Abstract
Reactive astrogliosis is a key hallmark of inflammatory responses in the pathogenesis of brain injury, including Parkinson’s disease (PD), but its role and regulatory mechanisms are not fully understood. Pannexin 1 (Panx 1) is a membrane channel that mediates substance release in many neurodegenerative diseases. However, the role of astrocyte Panx 1 in the regulation of PD-like neuroinflammation remains elusive. Here, we characterized the expression of Panx 1 in isolated primary astrocytes and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. The functions of Panx 1 in inflammatory cytokines expression and the viability of neuronal SH-SY5Y cells were examined in cultured cells treated with lipopolysaccharide (LPS) and 1-methyl-4-phenylpyridinium (MPP+). We found that Panx 1 expression was significantly increased under both LPS- and MPP+-treated conditions. Panx 1 downregulation suppressed LPS-induced pro-inflammatory cytokine expression but did not significantly affect MPP+-induced astrocyte apoptosis or inflammatory cytokine expression through treatment with the Panx 1 inhibitor carbenoxolone (CBX) and Panx 1 siRNA. Moreover, silencing Panx 1 in reactive astrocytes had a potentially protective effect on the viability of neuronal SH-SY5Y cells. Therefore, we propose that Panx 1 may serve as a key regulator in reactive astrocytes to intervene in the inflammatory response and maintain neuronal viability in the context of PD-like conditions.
Highlights
Parkinson’s disease (PD) is characterized by damage to the ascending nigrostriatal pathway, including progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and axon terminals in the striatum
As expected given previous results showing that pannexins are widely expressed in primary cultured astrocytes (Wei et al, 2016; Scemes et al, 2019), we found that Pannexin 1 (Panx 1) was more highly expressed in primary cultured astrocytes than Panx 2 and Panx 3 at the mRNA level (Figure 1A)
To investigate the expression of Panx 1 in reactive astrocytes in this process, we estimated the expression of astrocyte Panx 1 in an acute PD model with reduced doses of MPTP systemic administration (Jackson-Lewis and Przedborski, 2007; Meng et al, 2019)
Summary
Parkinson’s disease (PD) is characterized by damage to the ascending nigrostriatal pathway, including progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and axon terminals in the striatum. During the onset and progression of PD, astrocytes are converted into reactive astrocytes; during this process, the astrocytes undergo proliferation, hypertrophy and produce a variety of potential neuroprotective or toxic mediators, which are neurotoxic or neuroprotective to the surrounding DA neurons (Booth et al, 2017; Acioglu et al, 2021). Under both physiological and pathological conditions, astrocytes contribute to the functions of DA neurons
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