Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymoquinone is the main active constituent of Nigella sativa seeds with antioxidant and antiinflammatory properties. In the present study, primary dopaminergic cultures from mouse mesencephala were used to investigate the neuroprotective effects of thymoquinone against MPP(+) and rotenone toxicities. MPP(+) (10 microm on day 10 in vitro (i.v.) for 48 h) significantly decreased the number of THir by 40% compared with untreated control cultures. Rotenone at both short (20 nm on day 10 i.v. for 48 h) and long-term (1 nm on day 6 i.v. for 6 consecutive days) toxicities reduced the number of THir neurons by 33% and 24%, respectively. Treatment of cultures with thymoquinone (0.01, 0.1, 1, 10 microm on day 8 i.v. for 4 days) rescued about 25% of THir neurons at concentrations of 0.1 microm and 1 microm against MPP(+)-induced cell death. Against rotenone, thymoquinone afforded significant protection in both short- and long-term models. In short-term rotenone toxicity, thymoquinone (from days 8-12 i.v.) saved about 65%, 74% and 79% of THir neurons at concentrations of 0.01, 0.1 and 1 microm, respectively, compared with cell loss induced by rotenone. In long-term rotenone toxicity, concomitant treatment of cultures with thymoquinone significantly rescued about 83-100% of THir neurons compared with rotenone-treated cultures. In conclusion, the current study presents for the first time the potential of thymoquinone to protect primary dopaminergic neurons against MPP(+) and rotenone relevant to Parkinson's disease.
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PMID:Thymoquinone protects dopaminergic neurons against MPP+ and rotenone. 1908 49

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). The important biochemical features of PD, being profound deficit in dopamine (DA) content, reduced glutathione (GSH), and enhanced lipid peroxidation (LPO) in dopaminergic (DA-ergic) neurons resulting in oxidative stress, mitochondrial dysfunction and apoptosis. Rotenone-induced neurotoxicity is a well acknowledged preclinical model for studying PD in rodents as it produces selective DA-ergic neuronal degeneration. In our previous study, we have shown that chronic administration of rotenone to rats is able to produce motor dysfunction, which increases progressively with rotenone treatment and centrophenoxine (CPH) co-treatment is able to attenuate these motor defects. The present study was carried out to evaluate the antioxidant potential of CPH against rotenone-induced oxidative stress. Chronic administration of rotenone to SD rats resulted in marked oxidative damage in the midbrain region compared to other regions of the brain and CPH co-treatment successfully attenuated most of these changes. CPH significantly attenuated rotenone-induced depletion in DA, GSH and increase in LPO levels. In addition, the drug prevented the increase in nitric oxide (NO) and citrulline levels and also enhanced the activity of catalase and superoxide dismutase (SOD). Histological analysis carried out using hematoxylin and eosin staining has indicated severe damage to mid brain in comparison to cortex and cerebellum and this damage is attenuated by CPH co-treatment. Our results strongly indicate the possible therapeutic potential of centrophenoxine as an antioxidant in Parkinson's disease and other movement disorders where oxidative stress is a key player in the disease process.
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PMID:Effect of centrophenoxine against rotenone-induced oxidative stress in an animal model of Parkinson's disease. 1937 62

The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
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PMID:A highly reproducible rotenone model of Parkinson's disease. 1938 59

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility in PD include early satiety and weight loss from delayed gastric emptying and constipation from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the parkinsonian neurotoxin and mitochondrial complex I inhibitor rotenone causes delayed gastric emptying and enteric neuronal dysfunction when administered chronically to rats in the absence of major motor dysfunction or CNS pathology. When examined 22-28 days after initiation of rotenone infusion by osmotic minipump (3 mg/kg/day), 45% of rotenone-treated rats had a profound delay in gastric emptying. Electrophysiological recording of neurally-mediated muscle contraction in isolated colon from rotenone-treated animals confirmed an enteric inhibitory defect associated with rotenone treatment. Rotenone also induced a transient decrease in stool frequency that was associated with weight loss and decreased food and water intake. Pathologically, no alterations in enteric neuron numbers or morphology were apparent in rotenone-treated animals. These results suggest that enteric inhibitory neurons may be particularly vulnerable to the effects of mitochondrial inhibition by parkinsonian neurotoxins and provide evidence that parkinsonian gastrointestinal abnormalities can be modeled in rodents.
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PMID:Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease. 1940 96

Rotenone is a pesticide that has been successfully used to produce a rodent model of Parkinson's disease. We reported previously that rotenone potently augmented N-methyl-D-aspartate (NMDA)-evoked currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we investigated the effect of rotenone on the current-voltage relationship of NMDA-induced currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in slices of rat brain. In a physiologic concentration of extracellular Mg(2+) (1.2mM), a 30min perfusion with rotenone (100nM) produced a marked increase in current evoked by bath application of NMDA (30microM), especially when measured at relatively hyperpolarized currents. In the presence of rotenone, NMDA currents lost the characteristic region of negative-slope conductance that is normally produced by voltage-dependent block by Mg(2+). The voltage-dependent effect of rotenone on NMDA currents was mimicked by a low extracellular concentration of Mg(2+) (0.2mM) and was antagonized by a high level of Mg(2+) (6.0mM). Moreover, we report that the tyrosine kinase inhibitor genistein blocked the ability of rotenone to augment NMDA receptor currents. These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent process that attenuates voltage-dependent Mg(2+) block of NMDA-gated channels. These results support the hypothesis that an excitotoxic mechanism might participate in rotenone-induced toxicity of midbrain dopamine neurons.
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PMID:Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine neurons. 1942 6

Rotenone is a pesticide that has been shown to induce the pathological symptoms of Parkinson's disease (PD) in animal models. In this study, we investigated the protective effects of tranexamic acid (TA) on rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells. TA blocked the rotenone-induced phosphorylation of JNK and P38, the downregulation of BCL2 and the upregulation of BAX. Furthermore, TA not only decreased the rotenone-induced cleavage of caspase 9, PARP, and caspase 3, but also increased caspase 3 enzymatic activity. Our findings indicate that TA is able to protect neuronal cells against apoptosis and suggest that TA might potentially serve as an agent for prevention or therapy of PD.
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PMID:Tranexamic acid protects against rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1953 6

Since mild thermal stress seems to exert neuroprotection via induction of heat-shock protein 70 kDa (hsp70), we tested whether hsp70 would preserve striatal bioelectrical activity under conditions of mitochondrial impairment. Corticostriatal slices from rats that had undergone mild thermal stress were exposed to either rotenone or 3-nitropropionic acid (3-NP), that selectively inhibits mitochondrial complex I and complex II, respectively. Rotenone is utilized to obtain an experimental model of Parkinson's disease while 3-NP replicates Huntington's disease phenotype in experimental animals. The cerebral hsp70 increase did not alter field potential amplitude of the slices but partially protected them against rotenone-induced neurotoxicity. Similarly, induction of hsp70 had also a partial neuroprotective effect on the neurotoxicity caused by 3-NP on striatal field potential. Since rotenone and 3-NP treatments mimic the mitochondrial impairment and oxidative stress that contribute to development of Parkinson's disease and Huntington's disease, these data suggest that induction of hsp70 might represent a possible neuroprotective mechanism against the pathophysiological chain of events implicated in these neurodegenerative disorders.
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PMID:Induction of heat shock protein 70 reduces the alteration of striatal electrical activity caused by mitochondrial impairment. 1958 Aug 50

Gastrointestinal disorders, particularly severe constipation and delayed gastric emptying, are core symptoms of Parkinson's disease that affect most patients. However, the neuropathological substrate and physiological basis for this dysfunction are poorly defined. To begin to explore these phenomena in laboratory models of PD, rats were treated with either vehicle or rotenone (2.0 mg/kg, i.p.; 5 days/week) for 6-weeks. Myenteric plexus alpha-synuclein aggregate pathology and neuron loss were assessed 3-days and 6-months after the last rotenone injection. Gastrointestinal motility was assessed at 3-days, 1-month and 6-months after the last rotenone injection. Rotenone treatment caused an acute reduction in alpha-synuclein-immunoreactivity, but this was followed 6 months later by a robust increase in aggregate pathology and cytoplasmic inclusions that were similar in appearance to enteric Lewy-bodies in idiopathic PD. Rotenone-treated rats also had a moderate but permanent loss of small intestine myenteric neurons and an associated modest slowing of gastrointestinal motility 6-months after treatment. Our results suggest that a circumscribed exposure to an environmental toxicant can cause the delayed appearance of parkinsonian alpha-synuclein pathology in the enteric nervous system and an associated functional deficit in gastrointestinal motility. The rotenone model may therefore, provide a means to investigate pathogenic mechanisms and to test new therapeutic interventions into gastrointestinal dysfunction in PD.
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PMID:Chronic rotenone exposure reproduces Parkinson's disease gastrointestinal neuropathology. 1959 68

Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic alpha9/alpha10 and 5-HT3 receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone+saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.
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PMID:Effects of glutamate and alpha2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats. 1961 71

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant familial Parkinson's disease. We generated lines of Caenorhabditis elegans expressing neuronally directed human LRRK2. Expressing human LRRK2 increased nematode survival in response to rotenone or paraquat, which are agents that cause mitochondrial dysfunction. Protection by G2019S, R1441C, or kinase-dead LRRK2 was less than protection by wild-type LRRK2. Knockdown of lrk-1, the endogenous ortholog of LRRK2 in C. elegans, reduced survival associated with mitochondrial dysfunction. C. elegans expressing LRRK2 showed rapid loss of dopaminergic markers (DAT::GFP fluorescence and dopamine levels) beginning in early adulthood. Loss of dopaminergic markers was greater for the G2019S LRRK2 line than for the wild-type line. Rotenone treatment induced a larger loss of dopamine markers in C. elegans expressing G2019S LRRK2 than in C. elegans expressing wild-type LRRK2; however, loss of dopaminergic markers in the G2019S LRRK2 nematode lines was not statistically different from that in the control line. These data suggest that LRRK2 plays an important role in modulating the response to mitochondrial inhibition and raises the possibility that mutations in LRRK2 selectively enhance the vulnerability of dopaminergic neurons to a stressor associated with Parkinson's disease.
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PMID:LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. 1962 11


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