Baicalein Mediates Mitochondrial Autophagy via miR-30b and the NIX/BNIP3 Signaling Pathway in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is regarded as a severe neurodegenerative disorder. Baicalein is involved in the treatment of PD. This study explored the mechanism of baicalein in PD. The PD rat model was established using 6-hydroxydopamine. The neurologic score, dopamine (DA) content, apoptotic cells, and neuronal damage were evaluated after rats were treated with baicalein. Autophagy in PD rats was inhibited using 3-methyladenine (3-MA). The mitochondrial membrane potential (MMP) and autophagy-related proteins (LC3, P62) were detected. Next, agomiR-30b was transfected into PD rats. The targeting relation between miR-30b and NIX was predicted and verified. Then, sh-NIX was transfected into PD rats, and the effects of miR-30b and NIX on MMP, LC3, and P62 were assessed. When miR-30b was overexpressed using agomiR-30b, the NIX and BNIP3 levels were detected. Baicalein increased the neurological score and restored DA content, neurons, MMP, and mitochondrial autophagy protein levels. Baicalein inhibited miR-30b expression and miR-30b targeted NIX. miR-30b upregulation or NIX silencing reversed the effect of baicalein on MMP and mitochondrial autophagy. Baicalein upregulated NIX and BNIP3 expressions, while miR-30b overexpression inhibited NIX and BNIP3 expressions. In summary, baicalein mediated mitochondrial autophagy and restored neuronal activity by downregulating miR-30b and activating the NIX/BNIP3 pathway, thus protecting against PD.

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

“…Similarly, Zhang et al suggested that pretreatment of PC12 cells with baicalein inhibited H 2 O 2 ‐induced apoptosis by mitigating mitochondrial dysfunction (by inhibiting membrane potential loss, reducing cytochrome c release, upregulating Bcl‐2 expression, and downregulating Bax level in the mitochondria) and suppressing oxidative stress (by inhibiting mitochondrial ROS generation and lipid peroxidation) (Zhang, Ye, & Dong, 2010). Other studies have indicated that baicalein exerted protective effects against 6‐OHDA‐induced neurotoxicity both in vitro and in vivo through various mechanisms, which involved the activation of the Keap1/Nrf2/HO‐1 pathway, mediation of the PKCα and PI3K/AKT pathways, and promotion of mitophagy (via miR‐30b‐5p and the SIRT1/AMPK/mTOR pathway, as well as miR‐30b and the NIX/BNIP3 pathway) (Chen et al, 2021a; Chen et al, 2021b; Zhang et al, 2012). Furthermore, Zhang et al demonstrated that baicalein protected against rotenone‐induced injury in rat and SH‐SY5Y cell models by enhancing mitobiogenesis through increasing the levels of peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α), nuclear respiratory factor‐1 (NRF‐1), and mitochondrial transcriptional factor A (TFAM) via the cAMP‐responsive element‐binding protein (CREB) and glycogen synthase kinase‐3β (GSK‐3β) pathways (Zhang et al, 2017).…”

Conjugation, Prodrug, and Co-Administration Strategies in Support of Nanotechnologies to Improve the Therapeutic Efficacy of Phytochemicals in the Central Nervous System

“…Its anti-neuroinflammatory properties have been associated with the inhibition of the expression of inducible nitric oxide synthase, the production of NO and the nuclear factor-ḳB-signalling pathways in glial cells [ 150 ]. The involvement of baicalein in the treatment of PD has been also linked to its ability to restore DA content, neurons, mitochondrial membrane potential, and mitochondrial autophagy protein levels [ 153 ].…”

“…B-signalling pathways in glial cells [150]. The involvement of baicalein in the treatment of PD has been also linked to its ability to restore DA content, neurons, mitochondrial membrane potential, and mitochondrial autophagy protein levels [153].…”

Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson’s Disease Mice Model

“…It contains the LIR motif which enables it to regulate mitophagy via parkin-independent pathway. BNIP3 protein levels were found to be decreased in PD [ 29 ]. Recently Zhang et al have shown that increased BNIP3 binds to PINK1 and decreases the proteolytic cleavage of PINK1 resulting in activation of parkin-dependent mitophagy [ 30 ].…”