Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy

A Bainbridge, I Tachtsidis, S D Faulkner, D Price, T Zhu, E Baer, K D Broad, D L Thomas, E B Cady, N J Robertson, X Golay, A Bainbridge, I Tachtsidis, S D Faulkner, D Price, T Zhu, E Baer, K D Broad, D L Thomas, E B Cady, N J Robertson, X Golay

Abstract

Background: Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy ((31)P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and (31)P metabolite peak-area ratios during and after transient cerebral hypoxia-ischemia (HI) in the newborn piglet.

Methods: Twenty-four piglets (aged<24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~20 min). Whole-brain (31)P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by (31)P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp=exchangeable phosphate pool=Pi+PCr+2γ-NTP+β-NTP).

Results: During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between (31)P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and (31)P ratios 1h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] -0.29 ± 0.50 μM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] -2.41 ± 1.48 μM).

Conclusions: Both lowered Δ[oxCCO] and NTP/epp 1h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and (31)P ratios by 1 h after HI.

Keywords: (31)P; Cytochrome-c-oxidase; Hypoxia–ischemia; MRS; NIRS; Phosphorus.

© 2013.

Figures

Fig. 1
Fig. 1
31P MRS metabolite ratios and NIRS measurements plotted against time for each piglet: a) NTP/epp, b) Pi/epp, c) PCr/epp, d) Δ[oxCCO], e) Δ[Hbtot] and f) Δ[Hbdiff]. Data from all animals are shown. The mean time at which point ANTP is reached is shown in each plot by the line marked A (see the section “Relationships between Δ[oxCCO] and MRS measures during initial HI and titration” and Fig. 2). The mean time at which HI was ended and the recovery period began is shown on each plot by the line marked B.
Fig. 2
Fig. 2
Correlations between 31P metabolite ratios and Δ[oxCCO]. (a) NTP/epp plotted against Δ[oxCCO] during HI (all data shown; different symbols for individual piglets). The relationship between NTP/epp and Δ[oxCCO] is similar for all piglets but for low NTP/epp the Δ[oxCCO] distribution clearly separates. (b) An example of a double-linear fit of an individual piglet. (c and d) NTP/epp and Pi/epp respectively plotted against Δ[oxCCO] − A (see Eq. (1)). Point A for each plot is now at 0 and all data are plotted on the same axes with group-mean data shown (thick black line). (e) PCr/epp vs Δ[oxCCO] − ANTP. (f) ANTP plotted against APi with the linear regression line shown. Independently fitted ANTP is similar to APi.
Fig. 3
Fig. 3
MRS ratios plotted against Δ[oxCCO] during Recovery. Data from all animals are shown. Data are stratified according outcome. Plots a (NTP/epp), c (Pi/epp) and e (PCr/epp)show data from those animals that survived to 48 h. Plots b (NTP/epp), d (Pi/epp) and f (PCr/epp) show data from animals that died before 48 h. Dark lines on each plot are overall linear regression lines calculated using data from all animals. Recovery slopes are significantly less steep for piglets dying before 48 h.

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