Pyruvate treatment attenuates cerebral metabolic depression and neuronal loss after experimental traumatic brain injury

Abstract

Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000mg/kg, i.p.) or ethyl pyruvate (EP; 40mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40mg/kg of EP being as effective as 1000mg/kg of SP, and multiple treatments within 6h of injury did not improve upon outcomes seen following a single treatment.

Keywords: (14)C-2DG; Controlled cortical impact; Fluoro-Jade B; Pyruvate; Rat.

Fig. 1

Mean (bars represent SEM) asymmetry scores [((L−R)/L+R)*100] for CMRGlc in brain regions 24 h after Sham or CCI injury and a single treatment of saline (SAL), sodium pyruvate (SP) or ethyl pyruvate (EP). # p < 0.001 compared to Sham injury; ^a p < 0.05, ^b p < 0.01, ^c p < 0.001 compared to CCI-SAL.

Fig. 2

Diagram illustrating regions for counts of FJB+ neurons within the midline peri-contusional cortex (dark grey fill) and in the dorsal and ventral CA3 (light grey fill) and hilus (black fill). Numbers indicate the mm posterior to Bregma.

Fig. 3

Shows the mean (bars represent SEM) cell densities for dead/dying neurons in the left peri-contusional cortex, hilus and CA3 subsector of the hippocampus 24 h after CCI injury and a single treatment of saline (SAL), sodium pyruvate (SP) or ethyl pyruvate (EP). * p ≤ 0.05, ** p < 0.01 compared to CCI-SAL.

Fig. 4

Mean (bars represent SEM) asymmetry scores [((L−R)/L+R)*100] for CMRGlc in brain regions 24 h after Sham or CCI injury and four treatments of saline (SAL), sodium pyruvate (SP) or ethyl pyruvate (EP). SHAM denotes pooled data for Sham-SAL, Sham-SP and Sham-EP groups. # p < 0.001 compared to SHAM; ^a p ≤ 0.05, ^b p < 0.01, ^c p < 0.001 compared to CCI-SAL; ^d p < 0.05 compared to CCI-EP.

Fig. 5

Mean (bars represent SEM) cell densities for dead/dying neurons in the left peri-contusional cortex, hilus and CA3 subsector of the hippocampus 24 h after CCI injury and four treatments of saline (SAL), sodium pyruvate (SP) or ethyl pyruvate (EP). * p < 0.05, ** p < 0.01, *** p ≤ 0.001 compared to CCI-SAL.