Dl‑butylphthalide inhibits rotenone‑induced oxidative stress in microglia via regulation of the Keap1/Nrf2/HO‑1 signaling pathway

Abstract

Activated microglia are a source of superoxide which often increases oxidative stress in the brain microenvironment, increase production of reactive oxygen species (ROS) and directly or indirectly lead to dopaminergic neuronal death in the substantia nigra. Thus superoxide contributes to the pathogenesis of Parkinson's disease (PD). Evidence suggests that mitochondria are the main source of ROS, which cause oxidative stress in cells. Levels of ROS are thus associated with the function of the mitochondrial complex. Therefore, protecting the mitochondrial function of microglia is important for the treatment of PD. Dl-butylphthalide (NBP), a compound isolated from Chinese celery seeds, has been approved by the China Food and Drug Administration for the treatment of acute ischemic stroke. Recently, NBP demonstrated therapeutic potential for PD. However, the mechanism underlying its neuroprotective effect remains unclear. The present study aimed to investigate the effect of NBP on rotenone-induced oxidative stress in microglia and its underlying mechanisms. The results demonstrated that NBP treatment significantly increased mitochondrial membrane potential and decreased ROS level in rotenone-induced microglia. Western blot analysis showed that NBP treatment promoted entry of nuclear respiratory factor-2 (Nrf2) into the nucleus, increased heme oxygenase-1 (HO-1) expression and decreased the level of the Nrf2 inhibitory protein, Kelch-like ECH-associated protein 1. Overall, the findings indicated that NBP inhibited rotenone-induced microglial oxidative stress via the Keap1/Nrf2/HO-1 pathway, suggesting that NBP may serve as a novel agent for the treatment of PD.

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

“…For example, rotenone (Rot), a mitochondria complex I inhibitor, can induce excessive ROS generation and lead to severe oxidative stress, which is a causative factor of PD [13,14]. Rot induces liquefaction necrosis and selective DA cell degeneration in the midbrain [15,16]. 1-Methyl-4phenyl-1,2,3,6-tetrafluoropyridine (MPTP) can also cause oxidative stress and is commonly used as an inducer of PD in experimental models, especially in vivo [17].…”

Vincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson's disease through the NF‐κB and Nrf2/HO‐1 signaling pathways

“…[ 60 ] Luo et al clarified that Dl‐butylphthalide treatment substantially reduced ROS levels, elevated mitochondrial membrane potential, and mitigated oxidative stress in rotenone‐induced microglia through activating the Keap1/Nrf2/HO‐1 signaling, showing its potential in treating PD. [ 61 ] Since vincamine was previously shown to improve kidney functions and ameliorate oxidative damage in animal models of cisplatin‐induced acute kidney injury by facilitating the Nrf2/HO‐1 pathway activation, [ 37 ] we subsequently evaluated the regulation of vincamine on oxidative stress and Nrf2/HO‐1 pathway in PD mice. We confirmed that MPTP‐induced decrease in SOD activity and GSH level, increase in ROS production and MDA level, and reduction in phosphorylated Nrf2 and HO‐1 levels was abrogated by vincamine treatment, indicating vincamine‐induced alleviation on oxidative stress through activating Nrf2/HO‐1 pathway in PD.…”

Effect of Dl-3-n-Butylphthalide on olfaction in rotenone-induced Parkinson’s rats

“…Moreover, NBP can exert dopaminergic neuroprotection by inhibiting microglia-mediated neuroinflammation, suggesting that NBP has a good therapeutic effect on PD ( 20 ). Thus, NBP may be a new PD treatment drug ( 21 ). It is believed that more human clinical trials will be conducted to verify the safety and effectiveness of NBP in the treatment of PD in the near future.…”