Neuroprotective effects of protocatechuic aldehyde through PLK2/p-GSK3β/Nrf2 signaling pathway in both in vivo and in vitro models of Parkinson's disease

Abstract

Mitochondrial dysfunction and oxidative damage are closely related to the pathogenesis of Parkinson's disease (PD). The pharmacological mechanism of protocatechuic aldehyde (PCA) for PD treatment have retained unclear. The purposes of the present study were to clarify the neuroprotective effects of post-treatment of PCA for PD treatment by mitigating mitochondrial dysfunction and oxidative damage, and to further determine whether its effects were mediated by the polo-like kinase 2/phosphorylated glycogen synthase kinase 3 β/nuclear factor erythroid-2-related factor 2 (PLK2/p-GSK3β/Nrf2) pathways. We found that PCA improved 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic cell loss. Moreover, PCA increased the expressions of PLK2, p-GSK3β and Nrf2, following the decrease of α-synuclein (α-Syn) in MPTP-intoxicated mice. Cell viability was increased and the apoptosis rate was reduced by PCA in 1-methyl-4-phenylpyridinium iodide (MPP+)-incubated cells. Mitochondrial membrane potential (MMP), mitochondrial complex I activity and reactive oxygen species (ROS) levels in MPP+-incubated cells were also ameliorated by treatment with PCA. The neuroprotective effects of PCA were abolished by inhibition or knockdown of PLK2, whereas overexpression of PLK2 strengthened the protection of PCA. Furthermore, GSK3β and Nrf2 were involved in PCA-induced protection. These results indicated that PCA has therapeutic effects on PD by the PLK2/p-GSK3β/Nrf2 pathway.

Protective effects of irigenin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity through regulating the Keap1/Nrf2 pathway

“…Activation of Nrf2 signaling by a novel compound ITC‐3 inhibited oxidative stress and inflammation, abolished motor deficits and provided neuroprotection in a MPTP‐elicited animal model of PD (Lee et al, 2015). Hydralazine and protocatechuic aldehyde exerted neuroprotection in MPTP‐ or MPP + ‐induced PD models at least partially by activation of Nrf2 pathway (Guo et al, 2019; Guo et al, 2019). Indole derivative NC001‐8 showed a neuroprotective effect through activation of the Nrf2 antioxidative pathway in PD cell models (Wei et al, 2019).…”

PLK2 protects retinal ganglion cells from oxidative stress by potentiating Nrf2 signaling via GSK‐3β

“…Notably, upregulation of PLK2 enhances cell survival under conditions of oxidative stress. [ 18,23 ] Our data showed that PLK2 overexpression suppressed ROS production in H 2 O 2 ‐stimulated RGCs, whereas PLK2 knockdown produced opposite effects. These data indicate that PLK2 plays a key role in regulating cellular antioxidant capacity of RGCs under conditions of oxidative stress.…”

“…Previous studies have reported that PLK2 enhances Nrf2 activation through the regulation of GSK‐3β phosphorylation. [ 18,23 ] We then assessed the role of PLK2 in regulating GSK‐3β phosphorylation in H 2 O 2 ‐stimualted RGCs. We found that PLK2 overexpression dramatically elevated the levels of GSK‐3β phosphorylation in H 2 O 2 ‐stimualted RGCs (Figure 4A,B), whereas PLK2 knockdown had an opposite effect (Figure 4C,D).…”

Chinese Medicine PaBing-II Protects Human iPSC Derived Dopaminergic Neurons from Oxygen Stress

“…In the central nervous system cells, such as dopaminergic neurons, astrocytes, and microglia, Nrf2 maintains the redox balances through the up-regulation of antioxidant gene expression [23]. Previous researches have veri ed that Nrf2 mostly translocates to the nucleus in the dopaminergic neurons in the substantia nigra of PD patients, while it is present in the cytoplasm in the matched normal control group of the same age [16,24,25]. Besides, studies have also demonstrated that overexpression of Nrf2 can reduce the damage of 6-OHDA in dopaminergic neurons [19,26].…”