Loss of brain norepinephrine elicits neuroinflammation-mediated oxidative injury and selective caudo-rostral neurodegeneration Environmental toxicant exposure has been strongly implicated in the pathogenesis of Parkinsons disease (PD). Clinical manifestations of non-motor and motor symptoms in PD stem from decades of progressive neurodegeneration selectively afflicting discrete neuronal populations along a caudo-rostral axis. However, recapitulating this spatiotemporal neurodegenerative pattern in rodents have been unsuccessful. The purpose of this study was to generate such animal PD models and delineate mechanism underlying the ascending neurodegeneration. Neuroinflammation, oxidative stress, and neuronal death in mice brains were measured at different times following a single systemic injection of LPS. We demonstrate that LPS produced an ascending neurodegeneration that temporally afflicted neurons initially in the locus coeruleus (LC), followed by substantia nigra and lastly the primary motor cortex and hippocampus. To test the hypothesis that LPS-elicited early loss of noradrenergic LC neurons may underlie this ascending patter, we used a neurotoxin DSP-4 to deplete brain norepinephrine. DSP-4 injection resulted in a time-dependent ascending degenerative pattern similar to that generated by the LPS model. Mechanistic studies revealed that increase in NOX2-dependent superoxide/ROS production plays a key role in both LPS- and DSP-4-elicited neurotoxicity. We found toxin-elicited chronic neuroinflammation, oxidative neuronal injuries and neurodegeneration were greatly suppressed in mice deficient in NOX2 gene or treated with NOX2 specific inhibitor. Our studies document the first rodent PD model recapturing the ascending neurodegenerative pattern of PD patients and provide convincing evidence that the loss of brain norepinephrine is critical in initiating and maintaining chronic neuroinflammation and the discrete neurodegeneration in PD.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
Zip Code
Dang, Duy-Khanh; Shin, Eun-Joo; Kim, Dae-Joong et al. (2018) PKC?-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. Free Radic Biol Med 115:318-337
Lai, Ching-Long; Lu, Chun-Chung; Lin, Hui-Ching et al. (2018) Valproate is protective against 6-OHDA-induced dopaminergic neurodegeneration in rodent midbrain: A potential role of BDNF up-regulation. J Formos Med Assoc :
Hashiguchi, Takuyu; Shindo, Sawako; Chen, Shih-Heng et al. (2018) Sulfotransferase 4A1 Increases Its Expression in Mouse Neurons as They Mature. Drug Metab Dispos 46:860-864
Dang, Duy-Khanh; Shin, Eun-Joo; Kim, Dae-Joong et al. (2018) Ginsenoside Re protects methamphetamine-induced dopaminergic neurotoxicity in mice via upregulation of dynorphin-mediated ?-opioid receptor and downregulation of substance P-mediated neurokinin 1 receptor. J Neuroinflammation 15:52
Zhang, Wei; Gao, Jun-Hua; Yan, Zhao-Fen et al. (2018) Minimally Toxic Dose of Lipopolysaccharide and ?-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation. Mol Neurobiol 55:619-632
Lee, Sheng-Yu; Wang, Tzu-Yun; Chen, Shiou-Lan et al. (2018) Add-On Memantine Treatment for Bipolar II Disorder Comorbid with Alcohol Dependence: A 12-Week Follow-Up Study. Alcohol Clin Exp Res 42:1044-1050
Hou, Liyan; Li, Qiujuan; Jiang, Liping et al. (2018) Hypertension and Diagnosis of Parkinson's Disease: A Meta-Analysis of Cohort Studies. Front Neurol 9:162
Chang, Hui Hua; Chen, Po See; Wang, Tzu-Yun et al. (2017) Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder. J Affect Disord 221:151-157
Wang, Tzu-Yun; Lee, Sheng-Yu; Hu, Ming-Chuan et al. (2017) More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder. Psychoneuroendocrinology 85:42-48
Lu, Ru-Band; Lee, Sheng-Yu; Wang, Tzu-Yun et al. (2017) Long-term heroin use was associated with the downregulation of systemic platelets, BDNF, and TGF-?1, and it contributed to the disruption of executive function in Taiwanese Han Chinese. Drug Alcohol Depend 179:139-145

Showing the most recent 10 out of 86 publications