Naringenin targets on astroglial Nrf2 to support dopaminergic neurons. (January 2019)

• Record Type: Journal Article
• Authors: Wang, Guo-Qing; Zhang, Bei; He, Xue-Mei; Li, Dai-Di; Shi, Jing-Shan; Zhang, Feng
• Is Part Of: Pharmacological research. Volume 139(2019)
• Page Start: 452
• Page End: 459
• Publication Date: 2019-01
• Subjects: ara-C β-D-arabinofuranoside -- BDNF brain-derived neurotrophic factor -- DA dopamine -- GAP-43 growth associated protein-43 -- GDNF glial cell line-derived neurotrophic factor -- GFAP glial fibrillary acidic protein -- Iba1 ionized calcium-binding adapter molecule-1 -- LME leu-leu methyl ester -- NAR Naringenin -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PCNA proliferating cell nuclear antigen -- PD Parkinson's disease -- S100b S100 calcium binding protein B -- TH tyrosine hydroxylase; Naringenin -- Astroglia -- Neurotrophic factors -- Nrf2 -- Dopaminergic neurons; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.11.043
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Astroglia serve as a critical role in metabolic and neurotrophic support to neurons. The loss of astroglia-derived neurotrophic effects could be a primary contributor to Parkinson's disease (PD). Thus, understanding astroglia functions is an important strategy for enhancing neuronal survival. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in neuronal resistance to oxidative stress and glutamate-induced excitotoxicity. Balancing oxidative stress by up-regulation of Nrf2 has been demonstrated to be effective in neurodegenerative disease treatment. Naringenin (NAR), a dietary flavonoid, displays anti-oxidant, cardioprotective, anti-inflammatory and neuroprotective activities. However, the molecular mechanisms underlying NAR-mediated neuroprotection against neurodegeneration remain unelucidated. Here, the present study investigated whether NAR promoted astroglial neurotrophic effects to support neurons and the underlying mechanisms as well. In primary rat midbrain neuron-glia co-cultures, NAR conferred neurotrophic effects to support dopaminergic (DA) neurons survival in the concentration- and time-dependent manners. Furtherly, astroglia were essential for NAR-mediated neurotrophic actions. Also, NAR elicited astrogliosis and neurotrophic factors release in primary neuron-glia co-cultures and astroglia-enriched cultures. Mechanistically, astroglial Nrf2 activation participated in NAR-mediated neurotrophic actions to support DA neurons evidenced by the following observations: 1) NAR increased Nrf2 mRNA and protein expressions both in neuron-glia and astroglia-enriched cultures; 2) Nrf2-siRNA inhibited NAR-mediated astrogliosis and neurotrophic factors release; 3) astroglial Nrf2-siRNA abolished NAR-mediated neurotrophic effects on DA neurons. Together, this study demonstrates NAR enhanced astroglial neurotrophic effects on DA neurons through the regulation of Nrf2 activation, and these findings might open new potential promising avenues for neurotrophic factor-based treatment of PD.