Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic–Ischemic Brain Injury

Abstract

Neonatal hypoxia–ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia–ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia–ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia–ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia–ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

“…We introduce the concept of neuroprotective effects of mitochondria-targeted plastoquinone (SkQR1), which is a conjugate of plastoquinone with decylrhodamine 19 [80]. Plastoquinone is a major quinone contained in chloroplasts and cyanobacteria and acts as an electron transfer carrier in the photosynthesis system and exerts antioxidant effects.…”

Phenolic Acids-Rich Fractions from Agaricus bitorguis (Quél.) Sacc. Chaidam ZJU-CDMA-12 Mycelia Modulate Hypoxic Stress on Hypoxia-Damaged PC12 Cells

“…Dispersion of the mitochondrial membrane potential plays an extremely important role in process of cell death or apoptosis [ 32 ]. It was reported that mitochondrial dysfunction in neurons is the major cause of hypoxia-induced brain damage, which was caused by the reduced mitochondrial transmembrane potential and elevated ROS generation [ 33 , 34 ]. Here, we found that hypoxia enhanced ROS generation and reduced the ΔΨm in PC12 cells, indicating that hypoxia induced mitochondrial damage.…”

Phytoestrogen coumestrol attenuates brain mitochondrial dysfunction and long‐term cognitive deficits following neonatal hypoxia–ischemia

“…Previous studies analyzing early consequences of HI demonstrated that the mitochondria of hippocampus cells are impaired between 2 h and 18 h after the insult (Weis et al, 2012), and that some mitochondria developed a high degree of swelling at 3 h of reflow. The mitochondrial dysfunction is associated with high production of reactive oxygen species, which leads to oxidative stress; this makes the mitochondria a prime target of antioxidant neuroprotective strategies (Blomgren and Hagberg, 2006; Skulachev et al, 2018). In present study, both HI effects were prevented by coumestrol administered pre‐hypoxia, but not post‐hypoxia (Fig.…”

“…The pathogenesis of HI is complex and several mechanisms and pathways contribute for both early and delayed brain damage. The HI insult causes mitochondrial dysfunction characterized by mitochondrial swelling and exposure of permeability transition pores, associated with high production of reactive oxygen species (ROS), which leads to oxidative stress and consequent cell death (Jiang et al, 2019; Skulachev et al, 2018). Interestingly, the male neonate's brain is more susceptible to these effects, as compared to females, as well as to greater long‐term cognitive impairments (Hill and Fitch, 2012; Netto et al, 2017; Weis et al, 2012).…”