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, 225 (2), 391-401

Beneficial Effects of Sodium or Ethyl Pyruvate After Traumatic Brain Injury in the Rat

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Beneficial Effects of Sodium or Ethyl Pyruvate After Traumatic Brain Injury in the Rat

Nobuhiro Moro et al. Exp Neurol.

Abstract

Sodium pyruvate (SP) treatment initiated within 5 min post-injury is neuroprotective in a rat model of unilateral cortical contusion injury (CCI). The current studies examined: (1) effects of delayed SP treatments (1000 mg/kg, i.p., at 1, 12 and 24h), (2) effects of single (1h) or multiple (1, 12 and 24h) ethyl pyruvate treatments (EP; at 20 or 40 mg/kg, i.p.), and (3) mechanisms of action for pyruvate effects after CCI. In Experiment 1, both SP and EP treatment(s) significantly reduced the number of dead/dying cells in the ipsilateral hippocampus (dentate hilus+CA3(c) and/or CA3(a-b) regions) at 72 h post-CCI. Pyruvate treatment(s) attenuated CCI-induced reductions of cerebral cytochrome oxidase activity at 7 2h, significantly improving activity in peri-contusional cortex after multiple SP or EP treatments. Optical density measures of ipsilateral CD11b immuno-staining were significantly increased 72 h post-CCI, but these measures of microglia activation were not different from sham injury values in SP and EP groups with three post-CCI treatments. In Experiment 2, three treatments (1, 12 and 24h) of SP (1000 mg/kg) or EP (40 mg/kg) significantly improved recovery of beam-walking and neurological scores in the first 3 weeks after CCI, and EP treatments significantly improved spatial working memory 1 week post-CCI. Ipsilateral CA3(b) neuronal loss, but not cortical tissue loss, was significantly reduced 1 month post-CCI with pyruvate treatments begun 1h post-CCI. Thus, delayed pyruvate treatments after CCI are neuroprotective and improve neurobehavioral recovery; these effects may be mediated by improved metabolism and reduced inflammation.

Figures

Fig. 1
Fig. 1
Panel A illustrates the contoured areas used for counts of Fluoro-Jade B (FJB)-positive neurons in the CA3a-b and hilus+CA3c (combined PoDG plus CA3c regions). Also shown in panel A are the contour sites used for counts of lateral and medial CA3b neurons and PoDG neurons (excluding the CA3c) at one month post-surgery. Panels B and C illustrate data (mean ± SEM) for FJB-positive cells in the left/ipsilateral CA3a-b (B) and hilus+CA3c (C) at 72 h after cortical contusion injury (CCI) and treatment with either vehicle (Veh), sodium (SP) or ethyl pyruvate (EP). CCI groups (n=7/group) denoted in the legend box and panels B and C were treated post-injury as follows: CCI-Veh = Ringer's at 1, 12 and 24 h; CCI-SP 1000×3 = SP (1000 mg/kg) at 1, 12 and 24 h; CCI-EP 20×1 = EP (20 mg/kg) at 1 h; CCI-EP 40×1 = EP (40 mg/kg) at 1 h; CCI-EP 20×3 = EP (20 mg/kg) at 1, 12 and 24 h; CCI-EP 40×3 = EP (40 mg/kg) at 1, 12 and 24 h. Both SP and EP decreased the number of dead/dying hippocampal neurons, with dose-dependent neuroprotection apparent for the EP treatments. *: p<0.05, **: p<0.01, ***: p<0.001 compared to CCI-Veh group.
Fig. 2
Fig. 2
Immuno-staining of CD11b-positive microglia in the ipsilateral dorsal hippocampus (lateral CA3 region), 72 h after sham or cortical contusion injury (CCI) and treatments (at 1, 12 and 24 h) of either vehicle (Veh), sodium (SP, 1000 mg/kg) or ethyl pyruvate (EP, 40 mg/kg). In the Sham-Veh group CD11b-positive cells exhibited morphology characteristic of resident microglia (A), whereas staining characteristics of activated microglia were observed in the CCI-Veh group (B). CD11b-positive cells of the CCI-SP (C) or CCI-EP (D) treatment groups showed some morphology characteristic of stimulated or activated microglia, but the density of immuno-staining was reduced compared to the CCI-Veh group (see Table 2). Inserts in each panel are higher magnification images of cells within that panel. Scale bars: panels = 100 μm; inserts = 20 μm.
Fig. 3
Fig. 3
Mean (± SEM) beam-walk ratings for rats (n=7/group) after sham or cortical contusion injury (CCI) and treatments (at 1, 12 and 24 h) of either vehicle (Veh), sodium (SP, 1000 mg/kg) or ethyl pyruvate (EP, 40 mg/kg). The initial beam-walking deficits induced by CCI were equivalent in all groups. The recovery of beam-walking ability in the CCI-SP and CCI-EP groups was significantly improved compared to the spontaneous recovery rate seen in CCI-Veh controls. *: p<0.05 compared to CCI-Veh group.
Fig. 4
Fig. 4
Mean (± SEM) neurological scores of rats (n=7/group) with sham or cortical contusion injury (CCI) and treatments (at 1, 12 and 24 h) of either vehicle (Veh), sodium (SP, 1000 mg/kg) or ethyl pyruvate (EP, 40 mg/kg). Equivalent worsening of the combined neuroscore occurred in all CCI groups early after injury. Both the CCI-SP and CCI-EP groups exhibited significantly better recovery from these neurological deficits than did vehicle-treated rats with CCI. *: p<0.05 compared to CCI-Veh group.
Fig. 5
Fig. 5
Percent four/five alternation scores (mean ± SEM) for groups evaluated in the plus maze one week after sham (n=7) or cortical contusion injury (CCI) and treatments (at 1, 12 and 24 h) of either vehicle (Veh, n=5), sodium (SP, 1000 mg/kg, n=6) or ethyl pyruvate (EP, 40 mg/kg, n=5). Significant working memory deficits were observed for the CCI-Veh (p<0.01) and the CCI-SP (p<0.05) groups compared to Sham-Veh controls. The EP treatments after CCI significantly improved the percent four/five alternation scores. *: p<0.05 compared to CCI-Veh group.
Fig. 6
Fig. 6
Panel A shows the mean (± SEM) area of the left cortical mantle at 500 μm intervals (1.7 to -4.8 mm relative to Bregma) at one month after sham (n=7) or cortical contusion injury (CCI) and treatments (at 1, 12 and 24 h) of either vehicle (Veh, n=7), sodium (SP, 1000 mg/kg, n=7) or ethyl pyruvate (EP, 40 mg/kg, n=7). All CCI groups had significant loss of tissue area compared to Sham-Veh controls (p<0.001), but no significant difference was observed between the CCI groups. Panel B illustrates the percent tissue volume loss (mean ± SEM) in the left/injured cortex [100-((Left/Right) × 100)]. All CCI groups showed significant volume loss compared to the Sham-Veh group (p<0.001). Both the CCI-SP and CCI-EP groups showed slightly less volume loss that the CCI-Veh group, but these reductions were not significant.

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