Pyruvate dehydrogenase phosphatase1 mRNA expression is divergently and dynamically regulated between rat cerebral cortex, hippocampus and thalamus after traumatic brain injury: A potential biomarker of TBI-induced hyper- and hypo-glycaemia and neuronal vu

Cerebral pyruvate depletion and lactate acidosis are common metabolic characteristics of patients with traumatic brain injury (TBI) and are associated with poor prognosis. Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme coupling glycolysis to mitochondrial tricarboxylic acid (TCA) cycle. Brain PDH activity is regulated by its phosphorylation status and other effectors. Phosphorylation of PDH E1α1 subunit by PDH kinase inhibits PDH activity while dephosphorylation of phosphorylated PDHE1α1 by PDH phosphatase (PDP1) restores PDH activity. In situ hybridization showed that PDP1 mRNA is highly expressed in the cerebral cortex, hippocampus and thalamus of rat. Controlled cortical impact (CCI) induced a significant increase in PDP1 mRNA expression in ipsilateral cerebral cortex at 4 h (P < 0.05) and 24 h post CCI (P < 0.01) that returned to basal level 72 h post CCI. PDP1 mRNA level increased transiently in ipsilateral hippocampal dentate gyrus and CA1-3 subfields 4 h post CCI (P < 0.01) but decreased significantly 24 h and 72 h (P < 0.01) post CCI, coinciding with a marked increase in neuronal apoptosis in ipsilateral hippocampus 24 h post CCI. PDP1 mRNA expression in thalamus and other subcortical regions decreased persistently post CCI. Contralateral CCI and craniotomy showed similar effects on PDP1 mRNA expression as ipsilateral CCI. Because GFAP mRNA expression was induced in brain regions where PDP1 expression was altered, further study should determine the potential relationship between astrocyte activation, PDP1 alteration, and pyruvate metabolism following TBI.

► Dysregulated glucose metabolism is a serious problem in patients with severe TBI.
► PDH is a key enzyme coupling glycolysis to mitochondrial oxidative phosphorylation.
► PDH phosphatase1 (PDP1) restores PDH activity by catalyzing PDH dephosphorylation.
► TBI induced divergent alteration of PDP1 mRNA in rat cerebral cortex, hippocampus and thalamus.
► PDP1 dysregulation could be linked with energy metabolism in TBI.