Abstract
Astrocytes display regenerative potential in pathophysiologic conditions. In our previous study, heme oxygenase-1 (HO-1) promoted astrocytic mitochondrial functions in mice via the peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α) pathway on administering Korean red ginseng extract (KRGE) after traumatic brain injury (TBI). In this study, KRGE promoted astrocytic mitochondrial functions, assessed with oxygen consumption and adenosine triphosphate (ATP) production, which could be regulated by the translocase of the outer membrane of mitochondria 20 (Tom20) pathway with a PGC-1α-independent pathway. The HO-1–Tom20 axis induced an increase in mitochondrial functions, detected with cytochrome c oxidase subunit 2 and cytochrome c. HO-1 crosstalk with nicotinamide phosphoribosyltransferase was concomitant with the upregulated nicotinamide adenine dinucleotide (NAD)/NADH ratio, thereby upregulating NAD-dependent class I sirtuins. In adult neural stem cells (NSCs), KRGE-treated, astrocyte-conditioned media increased oxygen consumption and Tom20 levels through astrocyte-derived HO-1. HO inactivation by Sn(IV) protoporphyrin IX dichloride in TBI mice administered KRGE decreased neuronal markers, together with Tom20. Thus, astrocytic HO-1 induced astrocytic mitochondrial functions. HO-1-related, astrocyte-derived factors may also induce neuronal differentiation and mitochondrial functions of adult NSCs after TBI. KRGE-mediated astrocytic HO-1 induction may have a key role in repairing neurovascular function post-TBI in peri-injured regions by boosting astrocytic and NSC mitochondrial functions.
Highlights
Korean red ginseng extract (KRGE)-Induced the outer membrane of mitochondria 20 (Tom20) Is Coexpressed with Astrocytes in the Peri-Injured Regions of KRGE was administered with drinking water for 3 days in 8-week-old mice with or without traumatic brain injury (TBI) (Figure 1a)
At approximately bregma −1 to −2, the levels of protein (e.g., heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), Tom20, and proliferator-activating receptor-γ coactivator-1α (PGC-1α)) associated with mitochondrial functions were upregulated in peri-injured mouse brains subjected to KRGE administration after TBI
Nrf2 is an upstream factor for HO-1 [19]; we explored the impact of Nrf2 knockdown on protein levels of HO-1, Tom20, and PGC-1α by KRGE in oxygen–glucose deprivation (OGD)/R conditions (Figure 1f)
Summary
In central nervous system (CNS) injuries, Korean red ginseng extract (KRGE) and its components (e.g., ginsenoside) have favorable effects on neurovascular regeneration and anti-inflammation [1]. Several ginsenosides have improved behavior in animal models of neurological deficits [1]. Ginsenoside Rg1 is involved in neurotrophic factor-mediated adult hippocampal neurogenesis and exhibits antidepressant activity [2]. Ginsenoside Rb1 may be protective against traumatic brain injury (TBI) by enhancing the gap junction [3]
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