zed: 1) Mechanism of reactive microgliosis: For the last year, our research focused on the reactive microgliosis is crucial for the maintenance of long-term microglial activation. After demonstrating that continuing neuronal death/damage is crucial for the maintenance of microglial activation, we tried to further understand the molecular mechanisms by studying the role of reactive microgliosis in the creation of the self-propelling cycle. Reactive microgliosis occurs when neurons are damaged and has been generally considered to serve a passive role in cleaning the dead or damaged neurons or debris by phagocytosis. Our recent studies provided convincing evidence indicating that reactive microgliosis play a critical and active role in the formation of a self-propelling cycle and the subsequent neuro-degeneration. We have shown that a spectrum of noxious endogenous compounds in extracellular milieu, generated following neuronal injury, can activate microglia leading to reactive microgliosis. These compounds include membrane breakdown products, abnormally processed, modified or aggregated proteins (e.g.a-synuclein and -amyloid), and leaked cytosolic compounds (e.g.a-synuclein and neuromelanin). It appears that the microglial response to these endogenous toxic signals resembles their response to invading microbes. 2) Development of novel therapeutic drug for treatementof Parkinson's disease The role of the B2 Adrenergic Receptor(B2AR) in the regulation of chronic neurodegenerative inflammation within the CNS is poorly understood. The purpose of this study was to determine neuroprotective effects of long-acting B2AR agonists such as salmeterol in rodent models of Parkinsons disease. Results showed salmeterol exerted potent neuroprotection against both LPS and MPTP/MPP+-induced dopaminergic neurotoxicity both in primary neuron-glia cultures (at sub-nanomolar concentrations) and in mice (1-10 g/kg/day doses). Further studies demonstrated that salmeterol-mediated neuroprotection is not a direct effect on neurons;instead, it is mediated through the inhibition of LPS-induced microglial activation. Salmeterol significantly inhibited LPS-induced production of microglial pro-inflammatory neurotoxic mediators, such as TNFa, superoxide and nitric oxide, as well as the inhibition of TAK1-mediated phosphorylation of MAPK and p65 NF-kB. The anti-inflammatory effects of salmeterol required 2AR expression in microglia, but were not mediated through the conventional GPCR/cAMP pathway. Rather, salmeterol failed to induce microglial cAMP production, could not be reversed by either PKA inhibitors or an EPAC agonist, and was dependent on beta-arrestin2 expression. Together, our results demonstrate that administration of extremely low doses of salmeterol exhibit potent neuroprotective effects by inhibiting microglial cell activation through a b2AR/b-arrestin2-dependent but cAMP/PKA independent pathway.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2011
Total Cost
$2,646,914
Indirect Cost
City
State
Country
Zip Code
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
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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
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
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

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