Neuroprotection by quercetin via mitochondrial function adaptation in traumatic brain injury: PGC-1α pathway as a potential mechanism

Abstract

The aim of this study was to investigate the neuroprotective effects of quercetin in mouse models of traumatic brain injury (TBI) and the potential role of the PGC-1α pathway in putative neuroprotection. Wild-type mice were randomly assigned to four groups: the sham group, the TBI group, the TBI+vehicle group and the TBI+quercetin group. Quercetin, a dietary flavonoid used as a food supplement, significantly reduced TBI-induced neuronal apoptosis and ameliorated mitochondrial lesions. It significantly accelerated the translocation of PGC-1α protein from the cytoplasm to the nucleus. In addition, quercetin restored the level of cytochrome c, malondialdehyde and superoxide dismutase in mitochondria. Therefore, quercetin administration can potentially attenuate brain injury in a TBI model by increasing the activities of mitochondrial biogenesis via the mediation of the PGC-1α pathway.

Keywords: PGC-1α; mitochondria; neuroprotection; quercetin; traumatic brain injury.

Figure 1

Brain water content was examined at 1 day after TBI. Brain water content was significant lower in the groups with administration of quercetin (20, 50, 100 mg/kg) than vehicle‐treated group. Data are presented as mean ± S.E.M., *P < 0.05, **P < 0.01 versus sham group; ^# P < 0.05, ^### P < 0.001 versus TBI + vehicle group.

Figure 2

Apoptotic index was determined using TUNEL assays 1 day after TBI. Quercetin treatment significantly decreased the percentage of apoptotic cells after TBI(A‐E). Data are presented as mean ± S.E.M.; **P < 0.01 versus sham group; ^# P < 0.05 versus TBI + vehicle group.

Figure 3

Quercetin promoted translocation of PGC‐1α from cytoplasm to nucleus and enhanced PGC‐1α binding. (A‐D) The representative photomicrographs showing PGC‐1α immunohistochemistry of tissue from different group 24 hrs after TBI. (E, H) The nuclear PGC‐1α expression after quercetin treatment in mice with TBI, as measured by Western blot. (F, I) The cytoplasmic protein PGC‐1α expression after quercetin treatment in mice with TBI, as measured by Western blot. (G, J) The total protein PGC‐1α expression after melatonin treatment in mice with TBI, as measured by Western blot. Bars represent the mean ± S.E.M. *P < 0.05, **P < 0.01 and ***P < 0.001 compared with the sham group; ^# P < 0.05 compared with the TBI + vehicle group. Black arrows: PGC‐1α‐positive neuron cell.

Figure 4

The representative photomicrographs showing caspase‐3 immunohistochemistry of tissue from different group 1 day after TBI (A‐D, F). Except that, effect of quercetin on cleaved caspase‐3 expression in cortical neural cells in a mice model of TBI was assessed by Western blot analysis (E, G). Data are presented as mean ± S.E.M. *P < 0.05, **P < 0.01 versus. sham group; ^# P < 0.05 versus TBI + vehicle group. Black arrows: caspase‐3‐positive neuron cell.

Figure 5

Effect of quercetin on pro‐apoptotic protein expression was assessed following TBI. (A, B) The expression of Bax and cytochrome c in the ipsilateral cortex was evaluated by Western blotting 24 hrs after injury. Representative blots show the relative expression of (C, E) mitochondrial and (D, F) cytosolic Bax and cytochrome c. Expression was normalized to the level of COX IV or β‐actin. Data represent the mean ± S.E.M. (n = 6 per group). **P < 0.01, ***P < 0.001 versus sham group; ^# P < 0.05, ^## P < 0.05 versus TBI.

Figure 6

Quercetin attenuated mitochondrial oxidative stress caused by TBI. (A) Measurements of MDA levels (n = 6 per group). (B) The activities of SOD. Data represent the mean ± S.E.M. **P < 0.01, ***P < 0.001 versus sham group; ^# P < 0.05, ^## P < 0.01 versus TBI+vehicle.