Abstract
Astrocytes, as the largest population of glial subtype, play crucial roles in normal brain function and pathological conditions, such as Parkinson’s disease (PD). Restoring the functions of astrocyte is a promising new therapeutic target for PD. Astrocytes can express multiple types of neurotransmitter receptors, including functional α7 nicotinic acetylcholine receptor (α7nAChR). Previously, we found that a non-selective α7nAChR agonist nicotine exerted a protective effect against H2O2-induced astrocyte apoptosis via an α7nAChR-dependent pathway. However, the molecular mechanism of the antiapoptotic response of astroglial α7nAChR has not been studied. In the present study, using pharmacological inhibition and genetic knockout of α7nAChR, we assessed the antiapoptotic effects of an α7nAChR agonist PNU-282987 in primary cultured astrocytes treated with 1-methyl-4-phenylpyridinium (MPP+). PNU-282987 promoted the viability of astrocytes, alleviated MPP+ induced apoptosis, and decreased the number of GFAP+/TUNEL+ cells. Meanwhile, PNU-282987 upregulated the expression of the antiapoptotic protein Bcl-2 and downregulated the expression of the apoptotic protein Bax and cleaved-caspase-3. Moreover, the suppression of the JNK-p53-caspase-3 signaling may underlie the neuroprotective property of PNU-282987. Therefore, PNU-282987 ameliorates astroglial apoptosis induced by MPP+ through α7nAChR-JNK-p53 signaling. Our findings suggest that PNU-282987 may be a potential drug for restoring astroglial functions in the treatment of PD.
Highlights
As the largest population of glial subtype in the central nervous system, astrocytes play crucial roles in maintaining normal brain function and homeostasis (Santello et al, 2019; Valori et al, 2019)
MPP+ alone for 24 h increased lactate dehydrogenase (LDH) leakage by 56.0% compared to the control cells (100.0% ± 0.4 and 156.0% ± 1.7; control and MPP+ alone, respectively; p < 0.001 by one-way analysis of variance (ANOVA)), whereas pretreatment with PNU-282987 attenuated this LDH leakage
The neuroprotective effects of PNU-282987 on cell viability (100.0% ± 1.3 in control; 72.1% ± 0.7 in MPP+ alone, p < 0.001; 96.9% ± 1.8 in MPP+ + PNU-282987, p < 0.001 vs. MPP+ alone; 71.9% ± 1.7 in MPP+ + PNU-282987 + MLA, p < 0.001 vs. control, p < 0.001 vs. MPP+ + PNU-282987; one-way ANOVA) and LDH leakage (100.0% ± 0.3 in control; 155.6% ± 2.1 in MPP+ alone, p < 0.001; 115.5% ± 6.8 in MPP+ + PNU-282987, p = 0.005 vs. MPP+ alone; 159.8% ± 3.3 in MPP+ + PNU-282987 + MLA, p < 0.001 vs. control, p = 0.004 vs. MPP+ + PNU-282987; oneway ANOVA) of cultured astrocytes were blocked by 100 nM MLA (Figures 2C,D)
Summary
As the largest population of glial subtype in the central nervous system, astrocytes play crucial roles in maintaining normal brain function and homeostasis (Santello et al, 2019; Valori et al, 2019). Astrocytes become activated with heterogeneous and progressive changes in response to pathological conditions, such as inflammatory disease (Iglesias et al, 2017), acute traumatic brain injury (Burda et al, 2016), ischemia/hypoxia (Liu and Chopp, 2016), Alzheimer’s disease (Acosta et al, 2017), and Parkinson’s disease (PD) (Booth et al, 2017). Activated astrocytes leave their quiescent state and are characterized by cellular swelling, proliferation (astrocytosis), and hypertrophy-hyperplasia (astrogliosis) (Pekny and Nilsson, 2005). Astrocytes act as initiators or contributors in neuropathological conditions via both gain-of-function and loss-of-function mechanisms
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