fibrils in SH-SY5Y neuroblastoma [22]. The mechanism through which 7-BIO protects SH-SY5Y from toxicity could be mediated by microRNAs, a group of small non-coding RNAs that interfere with messenger RNAs (mRNAs). ...
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In the current study, the effects of 7-BIO as a specific GSK3β inhibitor was examined on cell survival and expression of miR-29a-3p and miR-34a-5p in neurotoxin MPP⁺ treated SH-SY5Y cells. Our findings revealed that while co-treatment of the cells with 7-BIO and MPP⁺ did not alter the toxicity induced by MPP⁺, pretreatment with 3.5 μM 7-BIO for 6 h increased the survival of the 2 mM MPP⁺ treated cells. Also, qRT-PCR analysis of gene expression showed that while miR-29a-3p was unchanged either in cells treated with either 2 mM MPP⁺ or 3.5 μM 7-BIO alone, miR-34a-5p was increased by MPP⁺ but decreased by 7-BIO. Pretreatment with 3.5 μM 7-BIO prior to MPP⁺ however, increased miR-29a-3p but decreased miR-34a-5p induced by MPP⁺. We therefore suggest that 7-BIO inhibition of GSK3β alleviates the MPP⁺ induced neurotoxicity by regulating miR-29a-3p and miR-34a-5p expressions in Parkinson's disease model SH-SY5Y cells.
... The intestine is a tissue that directly contacts the external environment, whereby it is often affected by environmental conditions, and communicates with neurons (76). In C. elegans, rotenone is a widely used mitotoxin that causes A c c e p t e d M a n u s c r i p t mitochondrial complex I dysfunction (77,78). A previous study found that the p38MAPK/CREB/ATF-7-dependent innate immune response pathway in intestinal cells was activated by rotenone exposure, protecting rotenone-induced dopaminergic neurodegeneration through mitophagy (5). ...
Article
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The nervous system is the central hub of the body, detecting environmental and internal stimuli to regulate organismal metabolism via communications to the peripheral tissues. Mitochondria play an essential role in neuronal activity by supplying energy, maintaining cellular metabolism, and buffering calcium levels. A variety of mitochondrial conditions are associated with aging and age-related neurological disorders. Beyond regulating individual neuron cells, mitochondria also coordinate signaling in tissues and organs during stress conditions to mediate systemic metabolism and enable organisms to adapt to such stresses. In addition, peripheral organs and immune cells can also produce signaling molecules to modulate neuronal function. Recent studies have found that mitokines released upon mitochondrial stresses affect metabolism and the physiology of different tissues and organs at a distance. Here, we summarize recent advances in understanding neuron-periphery mitochondrial stress communication and how mitokine signals contribute to the systemic regulation of metabolism and aging with potential implications for therapeutic strategies.
... PD models developed based on neurotoxins though helped in understanding the mechanism behind development of PD, but these studies lack the natural way of exposure to toxins (Meredith and Rademacher 2011;Bové et al. 2005). In our studies, we developed i.n. oil in water microemulsion of rotenone which is the common way of exposure to environmental toxin in agrochemical use for example in fisheries (Rojo et al. 2007). ...
Article
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Epidemiologically Parkinson’s disease (PD) is associated with chronic ingestion or inhalation of environmental toxins leading to the development of motor symptoms. Though neurotoxin-based animal models played a major role in understanding diverse pathogenesis, they failed to identify the risk assessment due to uncommon route of toxin exposure. Towards this, the available neurotoxin-based intranasal (i.n.) PD models targeting olfactory bulb (OB) have demonstrated the dopaminergic (DAergic) neurodegeneration in both OB and substantia nigra (SN). Despite that, the studies detecting the alpha-synuclein (α-syn) accumulation in OB and its progression to other brain regions due to inhalation of environmental toxins are still lacking. Herein, we developed oil in water microemulsion of rotenone administered intranasally to the mice at a dose which is not detectable in blood, brain, and olfactory bulb by LCMS method. Our data reveals that 9 weeks of rotenone exposure did not induce olfactory and motor dysfunction. Conversely, after 16 weeks of washout period, rotenone treated mice showed both olfactory and motor impairment, along with α-syn accumulation in the OB and striatum without glial cell activation and loss of dopaminergic neurons. The results depict the progressive nature of the developed model and highlight the role of α-syn in PD like pathology or symptoms. Together, our findings suggest the adverse consequences of early exposure to the environmental toxins on the olfactory system for a shorter period with relevance to the development of synucleinopathy or Parkinson’s disease in its later stage.
... A hole was drilled 3 mm lateral and 0.2 mm anterior to bregma over the left parietal cortex (Fig.1). To generate a PD model [38,39], the neurotoxin 6-hydroxydopamine (6-OHDA) was injected ventrally 5 mm below the dura mater into the left striatum of unconscious rats. The lesion group received 5 µl of normal cold saline containing 2.5 µg/µl of 6-OHDA-HCl (6-OHDA, Sigma) and 0.2% ascorbate. ...
Article
Traditional deep brain stimulation (DBS) is one of the acceptable methods to relieve the clinical symptoms of Parkinson’s disease in its advanced stages. Today, the use of closed-loop DBS to increase stimulation efficiency and patient satisfaction is one of the most important issues under investigation. The present study was aimed to find local field potential (LFP) features of parkinsonian rats, which can determine the timing of stimulation with high accuracy. The LFP signals from rats were recorded in three groups of parkinsonian rat models receiving stimulation (stimulation), without getting stimulation (off-stimulation), and sham-controlled group. The frequency domain and chaotic features of signals were extracted for classifying three classes by support vector machine (SVM) and neural networks. The best combination of features was selected using the genetic algorithm (GA). Finally, the effective features were introduced to determine the on/off stimulation time, and the optimal stimulation parameters were identified. It was found that a combination of frequency domain and chaotic features with an accuracy of about 99% was able to determine the time the DBS must switch on. In about 80.67% of the 1861 different stimulation parameters, the brain was able to maintain its state for about 3 min after stimulation discontinuation.Graphical abstract
... This type of study most often involves using animal models. Unfortunately, current models of PD are not progressive and lack several pathological and behavioural hallmarks that can be reliably measured and tracked (Bové et al., 2005;Duty and Jenner, 2011); these features are critical in understanding PD development and how therapies initiated at different time points in disease affect their trajectory. Most importantly, the animal models used need to be reproducible. ...
Article
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The consumption of cycad ( Cycas circinalis ) seeds has been linked to the development of Amyotrophic Lateral Sclerosis-Parkinsonism Dementia Complex (ALS-PDC) in humans. ALS-PDC is a clinically variable disease presenting as a combination of symptoms typical of PD and/or ALS. Chronic consumption of β-sitosterol β-D-glucoside (BSSG), a component of the cycad seed, by rats ( Rattus norvegicus ) has been previously reported to initiate a progressive pathology that develops over several months and manifests as behavioural and histopathological changes that resemble characteristic features of Parkinson’s disease. As part of an independent multi-site validation study, we have tried to replicate and further characterize the BSSG model with a focus on motor function, and associated immunohistochemical markers. Beginning at 3 months of age, male CD ® (Sprague Dawley) rats ( N = 80) were dosed orally with either a flour pellet or a flour pellet containing BSSG (3 mg) daily (5×/week) for 16 weeks consistent with previous reports of the model. Following BSSG intoxication, separate cohorts of animals ( n = 10/treatment) were exposed to a behavioural test battery at 16, 24, 32, or 40 weeks post-initial BSSG feeding. The test battery consisted of the open field test, cylinder test, and ultrasonic vocalization (USV) assessment. No changes in behaviour were observed at any time point. Following behavioural testing, animals were processed for immunohistochemical markers of substantia nigra integrity. Immunohistochemistry of brain tissue revealed no differences in the microglial marker, Iba1, or the dopaminergic integrity marker, tyrosine hydroxylase (TH), in the substantia nigra at any assessment point. The absence of any group differences in behaviour and immunhistochemistry indicates an inability to replicate previous reports. Further investigation into the sources of variability in the model is necessary prior to further utilization of the BSSG model in preclinical studies.
... Another basis for considering PD as a systemic disease is the involvement of mitochondrial dysfunction; it is widely known that mitochondrial dysfunction plays an important role in the pathogenesis of PD. For example, it has been shown that the activity of complex 1 is reduced not only in brains of PD patients but also in the platelets of PD patients [4,5,6], and mitochondrial complex 1 inhibitor has been used to establish PD mice models [7]. A number of genes responsible for familial PD, such as Parkin and PINK1, are related to the mitochondrial function [8]. ...
Article
For the development of disease-modifying therapies for Parkinson's disease (PD) the identification of biomarkers in the prodromal stage is urgently required. Because PD is considered a systemic disease even in the early stage, we performed a metabolomic analysis of the plasma from a mouse model of prodromal PD (p-PD). Increased levels of isobutyrylcarnitine in p-PD mice imply an abnormality in β-oxidation in mitochondria, and increased levels of pyrimidine nucleoside can be associated with mitochondrial dysfunction. Consistent with these results, the immunoblot analysis showed a defect in mitochondrial complex I assembly in p-PD mice. These results suggest that systemic mitochondrial dysfunction may exist in p-PD mice and contribute to the pathogenesis of PD, potentially being useful as early biomarkers for PD.
... neurotoxin model of PD. Unilateral, stereotaxic injection of 6-OHDA in the MFB or striatum results in a progressive phenotype involving dopaminergic cell death and depletion of striatal dopamine on the lesioned side[100][101][102] . The resulting imbalance in striatal dopamine causes pronounced motor deficits. ...
Article
Parkinson's disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein α-synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the disease's motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. In this study, we characterized the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.
... This neurotoxin causes a depletion of the transmitter content of dopaminergic nerve terminals and cell bodies (Ungerstedt, 1968), and it has mostly been injected unilaterally into the SNc of the medial forebrain bundle to elicit the loss of dopamine neurons in animals. Indeed, a bilateral lesion often causes aphagia and adipsia, leading to a loss of body weight and even the death of the animals (Dauer & Przedborski, 2003;Bové et al., 2005;Bezard & Przedborski, 2011). ...
Thesis
La queue de l’aire tegmentale ventrale (tVTA) est le principal contrôle inhibiteur des neurones dopaminergiques du mésencéphale. Cette structure, bien qu’aujourd’hui très étudiée, n’est cependant pas encore référencée dans les atlas stéréotaxiques. Anatomiquement, nous avons pu apporter une définition de référence de la tVTA, à travers son analyse neurochimique, stéréologique, hodologique et génomique. Fonctionnellement, nous avons montré son rôle dans la réponse à des expériences émotionnelles aversives et nous avons testé son influence sur les symptômes moteurs et non-moteurs de la maladie de Parkinson. Nous avons ainsi montré qu’une co-lésion de la tVTA dans un modèle murin de la maladie permet une amélioration des performances motrices, des seuils nociceptifs et des symptômes de type dépressifs. Ce travail a ainsi participé au progrès de nos connaissances sur la tVTA et ouvre de nouvelles pistes d’exploration quant à son implication fonctionnelle.
... The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which induces the selective loss of dopaminergic neuron in nigrostriatal pathway is one of the well-known ways to induce such experimental PD model. [30][31][32]. We, here focus on investigation of the effects of silibinin on oxidative stress and mitochondrial function in MPTP-induced mouse models of PD and aim to elucidate the underlying mechanisms, focusing on mitophagy. ...
Article
Silybum marianum (L.) Gaertn has been widely used to obtain a drug for the treatment of hepatic diseases. Silibinin (silybin), a flavonoid extracted and isolated from the fruit of Silybum Marianum is investigated in our study to explore its motor protective potential on Parkinson's disease (PD) model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PD is a neurodegenerative disease that causes a debilitating movement disorder, characterized by a progressive loss of nigrostriatal (substantia nigra and striatum) dopaminergic neurons. Several studies have proven that neurodegeneration is aggravated by neuroinflammation, oxidative stress and/or the presence of α-synuclein (α-syn) aggregation. Essentially no causal therapy for PD exists at present. Our results demonstrate that silibinin significantly attenuates MPTP-induced movement disorder in behavioral tests. Immunohistochemical analysis shows that MPTP injection results in the loss of dopaminergic neurons in the substantia nigra, and the decrease of the striatal tyrosine hydroxylase. However, MPTP-injected mice were protected against dopaminergic neuronal loss by oral administration of silibinin (280 mg/kg) that increased expressions of PTEN-induced putative kinase 1 (PINK1) and Parkin, suggesting mitophagy activation. The neuroprotective mechanism of silibinin involves not only reduction of mitochondrial damage by repressing proinflammatory response and α-syn aggregation, but also enhancement of oxidative defense system. Namely, protection of dopaminergic nerves is due to promotion of mitophagy, leading to clearance of the toxic effects of damaged mitochondria. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for PD.
... Mitochondrial toxin exposure results in the selective degeneration of SN neurons (Bove et al., 2005). To test whether we can recapitulate the selective vulnerability of DA neurons in vitro, we compared the effects of mitochondrial toxins on neuronal survival between 5-stage and mFPderived cultures ( Figure 3A). ...
Article
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In Parkinson’s disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN- and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN- or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery.
... According to a previous study, autophagy, which eliminates aggregated α-synuclein, may represent a potential neuroprotective strategy in PD [9,12]. 6-Hydroxydopamine (6-OHDA) is commonly used to develop in vitro models of PD [13]. The structure of 6-OHDA is similar to that of dopamine, and it can easily oxidize into hydrogen peroxide and para-quinone [14]; it can enter neuronal cells and generate intracellular reactive oxygen species (ROS), ultimately causing neuronal cell death [15]. ...
Article
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Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, after Alzheimer’s disease. In our previous study, we found that amber—a fossilized plant resin—can protect cells from apoptosis by decreasing the generation of reactive oxygen species (ROS). In this study, we focused on the effect of amber on 6-hydroxydopamine-induced cell apoptosis in the human neuroblastoma cell line SHSY5Y (one model for PD). Initially, we determined the protective effect of amber on the PD model. We found that amber extract has a protective effect against 6-hydroxydopamine-induced cell apoptosis. The decrease in ROS, cleaved caspase-3, pERK, and extracellular signal-regulated kinase (ERK) protein levels confirmed that amber extract decreases apoptosis via the ROS-mediated ERK signaling pathway. Furthermore, we determined the effects of amber extract on autophagy. The results showed that amber extract increased the levels of LC3II and Beclin-1, suggesting that amber extract can protect neuronal cells against 6-hydroxydopamine-induced cell apoptosis by promoting autophagy.
... Findings from studies based on the well-known Parkinsonian neuroxins such as MPTP, paraquat (a herbicide commonly used in Taiwan in rice fields) and rotenone [180,181], suggest that environmental factors may be more important than genetic factors in development of PD. Internal organs constantly exchange signals and change in size or function in response to environmental or internal challenges. ...
Article
Full-text available
Background Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. Aim of Review: In this review, we summarize how the alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved in neuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further explored in humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
... Environmental exposures to various neurotoxicants that alter dopaminergic neurotransmission contribute to the development of age-related movement disorders (Ball et al. 2019;Bové et al. 2005;Di Monte 2003). The neurotoxicant methylmercury (MeHg) is an organic mercurial formed in the water ecosystem mainly by bacterium-mediated methylation of inorganic mercury. ...
Article
Full-text available
Methylmercury (MeHg) neurotoxicity exhibits age-dependent effects with a latent and/or persistent neurotoxic effect on aged animals. Individual susceptibility to MeHg neurotoxicity is governed by both exposure duration and genetic factors that can magnify or mitigate the pathologic processes associated with this exposure. We previously showed the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) modulates the response of worms to high levels of MeHg, mitigating its effect on neuronal morphology in pre-vesicles in cephalic (CEP) dopaminergic neurons. Here we sought to better understand the long-term effects of MeHg exposure at low levels (100-fold lower than that in our previous report) and the modulatory role of the LRRK2 mutation. Worms exposed to MeHg (10 or 50 nM) at the larval stage (L1 stage) were compared at adult stages (young age: day 1 adult; middle age: day 5 adult; old age: day 10 adult) for the swimming speeds in M9 buffer, moving speeds during locomotion on an OP50-seeded plate, and the numbers of CEP dopaminergic pre-vesicles, vesicular structures originating from the dendrites of CEP for exportation of cellular content. In addition, the expression levels of Caenorhabditis elegans homologs of dopamine transporter (dat-1) and tyrosine hydroxylase (cat-2) were also analyzed at these adult stages. Our data showed that swimming speeds were reduced in wild-type worms at the day 10 adult stage at 50 nM MeHg level; yet, reduced swimming speeds were noted in the G2019S LRRK2 transgenic line upon MeHg exposures as low as 10 nM. Compared to locomotor speeds, swimming speeds appear to be more sensitive to the behavioral effects of developmental MeHg exposures, as the locomotor speeds were largely intact and indistinguishable from controls following MeHg exposures. Furthermore, we showed an age-dependent modulation of dat-1 and cat-2 expressions, which could also be modified by the LRRK2 mutation. Although MeHg exposures did not change the number of pre-vesicles, the LRRK2 mutation was associated with increased numbers of pre-vesicles in aged worms. Our data suggest that the latent behavioral effects of MeHg are sensitized by the G2019S LRRK2 mutation, and the underlying mechanism likely involves age-dependent changes in dopaminergic signaling.
... Findings from studies based on the well-known Parkinsonian neuroxins such as MPTP, paraquat (a herbicide commonly used in Taiwan in rice fields) and rotenone [180,181], suggest that environmental factors may be more important than genetic factors in development of PD. Internal organs constantly exchange signals and change in size or function in response to environmental or internal challenges. ...
... ROT crosses the blood-brain barrier (BBB) and accumulates in cellular organelles, particularly mitochondria [16,17]. From this point, it causes neuronal toxicity [18] and a decline in adenosine triphosphate (ATP) production. ...
Article
Full-text available
Parkinson’s disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or supplements consisting of live active lactic acid bacteria strains might alleviate and improve PD-related phenotypes. This is why we aimed to elucidate how the administration of rotenone (ROT) disrupts homeostasis and the possible neuroactive potential of valproic acid (VPA), antiparkinsonian agents (levodopa and carbidopa – LEV+CARB), and a mixture of six Lactobacillus and three Bifidobacterium species (PROBIO) might re-establish the optimal internal parameters. ROT causes significant changes in the central nervous system (CNS), notably reduced neurogenesis and angiogenesis, by triggering apoptosis, reflected by the increased expression of PARKIN and PINK1 gene(s), low brain dopamine (DA) levels, and as opposed to LRRK2 and SNCA compared with healthy zebrafish. VPA, LEV/CARB, and PROBIO sustain neurogenesis and angiogenesis, manifesting a neuroprotective role in diminishing the effect of ROT in zebrafish. Interestingly, none of the tested compounds influenced oxidative stress (OS), as reflected by the level of malondialdehyde (MDA) level and superoxide dismutase (SOD) enzymatic activity revealed in non-ROT-exposed zebrafish. Overall, the selected concentrations were enough to trigger particular behavioral patterns as reflected by our parameters of interest (swimming distance (mm), velocity (mm/s), and freezing episodes (s)), but sequential testing is mandatory to decipher whether they exert an inhibitory role following ROT exposure. In this way, we further offer data into how ROT may trigger a PD-related phenotype and the possible beneficial role of VPA, LEV+CARB, and PROBIO in re-establishing homeostasis in Danio rerio.
... However, the normal lifespan of mice is 12-36 months [10] , which means that for diseases that begin late or have a slow rate of progression, mice may not fully exhibit the whole course of the disease. For mutations that can only induce late-onset symptoms or slow progressive disease, mice models may not exhibit observable symptoms in their lifetime without extra administration, such as drug stimulation [46] . Furthermore, due to the short lifespan of mice, it is hard to identify whether a symptom (e.g., vision loss) is caused by pathological neuronal death or age-related reasons [9] . ...
Article
Full-text available
Animal models have great importance in the research of human neurodegenerative diseases due to their value in symptom mimicking, mechanism investigation, and preclinical tests. Although non-human primate and large animal models have good performance in disease modeling due to their high maintenance cost and critical ethical standards, rodent models are commonly used. Rodent models have been successfully applied in modeling many neurological diseases; however, their genetic background, neuroanatomical features, and nervous system development are different from those of humans. Moreover, the short lifespan and small body size of rodent models also limit the monitoring of disease progression and observation of clinical symptoms in studying neuronal disorders that are late-onset or have a long course of progression. In comparison with rodents, rabbits are phylogenetically closer to humans and have closer similarities to humans in brain development, thus are an alternate animal model for human neurological diseases.
... Among the toxic animal models of Parkinson's disease, rotenone represents one of the most used approaches. It causes highly selective dopaminergic degeneration and α-synuclein aggregation in these neurons, and its prolonged exposure reproduces characteristics of Parkinson's disease via excess generation of free radicals mediated oxidative stress (Betarbet et al. 2000(Betarbet et al. , 2002Bové et al., 2005;Pan-Montojo et al., 2010;Sharma and Nehru 2013;Jia et al., 2014;Prasad and Hung, 2020). Data from some studies showed that in-vivo rotenone infusion caused selective upregulation of α-synuclein in the substantia nigra and increased the occurrence of higher-molecular-weight, aggregated forms of α-synuclein (Betarbet et al., 2000(Betarbet et al., , 2002Höglinger et al., 2003;Sherer et al., 2007). ...
Article
Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.
... Rotenone is highly lipophilic in nature, and owing to this property it can easily penetrate and cross through different membranes and induce neurodegeneration after its administration [14]. Animal models of Parkinson's disease, though not perfect, have expanded our understanding of disease etiology at biochemical and molecular levels [15]. Therefore, researchers have relied on experimental animal models that use neurotoxins that elicit parkinson's disease-like symptoms [16]. ...
Article
Full-text available
Parkinson's disease (PD) is a progressive neurological disorder characterized by progressive loss of dopaminergic neurons in substantianigra pars compacta (SNPc) and other brain regions. The pathogenic events that occur in this disorder include mitochondrial dysfunction, oxidative stress and formation of cytoplasmic inclusions containing α-synclein and ubiquitin. Rotenone model of Parkinson's disease involves substantiated exposure to pesticides and complex-1 inhibition in mitochondria in the neurons, a prominent event of Parkinson's disease etiology. The present study aims to evaluate the neuroprotective effect of pioglitazone, a peroxisome proliferator activated receptor gamma (PPAR-γ) agonist, on rotenone induced neurodegeneration and biochemical alterations. Rotenone (3 mg/kg, i.p.) was used to induce neurodegeneration. Administration of rotenone for 21 days significantly increased the tremors, muscular rigidity, and reduced the grip strength, motor activity, and numbers of poking, rearing behavior in experimental rats. Treatment with pioglitazone (10, 20 and 30 mg/kg, p.o.) for 21 days decreased the tremors, muscular rigidity and significantly increased the grip strength, rearing behavior, motor activity and number of poking in rats. Rotenone significantly increased lipid peroxidation and reduced the levels of defensive antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) in rat brain. Pioglitazone reversed these effects of rotenone on oxidative stress indices; indicating neuroprotection in rat brains.
... We chose to base this work on the MPTP model as proof of principle. While toxicological models may not provide a true pathogenesis of PD because they cause acute not gradual neurodegeneration, they are a widely accepted model platform for studying the neurochemistry of PD. (Bové et al., 2005;Fernagut et al., 2007;Fornai et al., 2005;Greenamyre et al., 2003;Tillerson et al., 2002) Protocols for MPTP administration vary from study to study making it difficult to compare results, however, a common protocol involves acute peripheral injections of a high concentration of MPTP. This protocol not only produces a substantial decrease of striatal dopamine by at least 40-50%,(Jackson-Lewis et al., 1995; Jackson-Lewis & Przedborski, 2007) but also a decrease in serotonin concentrations across multiple brain regions, (Nayyar et al., 2009;Sundström et al., 1987;Vučković et al., 2008) although serotonergic cell loss is not observed. ...
Preprint
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Loss of midbrain dopaminergic neurons is well characterized to underlie the motor symptoms of Parkinson’s Disease (PD). There are, however, a host of non-motor, and often devastating PD symptoms and less is known about how these symptoms are mediated by neurotransmitters. Serotonin neurochemistry is linked to various aspects of the disease such as PD-associated depression, levodopa (L-Dopa) induced depression and L-Dopa induced dyskinesia (LID). Depression and LID significantly reduce quality of life for PD patients so understanding serotonin neurotransmission in PD models is of great merit for reducing these symptoms. Here we use niche, fast electrochemistry paired with mathematical modeling and machine learning to, for the first time, robustly evaluate serotonin in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Mice treated with an acute MPTP paradigm had lower concentrations of in vivo , evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to an SSRI, as strongly as did control animals, following the clinical literature showing that antidepressant success during PD is highly variable. Following levodopa (L-DOPA) administration, using a novel machine learning analysis tool, we see a dynamic shift from evoked serotonin release to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we find that this post L-DOPA dopamine release is less regulated, staying in the synapse for longer. This finding, perhaps to lack of autoreceptor control, may underlie the clinical presentation of LIDS. For the first time, this work shows the chemical intricacies of serotonin and how this modulator underlies several important non-motor deficits of PD, opening up new avenues of study for ultimately alleviating these symptoms.
... Environmental toxins are associated with sporadic PD and have been partially simulated in animal models of PD. The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which induces the selective loss of dopaminergic neuron in nigrostriatal pathway [22][23][24] is one of the well-known ways to establish such experimental PD model. We, here, investigated the therapeutic effects of silibinin in MPTP-induced mouse model of PD in order to elucidate the underlying mechanisms, focusing on oxidative stress, α-synuclein and mitochondrial dynamics. ...
Article
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Besides motor disorder, cognitive dysfunction is also common in Parkinson’s disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.
... Since it is thought that the oral and nasal pathway is a common environmental exposure route of pesticides [17], the continuous administration of rotenone through oral gavage or intranasal route in rodents may more accurately, but incompletely, replicate the etiology of human PD. However, orally administrated rotenone is slightly absorbed from the gastrointestinal tract, and metabolized in the liver by NADP-linked hepatic microsomal enzymes [60]. Due to the lower bioavailability of orally administrated rotenone, higher doses (5-40 mg/kg) of rotenone are required to produce PD symptoms (e.g., motor deficits) in mice, and may cause acute toxicity [21]. ...
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Background: Taste impairments are often accompanied by olfactory impairments in the early stage of Parkinson's disease (PD). The development of animal models is required to elucidate the mechanisms underlying taste impairments in PD. Objective: This study was conducted to clarify whether the intranasal administration of rotenone causes taste impairments prior to motor deficits in mice. Methods: Rotenone was administrated to the right nose of mice once a day for 1 or 4 week(s). In the 1-week group, taste, olfactory, and motor function was assessed before and after a 1-week recovery period following the rotenone administration. Motor function was also continuously examined in the 4-weeks group from 0 to 5 weeks. After a behavioral test, the number of catecholamine neurons (CA-Nos) was counted in the regions responsible for taste, olfactory, and motor function. Results: taste and olfactory impairments were simultaneously observed without locomotor impairments in the 1-week group. The CA-Nos was significantly reduced in the olfactory bulb and nucleus of the solitary tract. In the 4-week group, locomotor impairments were observed from the third week, and a significant reduction in the CA-Nos was observed in the substantia nigra (SN) and ventral tegmental area (VTA) at the fifth week along with the weight loss. Conclusion: The intranasal administration of rotenone caused chemosensory and motor impairments in an administration time-period dependent manner. Since chemosensory impairments were expressed prior to the locomotor impairments followed by SN/VTA CA neurons loss, this rotenone administration model may contribute to the clarification of the prodromal symptoms of PD.
... Dysfunctional mitochondria show a reduction in energy production and utilization. The effect of environmental toxins such as herbicides, pesticides, fungicides, and insecticides on health is a major concern [9,10]. Many studies suggest a close relationship between exposure of these toxic chemicals and the development of PD [11][12][13][14]. ...
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Parkinson’s disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.
... A considerable part of PD cases according to Udagedara et al. (2019) is considered to be caused by cerebrovascular changes. A wide body of studies claimed environmental toxins such as herbicides, pesticides and natural toxins to be potentially responsible for neuronal cell death (Bové et al. 2005; Salama and Arias-Carrion 2011). ...
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... Due to its lipophilic nature, rotenone, a naturally occurring isoflavonoid from tropical plants [29], is membrane permeable and capable of entering all neuron types, where it inhibits complex I of the mitochondria respiratory chain [30]. Despite being an unselective compound, chronic systemic exposure to rotenone in animals has been shown to reproduce some of the key features of PD, including selective degeneration of TH + , DAT + and VMAT2 + neurons and the formation of α-synuclein-containing intracellular inclusions in nigral DAergic cells [31]. ...
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... and current research suggests that neuronal degeneration of brainstem nuclei, including the pontine tegmental area and medulla, is the pathophysiological cornerstone of RBD [7,47]. Our current results comparing the effect of rotenone, paraquat and ASYN between neuronal subtypes suggest that this variability in the prevalence of motor and non-motor symptoms can be explained by the differences in the sensitivity to ASYN and oxidative stress between the different neuronal subtypes, with dopaminergic neurons being the most sensitive against both oxidative stress (caused by rotenone and paraquat [48][49][50][51][52]) and ASYN oligomers, which would explain why lack of dopaminedependent motor symptoms are always present in PD patients. The effect of these noxae on enteric neurons is difficult to interpret, as we observed a high variability between experiments. ...
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Parkinson′s disease (PD) pathology progresses throughout the nervous system affecting numerous neuronal structures. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed alpha-synuclein (ASYN) on endogenous ASYN. The appearance of the pathology in dopaminergic neurons leads to neuronal cell death and motor symptoms. However, the effect on other neuronal structures is more inconsistent, leading to a higher variability in the prevalence of non-motor symptoms. Thus, the sensitivity to the pathology seems to vary among neuronal subtypes. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology and the effect of monomeric and oligomeric ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type mice. Our results showed that pathology progression did not occur in the absence of endogenous ASYN and that dopaminergic neurons were more sensitive to ASYN and rotenone when compared to all other neuronal subtypes. Remarkably, the toxic effect of endocytosed ASYN-oligomers was independent of the presence of endogenous ASYN and directly related to the disturbance of the mitochondrial membrane potential. Thus, we suggest that the interaction between ASYN and mitochondria plays an important role in the toxicity of trans-synaptically transported ASYN and in the progression of PD pathology. These results question the prion-disease hypothesis and propose that endocytosed ASYN impairs the host′s mitochondrial function thereby also contributing to PD-pathology progression.
Chapter
Parkinson disease (PD) is characterized by dopaminergic neuron loss of the substantia nigra compacta (SNc) and motor alterations. Here, we used the experimental model of inhalation of the mixture of manganese chloride (MnCl2) and manganese acetate Mn (OAc)3 for inducing PD. This model causes bilateral and progressive degeneration of the SNc dopaminergic neurons. Melatonin has antioxidant properties and it has been suggested that it contributes to the protective effect in neurodegenerative diseases. Therefore, we aimed to determine whether melatonin pretreatment protects against the Mn-induced alterations. Before Mn inhalation, three groups were trained for motor performance (1. control group, 2. Mn mixture exposed without pretreatment, and 3. melatonin-pretreated/Mn-exposed groups) for motor tests. The motor coordination was evaluated through the single-pellet reaching task and the beam-walking test. After five months, all the animals were sacrificed. Dendritic spines were counted in the striatum medium-sized spiny neurons and the number of TH-immunoreactive neurons in the SNc. Our findings show that the melatonin-pretreated animals had better motor coordination and less dendritic spines and TH immunoreactive neuron loss than the Mn-inhalation-only group. Therefore, melatonin pretreatment has a neuroprotective effect and could be considered an alternative treatment before the more severe PD symptoms appear.
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Parkinson's disease (PD) is a progressive neurodegenerative disease with no satisfactory therapy options. Similar to other neurodegenerative conditions, such as Alzheimer's and Huntington's diseases, oxidative stress plays a key factor in the neurodegeneration process. To counteract the uncontrolled increase of reactive oxygen species (ROS) and oxidative stress-dependent cell death, several preclinical and clinical tests exploit natural-derived organic antioxidants, such as polyphenols. Despite some promising results, free antioxidants show scarce brain accumulation and may exhaust their scavenging activity before reaching the brain. In this work, we developed an antioxidant therapeutic nanoplatform consisting of nano-sized functionalized liposomes loaded with selected polyphenol-rich vegetal extracts with high blood-brain barrier crossing capabilities. The antioxidant extracts were obtained from the grape seeds and skins as a byproduct of wine production (i.e., pomace), following a sustainable circular approach with reduced environmental impact. The antioxidant nanoplatform was successfully tested in a relevant in vitro model of PD, where it completely rescued the ROS levels, prevented the aggregation of α-synuclein fibrils, and restored cell viability, paving the way for preclinical translation of the approach.
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Motoric disturbances in Parkinson’s disease (PD) derive from the loss of dopaminergic neurons in the substantia nigra. Intestinal dysfunctions often appear long before manifestation of neuronal symptoms, suggesting a strong correlation between gut and brain in PD. Oxidative stress is a key player in neurodegeneration causing neuronal cell death. Using natural antioxidative flavonoids like Rutin, might provide intervening strategies to improve PD pathogenesis. To explore the potential effects of micro (mRutin) compared to nano Rutin (nRutin) upon the brain and the gut during PD, its neuroprotective effects were assessed using an in vitro PD model. Our results demonstrated that Rutin inhibited the neurotoxicity induced by A53T α -synuclein (Syn) administration by decreasing oxidized lipids and increasing cell viability in both, mesencephalic and enteric cells. For enteric cells, neurite outgrowth, number of synaptic vesicles, and tyrosine hydroxylase positive cells were significantly reduced when treated with Syn. This could be reversed by the addition of Rutin. nRutin revealed a more pronounced result in all experiments. In conclusion, our study shows that Rutin, especially the nanocrystals, are promising natural compounds to protect neurons from cell death and oxidative stress during PD. Early intake of Rutin may provide a realizable option to prevent or slow PD pathogenesis.
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Parkinson’s disease (PD) is a neurodegenerative disorder which mainly targets motor symptoms such as tremor, rigidity, bradykinesia and postural instability. The physiological changes occur due to dopamine depletion in basal ganglia region of the brain. PD aetiology is not yet elucidated clearly but genetic and environmental factors play a prominent role in disease occurrence. Despite of various environmental factors, pesticides exposure has been convicted as major candidate in PD pathogenesis. Among various pesticides 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely investigated in PD following with paraquat (PQ), maneb (MB), organochlorines (OC) and rotenone. Effect of these pesticides has been suggested to be involved in oxidative stress, alterations in dopamine transporters, mitochondrial dysfunction, α-synuclein (αSyn) fibrillation, and neuroinflammation in PD. The present review discusses the influence of pesticides in neurodegeneration and its related epidemiological studies conducted in PD. Furthermore, we have deliberated the common pesticides involved in PD and its associated genetic alterations and the probable mechanism of them behind PD pathogenesis. Hence, we conclude that pesticides play a prominent role in PD pathogenesis and advance research is needed to investigate the alterations in genetic and mechanistic aspects of PD.
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In recent years, the increase in the synthesis of biopesticides for alternative agricultural uses has necessitated the study of their impacts. Among these compounds, several of them are known to exert endocrine-disrupting effects causing deregulation of a variety of physiological functions affecting cell signaling pathways involved in neural cell differentiation leading to developmental neurotoxicity. In this current paper, we thus determined the impact of the biopesticide A6 on zebrafish larvae, which is structurally linked to estrogenic endocrine disruptors. The objective of this study was to define the toxicity of A6, the mechanisms responsible, and to evaluate its effects on the locomotor activity at nanomolar concentrations (0, 0.5, 5, and 50 nM). We show through its blue fluorescence properties that A6 accumulates in different parts of the body as intestine, adipose tissue, muscle, yolk sac and head. We display also that A6 disrupt the development and affects the function of the central nervous system, especially the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. We studied whether A6 disturbs the target genes expression and recorded that it downregulated genes embroiled in TH expression, suggesting that A6’s neurotoxic effect may be the result of its binding propinquity to the estrogen receptor.
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Background Parkinson’s disease (PD) exhibits the extra pyramidal symptoms caused due to the dopaminergic neuronal degeneration in the substantia nigra of the brain and depletion of aldehyde dehydrogenase (ALDH) enzyme. Objective This study was designed to enlighten the importance of Aldehyde dehydrogenase enzyme in protecting the dopamine levels in a living system. Camalexin, a potentially active compound has been evaluated for its dopamine enhancing and aldehyde dehydrogenase protecting role in pesticide induced Parkinson’s disease. Methods AutoDock 4.2 software was employed to perform the docking simulations between the ligand camalexin and standard drugs Alda-1, Ropirinole with three proteins 4WJR, 3INL, 5AER. Consequently, the compound was evaluated for its in vivo neuroprotective role in zebrafish model by attaining Institutional Animal Ethical Committee permission. The behavioral assessments and catecholamine analysis in zebrafish were performed. Results The Autodock result shows that the ligand camalexin has a lower binding energy (-3.84) that indicate higher affinity with the proteins when compared to the standard drug of proteins (-3.42). In zebrafish model, behavioral studies provided an evidence that camalexin helps in improvement of motor functions and cognition. The catecholamine assay has proved there is an enhancement in dopamine levels, as well as an improvement in aldehyde dehydrogenase enzyme also. Conclusion The novel compound, camalexin, hence offers a protective role in Parkinson’s disease model by its interaction with neurochemical proteins and also in alternative in vivo model.
Article
Parkinson's Disease (PD) is the second most common neurodegenerative disorder that has been the center of the vast majority of researches. The development of various environmental and transgenic animal models of PD has provided evidence for discovering new drug therapies. The management of PD has always been challenging due to the progressive neurodegeneration, numerous genetic and environmental risk factors, and a broad spectrum of Motor Symptoms (MS) and Non Motor Symptoms (NMS). Therapies such as levodopa etc., result in long term side-effects. In the last twenty years, more researches have been done on Ayurvedic herbal preparations showing their neuroprotective properties with minimal side-effects. Some of the most common herbal preparations are Bacopa monnieri, Mucuna Pruriens (MP), Withania Somnifera (WS) etc., which delay and slow down the neurodegeneration. The article focuses on the importance of ayurvedic therapies in management and treatment of PD.
Thesis
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Parkinson’s disease (PD) is the second most common neurodegenerative disease and it is characterized by degeneration of dopaminergic neurons in the substantia nigra of mid brain that lead to impairments of motor functions (Merve et al, 2017). The loss of dopaminergic neurons give rise to motor symptoms like bradykinesia, rest tremor, postural instability, and shuffling gait; non-motor symptoms like impaired olfaction, constipation, depression, increased daytime sleep, rapid eye movement sleep disorder, and behavioral deficits are also commonly observed (Saleem et al, 2012). Presently, the treatment strategies for PD include Deep Brain Stimulation and Levo-dopa therapy. However the medication is limited only to improve the progressing symptoms and that too with more of side effects (Zrinzo et al, 2012; Fahn et al, 2000) and there is no therapy available that will cure the disease. Developing a therapeutic strategy for neurodegenerative disease such as PD remains a challenge till date. While attempting to understand the PD progression researchers have developed several animal models including Drosophila. A suitable model for sporadic PD should show histopathologically characterizable progressive loss of dopamine neurons together with other neurons and significant reduction in dopamine level. Since PD is a late onset neurodegenerative disease, the symptoms depiction in the model organism should be in a stage of adulthood equivalent to the age where PD sets in. The model animal should also manifest disease in such a way that it would mimic the PD affected human motor symptoms. Numerous case studies have reported that the subjects having exposure to pesticides, herbicides showed symptoms similar to Parkinsonism. Laboratory exposure of model organisms to environmental toxins like PQ is therefore productively employed to study the disease progressions. Studies on post-mortem brains from PD patients have implicated the vi role of oxidative damage in the pathogenesis of PD (Yuan et al, 2016; Zeevalk et al, 2008; Bosco et al, 2006). Accumulation of free radicals and subsequent neurodegeneration in specific brain regions have been proposed as the underlying factors in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (Halliwell, 2006) suggesting that oxidative modifications of enzymes and structural proteins play a significant role in their pathogenesis. Several researchers employ natural compounds with neuroprotective properties; try to explore ways for their therapeutic application. Curcumin, a natural active compound present in Curcuma Longa L (Turmeric) has been shown to possess potent neuroprotective properties. It is largely used in food as spices, coloring agent, and traditional medicines in India, China, Southeast Asia (Aggarwal et al, 2007) and properties of curcumin performing neuroprotective effect, anti-oxidant, anti-inflammatory and anti-cancer are well known. It crosses the blood-brain barrier and exerts protective action on neurons in central neurological disease (Lee et al, 2013). Through Drosophila model, curcumin have been shown to extend life span, sequester oxidative stress mediated free radicals, enhance locomotor ability and show chemo preventive property, improves characteristic symptoms associated with PD (Nguyen et al, 2018; Liu et al, 2013; Lee et al, 2010) suggesting its potential use in treatment applicability in higher organisms. However, all the available investigations were performed in young model organisms. It is reported that there exists significant change of about 23% in genome-wide transcript profiles with age in Drosophila (Pletcher et al, 2002) and genotropic drugs would be effective only during those life cycle stages wherein target molecules are available (Soh et al, 2013) suggesting that targets of genotropic compounds under study may well not be present in all life stages. However, no reports are available regarding the efficacy of vii curcumin in PD models during later phases of adult life. Therefore, it is necessary to understand the neuprotective efficacy of compounds at the adult phases like the transition phase in Drosophila, where the disease such as idiopathic PD sets in. Therefore, understanding the mechanistic insights of the disease and applying this knowledge, one can attempt to find the remedial measures that can be further validated in human.
Article
Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO)-positron emission tomography (PET) is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo, however it is yet to be fully explored in PD. Herein we investigate the utility of TSPO-PET, in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1) - a novel biomarker of proinflammatory myeloid cells - for detecting innate immune responses in the 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1-knockout mice were stereotaxically injected with 6-OHDA in the left striatum; control mice were saline-injected. At day 7 or 14 post-surgery, mice were administered 18F-GE-180, 64Cu-TREM1-mAb or 64Cu-Isotype control-mAb and imaged by PET/CT. Ex vivo autoradiography (ARG) was performed to obtain high resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death and quantitative PCR and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-OHDA-injected mice compared to those injected with saline. ARG afforded higher resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-OHDA- compared to saline-injected mice at both 7- and 14-days post-toxin. Interestingly, 18F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-OHDA mice, whereas 64Cu-TREM1-mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO- and TREM1-PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.
Chapter
One of the major scientific questions in Parkinson’s disease (PD) research is what makes the dopaminergic neurons in the substantia nigra pars compacta vulnerable. Since the early 90s, oxidative stress has been suggested to promote the loss of dopaminergic cells. Oxidative stress is defined as an increase in the steady-state levels of reactive oxygen species. Cells have evolved antioxidant systems and a wide range of mechanisms for the removal or repair of oxidative damage, but disease follows when these processes are surpassed by oxidative damage. The three major risk factors linked to PD (aging, environmental exposures and genetic alterations) have been reported to promote oxidative damage. As such, post-mortem analysis of PD brains has demonstrated an increased accumulation of oxidized proteins, nucleic acids and lipids. In this chapter, we provide an overview to redox homeostasis and the pathogenic mechanisms involved in the alterations in redox homeostasis that occurs in PD. We will discuss the intrinsic properties of dopaminergic neurons that make them vulnerable to oxidative damage, and the mechanisms by which alterations in the cellular redox homeostasis contribute to neurodegeneration. We will also overview how environmental toxicants disrupt redox homeostasis in neuronal cells and glial populations.KeywordsParkinson’s diseaseRedox homeostasisOxidative stressReactive oxygen speciesAntioxidantsα-synuclein
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Parkinson's disease (PD) is a multifactorial disorder involving a complex interplay between a variety of genetic and environmental factors. In this scenario, mitochondrial impairment and oxidative stress are widely accepted as crucial neuropathogenic mechanisms, as also evidenced by the identification of PD-associated genes that are directly involved in mitochondrial function. The concept of mitochondrial dysfunction is closely linked to that of synaptic dysfunction. Indeed, compelling evidence supports the role of mitochondria in synaptic transmission and plasticity, although many aspects have not yet been fully elucidated. Here, we will provide a brief overview of the most relevant evidence obtained in different neurotoxin-based and genetic rodent models of PD, focusing on mitochondrial impairment and synaptopathy, an early central event preceding overt nigrostriatal neurodegeneration. The identification of early deficits occurring in PD pathogenesis is crucial in view of the development of potential disease-modifying therapeutic strategies.
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Background In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an “off” period (also referred to as “off medication”), when the medication is not working and the motor symptoms of parkinsonism are present, and an “on” period, when the medication is causing improved mobility (also referred to as “on medication”), often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. Methods We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clinical evaluations included the Unified Parkinson's Disease Rating Scale, a dyskinesia scale, and timed tests conducted before and after surgery, when patients were off and on medications. Results After one year of electrical stimulation of the subthalamic nucleus, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III, respectively) off medication improved by 60 percent (P<0.001). The subscores improved for limb akinesia, rigidity, tremor, and gait. In the testing done on medication, the scores on part III improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was reduced by half. The cognitive-performance scores remained unchanged, but one patient had paralysis and aphasia after an intracerebral hematoma during the implantation procedure. Conclusions Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The severity of symptoms off medication decreases, and the dose of levodopa can be reduced, with a consequent reduction in dyskinesias.
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Lentiviral delivery of glial cell line–derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.
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Paraquat (PQ) is a well described pneumotoxicant that produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide (O2⨪). NO synthase (NOS) has been shown to participate in PQ-induced lung injury. Current theory holds that NO reacts with O2⨪ generated by PQ to produce the toxin peroxynitrite. We asked whether NOS might alternatively function as a PQ diaphorase and reexamined the question of whether NO/O2⨪ reactions were toxic or protective. Here, we show that: (i) neuronal NOS has PQ diaphorase activity that inversely correlates with NO formation; (ii) PQ-induced endothelial cell toxicity is attenuated by inhibitors of NOS that prevent NADPH oxidation, but is not attenuated by those that do not; (iii) PQ inhibits endothelium-derived, but not NO-induced, relaxations of aortic rings; and (iv) PQ-induced cytotoxicity is potentiated in cytokine-activated macrophages in a manner that correlates with its ability to block NO formation. These data indicate that NOS is a PQ diaphorase and that toxicity of such redox-active compounds involves a loss of NO-related activity.
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The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.
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Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.
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In the previous paper (Gerfen et al., 1987) mesostriatal dopaminergic neurons were shown to be subdivided into dorsal and ventral tiers that project to the striatal matrix and patch compartments, respectively. The present study provides experimental evidence that these patch-matrix mesostriatal dopaminergic systems are biochemically and developmentally distinct. A 28 kDa calcium-binding protein (CaBP, or calbindin-D28 kDa) is expressed in dorsal tier mesostriatal dopaminergic neurons. The distribution of such neurons, located in the ventral tegmental area, dorsal tier of the substantia nigra pars compacta, and retrorubral area, matches that of dopaminergic neurons that project to the striatal matrix. Dopaminergic neurons that do not express CaBP--those in the ventral tier of the pars compacta and in the pars reticulata--are distributed in a pattern that matches the origin of the dopaminergic projection to the striatal patches. During development, dopaminergic afferents to the striatal patch compartment are in place prior to the development of those to the matrix. Injections of the neurotoxin 6-hydroxydopamine (6-OHDA) into the striatum of newborn rats result in a selective and long-lasting depletion of dopaminergic afferents in the striatal patches. The later-developing matrix projection is relatively spared by such lesions. The distribution of surviving dopaminergic neurons, labeled with tyrosine hydroxylase (TH) immunoreactivity, matches the pattern of dorsal tier neurons previously shown to provide inputs to the matrix. Surviving neurons also express CaBP immunoreactivity and have dendrites that spread mediolaterally, in the plane of the pars compacta. On the other hand, those neurons that project to the patches are selectively lesioned by the neonatal 6-OHDA striatal injections, do not express CaBP, and have dendrites that are directed ventrally into the pars reticulata.
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