Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Abstract

Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75 receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75 expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75-dependent ceramide generation and internalizes p75. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson's disease.

Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms

“…Future studies involving, for example, short interfering RNAs specific to SGK-1, could further clarify the mechanism of astrocytic glucocorticoid-induced HMGB1 release. Glucocorticoids open astrocytic pannexin-1 channels, thereby releasing ATP [59]. The current findings also showed that blocking connexins and pannexins, and specifically pannexin-1, led to significantly decreased HMGB1 release, demonstrating that pannexin-1 is involved in corticosterone-induced HMGB1 release in primary cultured cortical astrocytes.…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Brain-derived neurotrophic factor (BDNF) has been certified playing a key role in the regulation of redox-sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ, leading to induction of the CK2-Nrf2 signaling axis, thereby protecting dopaminergic neurons from ferroptosis (Ishii et al, 2019). Although we hypothesize the regulation of Nrf2 in the ferroptosis process of neurodegenerative diseases, it is unclear whether the neuroprotective effect in neurodegenerative disease model is through targeting Nrf2 to suppress ferroptosis regulation.…”

L‐glutamine protects mouse brain from ischemic injury via up‐regulating heat shock protein 70

“…Multiple experimental evidence indicates that the process of reactive astrocyte proliferation exerts a necessary beneficial function . Astrocyte proliferation plays an important role in regulating brain microenvironment through extracellular neurotransmitter regulation and neural growth factor secretion in the period of acute cerebral ischemia. Acting as a transcriptional factor that involved in cell survival and proliferation, STAT3 is an early trigger for astrogliosis .…”