Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.

Pretreatment with tert-butylhydroquinone attenuates cerebral oxidative stress in mice after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a worldwide health problem, identified as a major cause of death and disability. Increasing evidence has shown that oxidative stress plays an important role in TBI pathogenesis. The antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is a known mediator in protection against TBI-induced brain damage. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), a novel Nrf2 activator, can protect against TBI-induced oxidative stress. METHODS: Adult male imprinting control region mice were randomly divided into three groups: (1) sham + vehicle group; (2) TBI + vehicle group; and (3) TBI + tBHQ group. Closed-head brain injury was applied using the Feeney weight-drop method. We accessed the neurologic outcome of mice at 24 h after TBI, and subsequently measured protein levels of Nrf2 and the NOX2 subunit of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), the concentration of malondialdehyde, superoxide dismutase activity, and brain edema. RESULT: The NOX2 protein level was increased fivefold in the TBI + vehicle group, whereas pretreatment with tBHQ markedly attenuated the NOX2 protein expression relative to that in the TBI + vehicle group. TBI increased Nrf2 formation by 5% compared with the sham group, whereas treatment with tBHQ further upregulated the Nrf2 protein level by 12% compared with the sham group. The level of the oxidative damage marker malondialdehyde was reduced by 29% in the TBI + tBHQ group compared with the TBI + vehicle group, Moreover, pretreatment with tBHQ significantly increased the antioxidant enzyme superoxide dismutase activity. Administration of tBHQ also significantly decreased TBI-induced brain edema and neurologic deficits. CONCLUSIONS: Pretreatment with tBHQ effectively attenuated markers of cerebral oxidative stress after TBI, thus supporting the testing of tBHQ as a potential neuroprotectant and adjunct therapy for TBI patients.

Hemodynamic changes due to infiltration of the scalp with epinephrine-containing lidocaine solution: a hypotensive episode before craniotomy.

Epinephrine-containing lidocaine solution is commonly infiltrated on the scalp before craniotomy. But the hemodynamic changes caused by epinephrine-containing lidocaine solution have been less intensely studied. A prospective randomized double blind control study was designed to observe hemodynamic changes caused by epinephrine-containing lidocaine solution in neurosurgical operations under general anesthesia. One hundred twenty patients undergoing scheduled craniotomy were allocated randomly to 4 groups. All the patients received 1% lidocaine 16 mL with different dose (concentration) epinephrine: group 1 with 40 microg (2.5 microg/mL); group 2 with 80 microg (5 microg/mL); group 3 with 160 microg (10 microg/mL); and group 4 (control group) without epinephrine. mean arterial pressure (MAP) and heart rate were recorded at 30-second interval in 5 minutes after the beginning of local infiltration. In group 1, group 2, and group 3, the lowest MAP and the highest MAP during this period also were recorded. Bleeding was assessed after raising the craniotomy flap. Compared with the baseline, significant hemodynamic changes, particularly decrease in MAP with increase in heart rate at 1.5 minutes after the beginning of local infiltration, were observed in group 1, group 2, and group 3 (P<0.001), but not in group 4. The highest MAP increased significantly compared with the baseline in group 3 (P<0.05), but not in group 1 or group 2. Epinephrine-containing lidocaine solution reduced bleeding significantly (P<0.01). Infiltration with epinephrine-containing lidocaine solution elicits temporary but significant hemodynamic changes including hypotension before craniotomy. Commonly clinically used concentrations of epinephrine (2.5 to 10 microg/mL) can reduce the bleeding on the scalp.