Paroxetine Prevents Loss of Nigrostriatal Dopaminergic Neurons by Inhibiting Brain Inflammation and Oxidative Stress in an Experimental Model of Parkinson’s Disease

Chung, Young Cheul; Kim, Sang R.; Jin, Byung Kwan

doi:10.4049/jimmunol.1000208

Cited by 137 publications

(179 citation statements)

References 52 publications

(66 reference statements)

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“…Although the specific cause of PD is yet to be established, a growing body of evidence supports the theory that microglial activation-derived oxidative stress increases the risk of PD (3). In the substantia nigra (SN) of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of PD, key enzymes involved in reactive oxygen species (ROS) production, such as microglial NAPDH oxidase, are upregulated in damaged areas and contribute to DA neuronal death (4)(5)(6)(7). In addition, proinflammatory cytokines, such as IL-1b and TNF-a, are augmented in PD patients (8,9) and participate in DA neuronal death in the MPTP model of PD (10,11).…”

Section: P Arkinson's Disease (Pd) Is a Common Neurodegenerativementioning

confidence: 99%

“…The total number of TH-positive neurons was counted in the various animal groups at 7 d postinjection (MPTP or saline) using the optical fractionator method performed on an Olympus Computer Assisted Stereological Toolbox system version 2.1.4 (Olympus Denmark, Ballerup, Denmark) as previously described (4,5). Actual counting was performed using a 1003 oil objective.…”

Section: Stereological Cell Countsmentioning

confidence: 99%

“…As previously described (4,5), the OD of TH-positive fiber in striatum (STR) was examined at 35 original magnification using the IMAGE PRO PLUS system (Version 4.0; Media Cybernetics, Silver Spring, MD) on a computer attached to a light microscope (Zeiss Axioskop, Oberkochen, Germany) interfaced with a CCD video camera (Kodak Mega Plus model 1.4 I; Kodak, New York, NY). To control variations in background illumination, the average of background density readings from the corpus callosum was subtracted from that of density readings of the STR for each section.…”

Section: Densitometric Analysismentioning

confidence: 99%

“…Brains were dissected from the skull, postfixed overnight in buffered 4% paraformaldehyde at 4˚C, stored in 30% sucrose solution at 4˚C until they sank, and freeze-sectioned with a sliding microtome into 30-mm-thick coronal sections. All sections were collected in six separate series and processed for immunostaining, as described previously (4,5). In brief, brain sections were rinsed in PBS and incubated overnight at room temperature (RT) with primary Abs, specifically anti-macrophage Ag complex-1 (MAC-1; 1:200 dilution; Serotec, Oxford, U.K.) for microglia and anti-tyrosine hydroxylase (TH; 1:2000 dilution; Pel-Freez Biologicals, Rogers, AR) for DA neurons.…”

Section: Tissue Preparation and Immunostainingmentioning

confidence: 99%

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Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

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109

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This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

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Section: P Arkinson's Disease (Pd) Is a Common Neurodegenerativementioning

confidence: 99%

Section: Stereological Cell Countsmentioning

confidence: 99%

Section: Densitometric Analysismentioning

confidence: 99%

Section: Tissue Preparation and Immunostainingmentioning

confidence: 99%

See 2 more Smart Citations

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

Self Cite

109

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“…Fluoxetine, paroxetine, and sertraline were all found to have this effect in animals [293][294][295][296][297][298][299][300]. In contrast to these findings, mRNA expression of TNF-α, IL-1α, IL-1β, and intercellular adhesion molecule-1 (ICAM-1) was increased in vivo using polymerase chain reaction (PCR) analysis and may affect the BBB permeability [14].…”

Section: Antidepressants Affect the Neuroinflammatory Environmentmentioning

confidence: 94%

Antidepressant use and risk of central nervous system metastasis

et al. 2016

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Molecular insights of NADPH oxidases and its pathological consequences

Waghela

Vaidya

Agrawal

et al. 2020

Cell Biochemistry & Function

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Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. Significance of the study The NOXs are multi‐subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

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Paroxetine Prevents Loss of Nigrostriatal Dopaminergic Neurons by Inhibiting Brain Inflammation and Oxidative Stress in an Experimental Model of Parkinson’s Disease

Abstract: Material Supplementary 8.DC1http://www.jimmunol.org/content/suppl/2010/06/18/jimmunol.100020

Cited by 137 publications

References 52 publications

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Antidepressant use and risk of central nervous system metastasis

Molecular insights of NADPH oxidases and its pathological consequences

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