Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease

Ghosh, Alip; Roy, Avik; Liu, Xiaojuan; Kordower, Jeffrey H.; Mufson, Elliott J.; Hartley, Dean M.; Ghosh, Sankar; Mosley, R. Lee; Gendelman, Howard E.; Pahan, Kalipada

doi:10.1073/pnas.0704908104

Cited by 401 publications

(453 citation statements)

References 33 publications

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“…Several studies support the hypothesis that activation of the nuclear factor kappa-B (NF-kB) plays an important role in PD pathogenesis. Ghosh et al 17 have shown that NF-kB activation is induced in the SNpc of patients with PD and MPTP-treated mice. On the other hand, the selective inhibition of NF-kB protected dopaminergic neurons from the MPTP toxicity 17 .…”

Section: Evidence Of Neuroinflammation In Parkinson's Diseasementioning

confidence: 99%

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

Bassani

Vital

Rauh

2015

Arq. Neuro-Psiquiatr.

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Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1.6% of people over 60 years old 1,2 . PD is also the most common cause of parkinsonism, corresponding to 74.7% of all cases in a Brazilian study 3 . The disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), loss of their ascending projections to the striatum (caudate and putamen), and consequent decrease of striatal dopamine (DA) content, which leads to severe locomotion difficulties and cardinal motor symptoms such as tremor at rest, rigidity, postural instability and slowness of body movements (bradykinesia) 4,5 . By the time a patient is diagnosed, approximately 60% of SNpc neurons are degenerated and 80% of striatal DA content is depleted 4,5 . In addition to neuronal damage, PD is characterized by the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites, mainly in the SNpc 6 . Currently, the pharmacological and non-pharmacological treatments approved for PD offer only symptomatic relief for patients. As these treatments are not able to stop or reverse the neurodegenerative process, PD remains incurable. The motor symptoms can be reduced by many drugs that increase the DA level in the central nervous system (CNS) or mimic its effects. The gold standard for the treatment of PD nowadays is Levodopa, a DA precursor. Other drugs commonly prescribed are DA receptor agonists, monoaminoxidase (MAO) AbStrACtParkinson's disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.Keywords: Parkinson's disease, neuroinflammation, anti-inflammatory. ResumoA doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. ...

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Section: Evidence Of Neuroinflammation In Parkinson's Diseasementioning

confidence: 99%

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

Bassani

Vital

Rauh

2015

Arq. Neuro-Psiquiatr.

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“…3,4 Although the mechanism of NF-kB activation in cerebral ischemia is still not completely understood, there is evidence that the upstream kinase IKK is involved. [5][6][7] NF-kB is well known for its anti-apoptotic action.…”

mentioning

confidence: 99%

“…6 In Parkinson's and Huntington's disease,a detrimental effect of IKK has been reported. 4,7 In parallel to the NF-kB pathway, cerebral ischemia activates the MAP kinases JNK and p38/MAPK 10 that signal to the transcription factor AP-1 and other targets. Indeed, ample evidence documents that JNK aggravates ischemic brain damage and neurodegenerative disorders.…”

mentioning

confidence: 99%

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

et al. 2011

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Neuronal apoptosis contributes to ischemic brain damage and neurodegenerative disorders. Key regulators of neuronal apoptosis are the transcription factor NF-jB and the MAP kinases p38/MAPK and JNK, which share a common upstream activator, the mitogen-activated protein kinase kinase kinase (MAP3K) TGFb-activated kinase 1 (TAK1). Here we investigate the function of TAK1 in ischemia-induced neuronal apoptosis. In primary cortical neurons, TAK1 was activated by oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia. We found that short-term inhibition of TAK1 protected against OGD in vitro and reduced the infarct volume after middle cerebral artery occlusion in vivo. Prolonged inhibition or deletion of the TAK1 gene in neurons was, however, not protective. Short-term, but not prolonged inhibition of TAK1 interfered with the activation of p38/MAPK and JNK by OGD, the induction of the pro-oxidative genes Cox-2, Nox-2, and p40 phox , and the formation of superoxide. We found that prolonged TAK1 inhibition upregulated another MAP3K, apoptosis signal-regulating kinase-1, which is able to compensate for TAK1 inhibition. Our study demonstrates that TAK1 is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia.

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“…Activation of NF-κB requires the activity of the IκB kinase (IKK) complex . Activated NF-κB has been detected in neurons and activated microglia in the SN of PD patients and MPTP-treated animals suggesting that some of the pro-inflammatory mechanisms regulated by the NF-κB pathways may play an important role in the pathogenesis of PD (Ghosh et al, 2007;Hunot et al, 1997). Recent studies have shown that blockade of NF-κB activity either directly or through IκB can inhibit components of the inflammatory pathways in microglia namely, the oxidative stress pathway and the production of pro-inflammatory cytokines (Anrather et al, 2006;Gauss et al, 2007).…”

Section: Immunomodulatory Therapiesmentioning

confidence: 99%

“…Recent studies have shown that blockade of NF-κB activity either directly or through IκB can inhibit components of the inflammatory pathways in microglia namely, the oxidative stress pathway and the production of pro-inflammatory cytokines (Anrather et al, 2006;Gauss et al, 2007). Selective inhibition of NF-κB activity by a peptide blocking the IKK complex prevented DA neuronal loss in MPTP-treated mice and suppressed microglial activation (Ghosh et al, 2007). Finally, a selective pharmacological IKK inhibitor has demonstrated neuroprotective properties in LPS-and MPTP-induced models of PD.…”

Section: Immunomodulatory Therapiesmentioning

confidence: 99%