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PubMed2005

A delivery strategy for rotenone microspheres in an animal model of Parkinson's disease.

In order to study the pathogenesis of Parkinson's disease (PD), and explore therapeutic drug or approaches, the accurate animal model of PD with inexpensive, biocompatible and convenient administration was necessary. The aim of the present work was to investigate a delivery strategy for rotenone microspheres in an animal model of PD. The rotenone microspheres were prepared by solvent evaporation technique. The rotenone microspheres showed high entrapment efficiency (97.4+/-2.2%) with particle size about 100 microm. In vitro release of rotenone microspheres demonstrated different profiles from medium with different pH or concentration of isopropyl alcohol. The most consistent medium with in vivo rotenone levels in rat plasma was PBS (pH 5.8) with 20% isopropyl alcohol, and the cumulated release amount of rotenone over 30 days was 95.4% in it. The rotenone microspheres (9 mg/kg) produced typical PD symptoms in rats, for example, the cataleptic behavior test demonstrated a obviously prolonged descent latency compared with control animals after administration, and the tyrosine hydroxylase (TH) immunohistochemistry tests showed typical histological evidence of selective degeneration of the nigrostriatal dopaminergic system (striatum and substantia nigra) in rotenone microspheres-treated rats. In addition, this delivery system for rotenone model showed many noticeable advantages such as inexpensive, biocompatible and expedient administration by direct subcutaneous injection. This information suggested that rotenone microspheres as a delivery strategy for setting up an ideal animal model of PD was feasible.

Animals↗
PubMed2003

The pesticide rotenone induces caspase-3-mediated apoptosis in ventral mesencephalic dopaminergic neurons.

In vivo, the pesticide rotenone induces degeneration of dopamine neurons and parkinsonian-like pathology in adult rats. In the current study, we utilized primary ventral mesencephalic (VM) cultures from E15 rats as an in vitro model to examine the mechanism underlying rotenone-induced death of dopamine neurons. After 11 h of exposure to 30 nm rotenone, the number of dopamine neurons identified by tyrosine hydroxylase (TH) immunostaining declined rapidly with only 23% of the neurons surviving. By contrast, 73% of total cells survived rotenone treatment, indicating that TH+ neurons are more sensitive to rotenone. Examination of the role of apoptosis in TH+ neuron death, revealed that 10 and 30 nm rotenone significantly increased the number of apoptotic TH+ neurons from 7% under control conditions to 38 and 55%, respectively. The increase in apoptotic TH+ neurons correlated with an increase in immunoreactivity for active caspase-3 in TH+ neurons. The caspase-3 inhibitor, DEVD, rescued a significant number of TH+ neurons from rotenone-induced death. Furthermore, this protective effect lasted for at least 32 h post-rotenone and DEVD exposure, indicating lasting neuroprotection achieved with an intervention prior to the death commitment point. Our results show for the first time in primary dopamine neurons that, at low nanomolar concentrations, rotenone induces caspase-3-mediated apoptosis. Understanding the mechanism of rotenone-induced apoptosis in dopamine neurons may contribute to the development of new neuroprotective strategies against Parkinson's disease.

Animals↗
PubMedDate not supplied

The effect of endogenous dopamine in rotenone-induced toxicity in PC12 cells.

Deficiencies in Complex I have been observed in Parkinson's disease (PD) patients. Systemic exposure to rotenone, a Complex I inhibitor, has been shown to lead to selective dopaminergic cell death in vivo and toxicity in many in vitro models, including dopaminergic cell cultures. However, it remains unclear why rotenone seems to affect dopaminergic cells more adversely. Therefore, the role of dopamine (DA) in rotenone-induced PC12 cell toxicity was examined. Rotenone (1.0 muM) caused significant toxicity in differentiated PC12 cells, which was accompanied by decreases in ATP levels, changes in catechol levels, and increased DA oxidation. To determine whether endogenous DA makes PC12 cells more susceptible to rotenone, cells were treated with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) to reduce DA levels prior to rotenone exposure, and then cell viability was measured. No changes in rotenone-induced toxicity were observed with or without AMPT treatment. However, a potentiation of toxicity was observed following coexposure of PC12 cells to rotenone and methamphetamine. To determine whether this effect was due to DA, PC12 cells were depleted of DA prior to methamphetamine and rotenone cotreatment, resulting in a large attenuation in toxicity. These findings suggest that DA plays a role in rotenone-induced toxicity and possibly the vulnerability of DA neurons in PD.

Adenosine Triphosphate↗
PubMed2006

Basic fibroblast growth factor protects against rotenone-induced dopaminergic cell death through activation of extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase pathways.

Administration of rotenone to rats reproduces many features of Parkinson's disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson's disease. However, the cell death mechanisms induced by rotenone and potential neuroprotective mechanisms against rotenone are not well defined. Here we report that rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor (bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein (BAD) by small interfering RNA rendered SH-SY5Y cells resistant to rotenone, implicating BAD in rotenone-induced cell death. Interestingly, bFGF induced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the rotenone model of Parkinson's disease.

Animals↗
PubMed2003

Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons.

Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase--null (gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced rotenone neurotoxicity. In neuron--glia cultures, dopaminergic neurons from gp91phox-/- mice were more resistant to rotenone neurotoxicity than those from gp91phox+/+ mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91phox+/+ mice but not from gp91phox-/- mice to neuron-enriched cultures markedly increased rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91phox+/+ mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.

Acetophenones↗
PubMed2007

Chronic rotenone treatment induces behavioral effects but no pathological signs of parkinsonism in mice.

It has been hypothesized that exposures to neurotoxic pesticides together with aging and genetic factors increase the risk for developing Parkinson's disease (PD) which is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Chronic treatment with the pesticide rotenone has been reported to induce parkinsonism in rats. Although transgenic mice (but not transgenic rats) are available to investigate the importance of environmental factors in genetically predisposed animals, the effects of chronic rotenone exposure have so far not been examined in intact mice. Therefore, we investigated the effects of chronic exposure to rotenone (2.5 or 4.0-5.0 mg/kg s.c. for 30-45 days) in mice aged 2.5, 5, or 12 months. During the treatment period, the effects on vitality and motor behavior were investigated. Furthermore, the toxicity of rotenone on dopaminergic nigrostriatal neurons and peripheral tissues was examined. In comparison with control mice, rotenone-treated mice had a decreased spontaneous motor activity, but the density of nigral dopaminergic neurons failed to show any significant changes, except for a tendency to decrease in old mice treated with 4 mg/kg. At the tested doses, rotenone caused a moderate hepatic fatty degeneration. The data indicate that rotenone is not able to cause the neuropathological characteristics of PD in mice under these testing paradigms, which were similar to those of the rotenone rat model. Further studies will have to clarify whether genetic mouse models of PD might be more sensitive to the neurotoxic effects of rotenone.

Animals↗
PubMed2005

Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine.

Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Recently, it has been shown that fraxetin (coumarin) and myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced by rotenone, increase the total glutathione levels in vitro, and inhibit lipid peroxidation. Thus, these considerations prompted us to investigate the way in which fraxetin and myricetin affect the endogenous antioxidant defense system, such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a comparative agent. Also, the expression and protein levels of HSP70 by Northern and Western blot analysis were assayed in SH-SY5Y cells. After incubation for 16 h, rotenone significantly increased the expression and activity of MnSOD, GPx, and catalase. When cells were preincubated with fraxetin, there was a decrease in the protein levels and activity of both MnSOD and catalase, in comparison with the rotenone treatment. The myricetin effect was less pronounced. Activity and expression of GPx were increased by rotenone and pre-treatment with fraxetin did not modify significantly these levels. The significant enhancement in HSP70 expression at mRNA and protein levels induced by fraxetin was observed by pre-treatment of cells 0.5 h before rotenone insult. These data suggest that major features of rotenone-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that fraxetin partially protects against rotenone toxicity affecting the main protection system of the cells against oxidative injury.

Acetylcysteine↗
PubMed2004

Rotenone, deguelin, their metabolites, and the rat model of Parkinson's disease.

Rotenone and deguelin are the major active ingredients and principal components of cuberesin from Lonchocarpus utilis used as a botanical insecticide and piscicide. They are also potent complex I (NADH:ubiquinone oxidoreductase) inhibitors. Rotenone was known earlier, and deguelin is shown here to induce a Parkinson's disease (PD)-like syndrome after subcutaneous treatment of rats by osmotic minipump. Rotenone at 3 mg/kg/day or deguelin at 6 but not 3 mg/kg/day induces degeneration of the nigrostriatal dopaminergic pathway, as shown by reduced tyrosine hydroxylase immunoreactivity with treatments for 5 or 6 days. The neuropathological lesions are associated with a brain level of parent rotenoid of 0.4-1.3 ppm but not with the much smaller brain level of 12abeta-hydroxyrotenoids or other metabolites analyzed by HPLC and LC/MS. We previously established that the hydroxylated metabolites and derivatives of rotenone and deguelin are all less active (i.e., detoxified) as complex I inhibitors relative to the parent rotenoids. The PD-like syndrome induced in rats by rotenone and deguelin is therefore due to the parent compounds rather than metabolites. Deguelin is about half as active as rotenone in inducing the PD-like syndrome in rats and in acute ip LD50 in mice. Rotenone and deguelin are metabolized by human recombinant 3A4 and 2C19 but not five other P450 enzymes. 2C19 is more selective than 3A4 in forming the 12abeta-hydroxyrotenoids. Identified sites of metabolic attack individually or in combination are as follows: 12abeta hydroxylation and 2-O-demethylation of both compounds, oxidation of the rotenone isopropenyl substituent to mono and diol derivatives, and probable oxidation of the deguelin dimethylchromene double bond. These toxicological features must be considered in using rotenone, deguelin, and their analogues as pesticides, candidate radioimaging and cancer chemopreventive agents, and models of PD.

Animals↗
PubMed2002

Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.

The effects of dietary administration of capsaicin and rotenone on 4-nitroquinoline 1-oxide (4-NQO)-induced tongue tumorigenesis were investigated in male F344 rats. In pilot studies, gavage with capsaicin and rotenone elevated the phase II enzymes glutathione S-transferase (GST) and quinone reductase (QR), in the liver and tongue. Also, a 10 week period of feeding of 500 p.p.m. capsaicin or rotenone together with 4-NQO exposure inhibited the occurrence of tongue dysplasia. Subsequently, a long-term study was conducted to test the protective effects of both compounds on 4-NQO-induced tongue carcinogenesis. One group was treated with 4-NQO alone (20 p.p.m. in drinking water for 8 weeks) and four other groups received the carcinogen treatment plus diets containing 500 p.p.m. test compounds for 10 weeks (initiation phase) or for 28 weeks (post-initiation phase). At the termination of the study (38 weeks), feeding of rotenone during the initiation phase, but not during the post-initiation phase, was found to significantly reduce the incidence of tongue squamous cell carcinoma (53% vs. 16%, 70% reduction, P b=e 0.0250) and severe dysplasia (80% vs. 42%, 70% reduction, P = 0.028). Capsaicin feeding during either the initiation or promotion phase and rotenone feeding during the promotion phase also reduced the frequency of tongue carcinoma without statistical significance. The treatment with two compounds especially rotenone lowered cell proliferation activity in the tongue, elevated phase II enzymes' activities of the liver and tongue, and increased the apoptotic index of tongue carcinoma. Although our results suggest that rotenone feeding during the initiation stage prevented 4-NQO-induced tongue carcinoma, chronic intravenous exposure of rotenone reproduces several features of human Parkinson's disease in rats (Nat. Neurosci., 3, 1301-1306, 2000), suggesting that additional studies to confirm the safety of rotenone are warranted.

4-Nitroquinoline-1-oxide↗
PubMed1996

Structural factors of rotenone required for inhibition of various NADH-ubiquinone oxidoreductases.

We performed a structure-activity study of a series of synthetic rotenone analogues to elucidate the structural factors of rotenone required for inhibition and to probe the structural properties of the rotenone binding site of various NADH-ubiquinone oxidoreductases (NDH), including both proton-pumping (NDH-1) and non-proton-pumping (NDH-2) enzymes, from bovine heart mitochondria, potato tuber (Solanum tuberosum L.) mitochondria and Escherichia coli (GR 19N) plasma membranes. Using a benzyloxy group as a substitute for the E-ring moiety of natural rotenone, systematically selected structural modifications of the A-ring became feasible. The inhibitory potency of bovine NDH markedly varied depending upon structural modifications of the A-ring. The native chemical structure (2,3-dimethoxy substitution) appeared to be the most favorable for the activity. The spatial location of the hydrogen-bond acceptable methoxy oxygens may be important for tight fitting into the binding site. However, replacing one of the two methoxy groups by an ethoxy group almost completely retained the activity, indicating that the binding environment of the A-ring moiety is spacious enough to accommodate a substituent larger than the methoxy group. The manner of action of the derivative lacking the 12-C = O group in the C-ring differed from that of natural rotenone, indicating that this functional group is important for supporting the inhibitory action of natural rotenone itself. Regarding potato tube and E. coli NDH-1, the sensitivity of the two enzymes to the inhibition by rotenone analogues was much lower than that of the bovine enzyme. The 2,3-dimethoxy substitution was the most favorable for the activity with potato NDH-1, whereas this substitution pattern was not necessarily the best with E. coli NDH-1. A rule governing inhibitory potency depending upon structural modifications was ambiguous for the two enzymes because of a small variation in the inhibitory potencies. These findings indicated that the local binding environment of the A-ring moiety of rotenone in bovine NDH is specific and differs considerably from that in potato and E. coli NDH-1.

Animals↗
PubMed2004

Neuroprotective effect of fraxetin and myricetin against rotenone-induced apoptosis in neuroblastoma cells.

Rotenone-induced apoptosis is considered to contribute to the etiology of Parkinson's disease (PD). We try to prevent the apoptosis induced by rotenone toxicity with 50 microM myricetin, 100 microM fraxetin and 100 microM N-acetylcysteine (NAC) that protect against reactive oxygen species (ROS), on SH-SY5Y human neuroblastoma cell line. Morphological changes induced by rotenone and intracellular ROS were assessed in live SH-SY5Y dopaminergic cells by confocal microscopy using the fluorescent dyes, dihydroethidium and 2',7'-dichlorofluorescein diacetate (DCFH-DA). DNA fragmentation was assayed as index of apoptosis. We also investigated oxidative stress parameters such as the glutathione redox status and lipid peroxidation. The exposure of the SH-SY5Y cells to rotenone 5 microM for 16 h produced severe morphological changes, DNA fragmentation and significative increases in the levels of hydrogen peroxide and superoxide anion. These increases were reduced by a 30-min pretreatment with fraxetin 100 microM or NAC 100 microM. DNA laddering produced by rotenone treatment was also inhibited by fraxetin and NAC. Treatment with 5 microM rotenone induced loss of reduced glutathione (GSH) and increased cellular levels of oxidized glutathione (GSSG). Fraxetin and NAC treatments restored glutathione redox ratio diminished after rotenone challenge and decreased the levels of lipid peroxidation. These results suggest that the natural antioxidants, such as fraxetin, may prevent the apoptotic death of dopaminergic cells induced by rotenone and mediated by oxidative stress.

Acetylcysteine↗
PubMed2005

Angiotensin II protects cultured midbrain dopaminergic neurons against rotenone-induced cell death.

In this study, we demonstrate that angiotensin II (Ang II) protects dopamine (DA) neurons from rotenone toxicity in vitro. Primary ventral mesencephalic (VM) cultures from E15 rats were grown for 5 days and then cultured in the presence of the mitochondrial complex I inhibitor, rotenone. Acute exposure (20 h) to 20 nM rotenone reduced the number of tyrosine hydroxylase-positive (TH+) neurons by 50 +/- 6% when compared to untreated cultures. Pre-treatment of VM cultures with 100 nM Ang II decreased TH+ neuronal loss to 25 +/- 10% at the 20-nM rotenone concentration. Ang II in the presence of the angiotensin type 1 receptor (AT1R) antagonist, losartan, was even more effective in protecting DA neurons showing a loss of only 13 +/- 4% at 20 nM rotenone. Conversely, the AT2R antagonist, PD123319, abolished the protective effects of Ang II. Furthermore, both the NMDA receptor antagonist, MK801, and the antioxidant, alpha-tocopheryl succinate (vitamin E analogue), prevented rotenone-induced toxicity. Here, we show that acute exposure of VM cultures to the pesticide rotenone leads to dopaminergic neuronal cell death and that angiotensin acting through the AT2 receptor protects dopamine neurons from rotenone toxicity.

Angiotensin II↗
PubMed2004

Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone.

Mitochondrial toxins such as the complex 1 inhibitor rotenone are widely used as pesticides and may be present in military environments. Administration of rotenone can induce biochemical and histological alterations similar to those of Parkinson's disease in rats. However, only a subset of animals show these effects and it is unclear whether more subtle alterations are caused by chronic administration of rotenone in those animals that appear resistant to its toxic effects on dopaminergic nerve terminals. To address this question, vehicle or rotenone (2.0, 2.5, or 3.5 mg/kg/day) was administered intravenously or subcutaneously for 21 days to adult rats, and rotenone effects on survival, motor behavior, and striatal tyrosine hydroxylase immunoreactivity (TH-IR) were examined. Both intravenous and subcutaneous rotenone induced a dose-dependent decrease in survival rates. Surviving animals showed a decrease in spontaneous rearing. Locomotor activity and movement initiation time were also altered in some of the experimental groups. Confirming previous results, TH-IR in the striatum was markedly decreased in rats that fell ill early in the study and in a few of the surviving rats with high rotenone doses. However, none of the surviving rats receiving 2.0 mg/kg/day showed TH-IR loss reminiscent of Parkinson's disease, and loss of striatal TH-IR across doses was not correlated with motor behavior in individual rats. Thus, chronic administration of low doses of rotenone induces motor anomalies even in animals that do not develop histological signs of Parkinson's disease, indicating a pervasive neurological effect of moderate mitochondrial dysfunction in vivo.

Animals↗
PubMed1997

Interaction of the mitochondrial NADH-ubiquinone reductase with rotenone as related to the enzyme active/inactive transition.

The interaction of rotenone with active ('pulsed') and thermally de-activated ('resting') membrane-bound Complex I (Kotlyar, A.B. and Vinogradov, A.D. (1990) Biochim. Biophys. Acta 1019, 151-158) as revealed by inhibition of NADH-ubiquinone- and ubiquinol-NAD+ reductase activities was studied. Ki = 1 x 10(-9) M, k(on) = 5 x 10(7) M-1 min-1 and k(off) = 0.02 min-1 (inhibitory effect of rotenone on NADH oxidation) and Ki = 2 x 10(-8) M (inhibition of reverse electron transfer) were determined for pulsed enzyme. The equilibrium between de-activated and active enzyme is reached (K approximately 100) after the slow strongly temperature-dependent de-activation process has completed. Rotenone partially prevents and reverses the enzyme de-activation. About two order of magnitude difference in affinity of rotenone to the active and de-activated forms of the enzyme was demonstrated. The strong difference in rotenone sensitivity of the direct and reverse reactions can not be accounted for delta mu H(+)-dependence of rotenone binding. We propose that two rotenone-specific inhibitory sites exist in Complex I: one is involved in NADH oxidation by ubiquinone and the other is operating in ubiquinol-NAD+ reductase reaction. The affinities of rotenone for both sites are strongly altered upon the slow enzyme active/inactive transition.

Animals↗
PubMed2000

Increased striatal dopamine turnover following acute administration of rotenone to mice.

Because of the potential role of mitochondrial dysfunction in nigrostriatal degeneration in Parkinson's disease, the effects of rotenone (an inhibitor of mitochondrial NADH dehydrogenase and a naturally occurring toxicant) on the levels of striatal dopamine (DA) and DA metabolites were evaluated after acute and subchronic administration to mice. Systemic acute treatment with relatively high doses of rotenone did not affect DA concentration, but caused a significant increase in both DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). DOPAC and HVA changes were measured at 1 day and were reversed within 1 week, paralleling the time course of rotenone-induced increase in striatal lactate levels. Subchronic administration with a relatively mild dose of rotenone did not significantly alter the striatal levels of DA and DOPAC, while it slightly reduced HVA concentration. No neurochemical signs of dopaminergic damage were seen when mice were co-exposed to rotenone and diethyldithiocarbamate, a compound known to enhance nigrostriatal injury caused by the neurotoxicant 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). Also, rotenone did not cause additional injury to animals previously lesioned by MPTP. Taken together, data indicate that rotenone is not capable of causing overt dopaminergic toxicity under the testing paradigms used in this study. Rather, an increase in DA turnover, as indicated by a higher (DOPAC+HVA)/DA ratio, seems to be associated to rotenone-induced striatal energy impairment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine.

The purpose of this study was to investigate the potential neuroprotective effects of myricetin (flavonoid) and fraxetin (coumarin) on rotenone-induced apoptosis in SH-SY5Y cells, and the possible signal pathway involved in a neuronal cell model of Parkinson's disease. These two compounds were compared to N-acetylcysteine. The viability of cells was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and cytotoxicity was assayed by lactate dehydrogenase (LDH) released into the culture medium. Parameters related to apoptosis, such as caspase-3 activity, the cleavage of poly(ADP-ribose) polymerase and the levels of reactive oxygen species were also determined. Rotenone caused a time- and dose-dependent decrease in cell viability and the degree of LDH release was proportionally to the effects on cell viability. Cells were pretreated with fraxetin, myricetin and N-acetylcysteine at different concentrations for 30 min before exposure to rotenone. Cytotoxicity of rotenone (5 microM) for 16 h was significantly diminished as well as the release of LDH into the medium, by the effect of fraxetin, myricetin and N-acetylcysteine, with fraxetin (100 microM) and N-acetylcysteine (100 microM) being more effective than myricetin (50 microM). Rotenone-induced apoptosis in SH-SY5Y cells was detected by an increase in caspase-3 activity and in the cleavage of poly(ADP-ribose) polymerase. After exposing these cells to rotenone, a significant increase in reactive oxygen species preceded apoptotic events. Fraxetin (100 microM) and N-acetylcysteine (100 microM) not only reduced rotenone-induced reactive oxygen species formation, but also attenuated caspase-3 activity and poly(ADP-ribose) polymerase cleavage at 16 h against rotenone-induced apoptosis. The effect of fraxetin in both experiments was similar to that of N-acetylcysteine. These results demonstrated the protective action of fraxetin and suggest that it can reduce apoptosis, possibly by decreasing free radical generation in SH-SY5Y cells. Myricetin at 100 microM was without any preventive effect.

Acetylcysteine↗
PubMed2003

Selective microglial activation in the rat rotenone model of Parkinson's disease.

Chronic rotenone exposure reproduces features of Parkinson's disease (PD) (Nat. Neurosci. 3 (2000) 1301; Exp. Neurol. 179 (2003) 9). We investigated the role of glial activation in rotenone toxicity in vivo. Male Lewis rats received 2-3 mg/kg rotenone per day for up to 4 weeks. In 50% of surviving rotenone-treated animals, there was nigrostriatal dopaminergic degeneration, marked by reduced tyrosine hydroxylase immunoreactivity). Extensive microglial activation, determined by OX-42-ir, occurred in striatum and nigra of rotenone-treated animals, and was prominent before anatomical evidence of dopaminergic lesions. Microglia enlarged and developed short, stubby processes in rotenone-treated animals. Rotenone-induced microglial activation was less pronounced in cortex. Reactive astrocytosis was minimal and limited to a thin rim around the lesion. Marked microglial activation with minimal astrocytosis is another pathological feature of PD reproduced by rotenone treatment.

Animals↗
PubMed2004

Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone.

The aim of this paper was to investigate whether rotenone, a pesticide causing experimental parkinsonism, causes direct damage to dopaminergic structure when injected intracerebrally and whether this action may be prevented by peripheral administration of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), an endogenous compound with anti-dopaminergic activity. Male Wistar rats were injected unilaterally into the median forebrain bundle with 2 microg rotenone, and received 1MeTIQ, 50 mg/kg i.p. 1 h before and then daily for 21 d. To compare the effect of intracerebral and peripheral treatment, rotenone was also given once or for 7 d in a dose of 10 mg/kg s.c. Dopamine, serotonin and their metabolites were assessed by HPLC in the substantia nigra and striatum. While a single subcutaneous rotenone dose did not produce any change in striatal dopamine metabolism, the multiple treatments resulted in changes suggesting a shift in the metabolism towards oxidative desamination and reduction of O-methylation. In contrast to systemic injections, intracerebral-administered rotenone produced a decrease in dopamine and its metabolites content in the striatum (dopamine decrease by 70%) and substantia nigra (dopamine decrease by 35%), without affecting the serotonin system. As those changes were observed 21 d after the injection of rotenone, they suggest a durable neurotoxic effect. The treatment with 1MeTIQ strongly reduced the fall of striatal dopamine concentration. The data suggest that rotenone given peripherally affects metabolic processes in dopaminergic neurons, and this seems to result from its neurotoxic action, which may be observed after an intracerebral injection. 1MeTIQ is able to counteract the damaging action of rotenone and seems to be a potential neuroprotective agent.

Animals↗