Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

Abstract Background Smad3 signaling is indicated to regulate microglia activity. Parkinson’s disease (PD) neurodegeneration is shown to be associated with aging and neuroinflammation. However, it remains unclear about the relationship among Smad3 signaling, aging, neuroinflammation, and PD. Methods Rats were treated with SIS3 (a specific inhibitor of Smad3, intranigal injection) and/or lipopolysaccharide (intraperitoneal injection). We investigated the effect of SIS3 and lipopolysaccharide and their mechanism of action on motor behavior and nigrostriatal dopaminergic system in the rats. Furthermore, we explored the effect of SIS3 and LPS and their potential signaling mechanism of action on inflammatory response by using primary microglial cultures. Finally, we investigated the relationship among aging, Smad3 signaling, and neuroinflammation using animals of different ages. Results Both SIS3 and lipopolysaccharide induced significant behavior deficits and nigrostriatal dopaminergic neurodegeneration in the rats compared with the vehicle-treated (control) rats. Significantly increased behavior deficits and nigrostriatal dopaminergic neurodegeneration were observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the rats treated with vehicle, SIS3, or lipopolysaccharide. Furthermore, both SIS3 and lipopolysaccharide induced significant microglia activation and proinflammatory factor (IL-1β, IL-6, iNOS, and ROS) level increase in the SN of rats compared with the control rats. Significantly enhanced microglial inflammatory response was observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the other three groups. For our in vitro study, both SIS3 and lipopolysaccharide induced significant proinflammatory factor level increase in primary microglia cultures compared with the control cultures. Significantly increased inflammatory response was observed in the cultures co-treated with SIS3 and lipopolysaccharide compared with the other three groups. MAPK (ERK/p38) contributed to microglial inflammatory response induced by co-treatment with SIS3 and lipopolysaccharide. Interestingly, there was decrease in Smad3 and pSmad3 expression (protein) and enhancement of neuroinflammation in the mouse SN with aging. Proinflammatory factor levels were significantly inversely correlated with Smad3 and pSmad3 expression. Conclusion Our study strongly indicates the involvement of SN Smad3 signaling deficiency in aging and PD neurodegeneration and provides a novel molecular mechanism underlying the participation of aging in PD and helps to elucidate the mechanisms for the combined effect of multiple factors in PD.

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Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.251341998 ◽

2001 ◽

Vol 98 (25) ◽

pp. 14669-14674 ◽

Cited By ~ 513

Author(s):

Y. Du ◽

Z. Ma ◽

S. Lin ◽

R. C. Dodel ◽

F. Gao ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurodegeneration ◽

Nigrostriatal Dopaminergic Neurodegeneration ◽

Mptp Model

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Faculty Opinions recommendation of Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002744.30019 ◽

2001 ◽

Author(s):

Eric Nestler

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurodegeneration ◽

Nigrostriatal Dopaminergic Neurodegeneration ◽

Mptp Model

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The Pivotal Role of Iron in NF-kappaB Activation and Nigrostriatal Dopaminergic Neurodegeneration: Prospects for Neuroprotection in Parkinson's Disease with Iron Chelators

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1999.tb07977.x ◽

1999 ◽

Vol 890 (1 NEUROPROTECTI) ◽

pp. 7-25 ◽

Cited By ~ 63

Author(s):

M.B. H. YOUDIM ◽

E. GRUNBLATT ◽

S. MANDEL

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pivotal Role ◽

Iron Chelators ◽

Dopaminergic Neurodegeneration ◽

Nf Kappab ◽

Nigrostriatal Dopaminergic Neurodegeneration

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Pyrethroid exposure and neurotoxicity: a mechanistic approach

Archives of Industrial Hygiene and Toxicology ◽

10.2478/aiht-2019-70-3263 ◽

2019 ◽

Vol 70 (2) ◽

pp. 74-89 ◽

Cited By ~ 12

Author(s):

Hamidreza Mohammadi ◽

Nasrin Ghassemi-Barghi ◽

Obeid Malakshah ◽

Sorour Ashari

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurological Disorders ◽

Neuronal Cell ◽

Cell Loss ◽

Future Research ◽

Dopaminergic Neurodegeneration ◽

Mechanistic Approach ◽

Disease Therapy ◽

Nigrostriatal Dopaminergic Neurodegeneration

AbstractPyrethroids are a class of synthetic insecticides that are used widely in and around households to control the pest. Concerns about exposure to this group of pesticides are now mainly related to their neurotoxicity and nigrostriatal dopaminergic neurodegeneration seen in Parkinson’s disease. The main neurotoxic mechanisms include oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The main neurodegeneration targets are ion channels. However, other receptors, enzymes, and several signalling pathways can also participate in disorders induced by pyrethroids. The aim of this review is to elucidate the main mechanisms involved in neurotoxicity caused by pyrethroids deltamethrin, permethrin, and cypermethrin. We also review common targets and pathways of Parkinson’s disease therapy, including Nrf2, Nurr1, and PPARγ, and how they are affected by exposure to pyrethroids. We conclude with possibilities to be addressed by future research of novel methods of protection against neurological disorders caused by pesticides that may also find their use in the management/treatment of Parkinson’s disease.

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The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease

Parkinson s Disease ◽

10.4061/2011/487450 ◽

2011 ◽

Vol 2011 ◽

pp. 1-25 ◽

Cited By ~ 25

Author(s):

Kemal Ugur Tufekci ◽

Sermin Genc ◽

Kursad Genc

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Experimental Studies ◽

Bacterial Endotoxin ◽

Dopaminergic Neurodegeneration ◽

Nigrostriatal Dopaminergic Neurodegeneration ◽

Peripheral Immune Cells

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by thein vivoadministration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized.

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