PARP-1 Inhibition Ameliorates Neuronal Damage in Valproic Acid-Induced Models of Autism Spectrum Disorder through the MKP-1/p38 Pathway

Abstract

Background: In this study, we explore the potential mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) inhibition on autism spectrum disorder (ASD) using 5-aminoisoquinolinone (5-AIQ), a PARP-1 inhibitor that has been shown to ameliorate ASD in black and tan brachyury (BTBR) mice. Methods: ASD animal models were established in neonatal Wistar rats by using valproic acid (VPA) induction, and the model rats were treated with 5-AIQ. The social interaction of neonatal rats in the models was evaluated through a three-chamber social test. VPA-induced ASD cell models were constructed in primary cortical neurons bearing PARP-1/mitogen-activated protein kinase phosphatase 1 (MKP-1) knockdown, followed by 5-AIQ treatment. Expressions of PARP-1 and MKP-1 were assessed by quantitative real-time polymerase chain reaction. The viability and apoptosis were measured by cell counting kit-8 (CCK-8) and TdT-mediated dUTP nick end labeling (TUNEL) assays. Reactive oxygen species (ROS) production was evaluated through specific kits. Levels of 4-Hydroxynonenal (4-HNE), PARP-1, MKP-1, phosphorylated-p38 (p-p38), p38, c-caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) were analyzed through Western blot. Results: The ability of social interaction among neonatal rats was suppressed in VPA-induced ASD animal models (p < 0.001). Expressions of 4-HNE, PARP-1, c-caspase-3, and Bax, as well as the ratio of p-p38/p38, were increased, while the expressions of MKP-1 and Bcl-2 were decreased in VPA-induced ASD animal models (p < 0.001). All these effects were reversed by 5-AIQ (p < 0.05). Suppressed viability, increased ROS production/apoptosis/ratio of p-p38/p38, upregulated PARP-1/c-caspase-3/Bax expression, and downregulated MKP-1/Bcl-2 expression in VPA-induced ASD cell models were reversed by 5-AIQ/small interfering RNA targeting PARP-1 (siPARP-1) (p < 0.01), while the effects of siPARP-1 were counteracted by small interfering RNA targeting MKP-1 (siMKP-1) (p < 0.001). Conclusions: PARP-1 inhibition ameliorates neuronal damage in VPA-induced models of ASD by the MKP-1/p38 pathway.