Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration

Iravani, Mahmoud M.; Kashefi, K.; Mander, Palwinder K.; Rose, Sarah; Jenner, Peter

doi:10.1016/s0306-4522(01)00562-0

Cited by 236 publications

(170 citation statements)

References 48 publications

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“…The results strongly supported the hypothesis that production of NO and expression of iNOS from thrombinactivated microglia may participate in the death of dopaminergic neurons. These results are consistent with previous studies showing that in iNOS-deficient mice, nigral dopaminergic neurons were protected from MPTP toxicity [13] and that LPS-induced iNOS expression and NO production in microglia led to the death of dopaminergic neurons in the SN [15] . However, it cannot be ruled out that other microlgia-derived proinflammatory cytokines may contribute to this degeneration.…”

Section: Discussion In Vivosupporting

confidence: 93%

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

Huang

et al. 2008

Neurosci. Bull.

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Objective To evaluate the role of thrombin-activated microglia in the neurodegeneration of nigral dopaminergic neurons in the rat substantia nigra (SN) in vivo. Methods After stereotaxic thrombin injection into unilateral SN of rats, immunostaining, reverse transcription polymerase chain reaction (RT-PCR) and biochemical methods were used to observe tyrosine hydroxylase (TH) immunoreactive positive cells, microglia activation, nitric oxide (NO) amount and inducible nitricoxide synthase (iNOS) expression. Results (1) Selective damage to dopaminergic neurons was produced after thrombin injection, which was evidenced by loss of TH immunostaining in time-dependent manner; (2) Strong microglial activation was observed in the SN; (3) RT-PCR demonstrated the early and transient expression of neurotoxic factors iNOS mRNA in the SN. Immunofluorescence results found that thrombin induced expression of iNOS in microglia. The NO production in the thrombininjected rats was significantly higher than that of controls (P < 0.05). Conclusion Thrombin intranigral injection can injure the dopaminergic neurons in the SN. Thrombin-induced microglia activation precedes dopaminergic neuron degeneration, which suggest that activation of microglia and release of NO may play important roles in dopaminergic neuronal death in the SN.

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Section: Discussion In Vivosupporting

confidence: 93%

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

Huang

et al. 2008

Neurosci. Bull.

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“…However, oxidative stress is intimately linked as well not only to inflammation but also to other components of the neurodegenerative process, such as nitrosative stress (68). Various isoforms of the nitric oxide (NO) producing enzyme nitric oxide synthase (NOS) are elevated in PD, indicating an important critical role for NO in disease of the pathophysiology mechanisms, considering that increased expression of glial and neuronal NOS isoforms in astrocytes and neurons contributes to the synthesis of peroxynitrite synthesis, which leads to the generation of NT (nitrotyrosine) (27). We demonstrated that DMF treatment may be considered a selective inhibitor of neuronal nitric oxide synthase (nNOS), producing dose-dependent protection against MPTP-induced NT increase.…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Campolo

Casili

Biundo

et al. 2017

Antioxidants & Redox Signaling

127

101

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Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-jB (NF-jB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of a-synucleinpositive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN + /Nrf-2 + cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-jB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.

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“…In this context, Iravani et al (13) suggested previously that cell counting using nigral sections at the easily identifiable level of the third nerve rootlets was a good index for evaluating changes in TH-positive cells in the SN.…”

Section: Discussionmentioning

confidence: 99%

“…Cell Counting-To examine the effects of LPS on the density of dopaminergic neurons and activation of microglial cells, nigral sections were prepared from the identifiable level of the third cranial nerve rootlets, which is a good index for degeneration of nigral dopaminergic neurons (13). The number of TH-positive neurons in the LPS-injected side was compared with the vehicle-injected side at the level of third cranial nerve rootlets in substantia nigra.…”

Section: Methodsmentioning

confidence: 99%

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Arai

Furuya

Yasuda³

et al. 2004

Journal of Biological Chemistry

118

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The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 g/l/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 g/l/site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 g/l/site increased interleukin-1␤ content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1␤, and caspase-11 expression in mice.Parkinson's disease (PD) 1 is histologically characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). High concentrations of microglial cells are present in the SN, and activation of these cells has been observed in the SN of PD patients (1, 2). Recent studies postulated that activation of microglia and neuroinflammatory processes may contribute to the pathogenesis of PD (3, 4). Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, is a potent inducer of inflammation and activator of microglia (5). Long term stimulation of innate immunity by LPS exacerbates motor neurodegeneration in a mouse model of amyotrophic lateral sclerosis, suggesting that the endotoxin LPS could be involved in neurodegenerative diseases caused by chronic peripheral bacterial infections especially in the presence of genetic or environmental risk factors (6).Dopaminergic neurons are far more sensitive to LPS-induced neurotoxicity than ␥-aminobutyric acidergic or serotonergic neurons, and intranigral injection of LPS induces selective and long lasting dopaminergic neurodegeneration via microglial activation in the SN (5). In PD patients, microglial activation, and selective and irreversible dopaminergic neurodegeneration in the SN are seen (1, 2); therefore intranigral injection of LPS is a suitable model for PD (5). With regard to the signal transduction by LPS, caspase-11 is considered to play a major role because resistance to LPS-induced sept...

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Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration

Cited by 236 publications

References 48 publications

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

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