Insights into Neuroinflammation in Parkinson’s Disease: From Biomarkers to Anti-Inflammatory Based Therapies

Rocha, Natália Pessoa; Miranda, Aline Silva de

doi:10.1155/2015/628192

Cited by 172 publications

(129 citation statements)

References 114 publications

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“…Multiple immunological stimuli have been shown to trigger microglial activation leading to sustained chronic inflammation in dopaminergic neurodegenerative processes (Hirsch et al, 2013; Hirsch et al, 2012; Rocha et al, 2015). In this study, we investigated the role of PKCδ signaling in regulating microglial activated-inflammatory responses and its relationship to dopaminergic neurotoxicity in both cell culture and murine models of PD.…”

Section: Discussionmentioning

confidence: 99%

“…Cytokines represent the major inflammatory mediators in the CNS that most often act through specific receptor-mediated mechanisms, thereby triggering the activation of downstream signaling cascades (Rocha et al, 2015). In the CNS, activated microglia produce numerous inflammatory cytokines including TNFα, IL-1β, and IL-6, which play a central role in initiating the proinflammatory response (Sadasivan et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon

Singh

Lawana

et al. 2016

Neurobiology of Disease

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Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCδ activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCδ contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including α-synuclein, tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCδ with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKCδ in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCδ in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCδ in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKCδ activated NFκB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFκB led to translocation of the p65 subunit to the nucleus, IκBα degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon

Singh

Lawana

et al. 2016

Neurobiology of Disease

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“…Recent studies have confirmed that neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases, including PD [22,23,24,25]. Neuroinflammatory mechanisms might contribute to a cascade of events that result in the progressive degeneration and/or death of neuron cells in PD [22].…”

Section: Discussionmentioning

confidence: 99%

“…Overactivation of microglia and overproduction of proinflammatory factors lead to the death of DA neurons. Inhibition of microglia activation could inhibit the production of proinflammatory factors, thereby protecting the brain from parkinsonism [24,25]. Thus, it is very important to regulate the function of microglia during the progress of PD.…”

Section: Discussionmentioning

confidence: 99%

GPER Agonist G1 Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson Disease

Guan

Yang

Fan

et al. 2017

Neuroimmunomodulation

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Objective: Epidemiological studies have shown that women of reproductive age have much less possibility of developing Parkinson disease (PD) than men. The beneficial effect of estrogen also has been well-described in both culture and animal models of PD. G protein-coupled estrogen receptor (GPER) is a membrane-associated estrogen receptor, and displayed a neuroprotective role in a mouse model of PD. Since GPER is highly expressed in microglia, we speculate that GPER mediates the neuroprotective function of estradiol through suppressing the neuroinflammation of PD. Methods: We investigated the effects of GPER agonist G1 and GPER antagonist G15 on the neurodegeneration of dopaminergic neuron, the activation of microglia, and the production of IL-1β, TNF-α, and IL-6 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of parkinsonism. Furthermore, we confirmed the effects of GPER activation on the production of IL-1β, TNF-α, and IL-6 in an in vitro MPP+ model in BV2 microglial cells. Results: After 12-day treatment with G1, mice showed an increase in the number of tyrosine hydroxylase-immunoreactive cells, reduced activation of microglia, and the abatement of proinflammatory cytokines, and the anti-inflammatory effect of G1 was abolished by G15. Meanwhile, in vitro studies demonstrated that GPER activation also reduced the release of proinflammatory cytokines from BV2 microglial cells after MPP+ stimulation. Conclusion: Our data suggest that GPER mediates the anti-neuroinflammatory effect of estrogen in experimental PD progression.

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“…Sustained microglial and astroglial activation near dying dopaminergic neurons in the SNpc is evident in PD patients and animal models of the disease (McGeer et al, 1988; Hirsch and Hunot, 2009). Several in vitro cell culture and in vivo animal studies have demonstrated the elevation of key enzymes involved in the production of reactive oxygen species (ROS) due to mitochondrial impairment and reactive nitrogen species (RNS) in dopaminergic neurons of the SN, including microglial gp91phox (Nox2) and inducible nitric oxide synthase (iNOS) (Gao et al, 2003b; Wu et al, 2003; Hunter et al, 2007; Hirsch et al, 2012; Murakami and Hirano, 2012; Strowig et al, 2012; Yan et al, 2014; Rocha et al, 2015). In addition, different pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukins IL-1β and IL-6, interferon gamma (IFN-γ), as well as other immune neurotoxins, are found either in the CSF or affected regions of PD brains (Nagatsu et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

Ghosh

Langley

Harischandra

et al. 2016

J Neuroimmune Pharmacol

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Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.

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Insights into Neuroinflammation in Parkinson’s Disease: From Biomarkers to Anti-Inflammatory Based Therapies

Cited by 172 publications

References 114 publications

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

GPER Agonist G1 Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson Disease

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

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