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

Sherer, Todd; Betarbet, Ranjita; Kim, Jin Ho; Greenamyre, J. Timothy

doi:10.1016/s0304-3940(03)00172-1

Cited by 282 publications

(208 citation statements)

References 14 publications

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“…Chronic administration of rotenone reproduced key features of PD in rodents, and microglial activation might be the predominant mechanism for rotenone-induced dopaminergic neuronal degeneration (Alam and Schmidt, 2002;Bonetta, 2002;Gao et al, 2002Gao et al, , 2003aPerier et al, 2003;Sherer et al, 2003;Hirsch et al, 2005). Therefore, inhibition of microglial activation and subsequent neuroinflammation may offer prospective clinical therapeutic benefit for PD and other neuroinflammation-related neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 97%

“…It is notable that microglial activation and subsequent inflammatory process induced by rotenone have been suggested to be the predominant mechanisms for degeneration of dopaminergic neurons in vivo and in vitro (Gao et al, 2002(Gao et al, , 2003aPerier et al, 2003;Sherer et al, 2003). Therefore, in the present study, we tried to explore whether the K ATP channel opener IPT could inhibit microglia-mediated neuroinflammation induced by rotenone and thus prevent dopaminergic neurodegeneration.…”

Section: Introductionmentioning

confidence: 98%

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Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

Zhou

Sun

et al. 2007

Neuropsychopharmacol

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Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K ATP ) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-a (TNF-a) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-a and prostaglandin E2 (PGE 2 ). These inhibitory effects of IPT could be reversed by selective mitochondrial K ATP (mitoK ATP ) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-a and PGE 2 . These data strongly suggest that the K ATP opener IPT may be a novel and promising neuroprotective drug via inhibiting microgliamediated neuroinflammation.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

Zhou

Sun

et al. 2007

Neuropsychopharmacol

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“…This finding was suggested to reflect an ongoing neurodegenerative process that persisted years after the initial toxic injury and could have been perpetuated, at least in part, by chronic neuroinflammation (Langston et al, 1999). Microglia have also been implicated in the production of reactive oxygen species (ROS) and the selective degeneration of nigrostriatal dopaminergic neurons caused by MPTP and other neurotoxicants in animal models and in vitro experimental paradigms (Gao et al, 2003a and b;Sherer et al, 2003;Wu et al, 2003;Ling et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration

Purisai

McCormack

Cumine

et al. 2007

Neurobiology of Disease

231

215

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Dopaminergic cells in the substantia nigra are highly vulnerable to the neurodegenerative process of Parkinson's disease. Therefore, mechanisms that enhance their susceptibility to injury bear important implications for disease pathogenesis. Repeated injections with the herbicide paraquat cause oxidative stress and a selective loss of dopaminergic neurons in mice. In this model, the first paraquat exposure, though not sufficient to induce any neurodegeneration, predisposes neurons to damage by subsequent insults. The purpose of this study was to elucidate the mechanisms underlying this "priming" event. We found that a single paraquat exposure was followed by an increase in the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including induction of NADPH-oxidase. If this microglial response was inhibited by the anti-inflammatory drug minocycline, subsequent exposures to the herbicide failed to cause oxidative stress and neurodegeneration. On the other hand, if microglial activation was induced by pretreatment with lipopolysaccharide, a single paraquat exposure became capable of triggering a loss of dopaminergic neurons. Finally, mutant mice lacking functional NADPH-oxidase were spared from neurodegeneration caused by repeated paraquat exposures. Data indicate that microglial activation and consequent induction of NADPH-oxidase may act as risk factors for Parkinson's disease by increasing the vulnerability of dopaminergic cells to toxic injury.

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“…Activated microglia have been reported in postmortem brain tissues from PD patients [90] . In addition, microglial activation has been found in some PD models in vivo, suggesting neuroinflammation as a common feature of both PD patients and laboratory models [91,[133][134][135] . Moreover, enhanced iNOS expression has been detected in the microglia of MPTP model animals, and mutant mice that lack iNOS exhibit a reduced susceptibility to this agent [92] .…”

Section: C-delta (Pkc-d) This In Turn Phosphorylates P53 Leadingmentioning

confidence: 99%

Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories

Doherty

2011

Neurosci. Bull.

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Abstract:The cellular messenger nitric oxide (NO) has been linked to neurodegenerative disorders due to the increased expression of the enzymes that catalyze its synthesis in postmortem tissues derived from sufferers of these diseases. Nitrated proteins have also been detected in these samples, revealing that NO is biologically active in regions damaged during neurodegeneration. Modulation of NO levels has been reported not only in the neurons of the central nervous system, but also in the glial cells (microglia and astroglia) activated during the neuroinflammatory response. Neuroinflammation has been found in some neurodegenerative conditions, and inhibition of these neuroinflammatory signals has been shown to delay the progress of such disorders. Thus NO and the pathways triggering its release are emerging as an important research focus in the search for strategies to prevent, halt or cure neurodegenerative diseases.

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

Cited by 282 publications

References 14 publications

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration

Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories

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