First Description of Reduced Pyruvate Dehydrogenase Enzyme Activity Following Subarachnoid Hemorrhage (SAH)

Abstract

Object: Several previous studies reported metabolic derangements and an accumulation of metabolic products in the early phase of experimental subarachnoid hemorrhage (SAH), which may contribute to secondary brain damage. This may be a result of deranged oxygen utilization due to enzymatic dysfunction in aerobic glucose metabolism. This study was performed to investigate, if pyruvate dehydrogenase enzyme (PDH) is affected in its activity giving further hints for a derangement of oxidative metabolism.Methods: Eighteen male Sprague-Dawley rats were randomly assigned to one of two experimental groups (n = 9): (1) SAH induced by the endovascular filament model and (2) sham-operated controls. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local cerebral blood flow (LCBF; laser-Doppler flowmetry) were continuously monitored from 30 min before until 3 h after SAH. Thereafter, the animals were sacrificed and PDH activity was measured by ELISA.Results: PDH activity was significantly reduced in animals subjected to SAH compared to controls.Conclusion: The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage.

Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage: an [18F]FDG-PET study over 7 days using an MRI-template based analysis tool

“…with dichloroacetate (DCA) or entering "new fuel" to the TCA cycle e.g. via acetyl-L-carnitine (ALCAR) could have neuroprotective effect and attenuate or prevent from secondary brain injury following aSAH 12 . Finally, mitochondrial dysfunction following aSAH is shown to activate the autophagy of neuronal cells, possibly leading to early brain injury and DCI 37 .…”

“…Several mechanisms during the acute phase of SAH contribute to DCI and poor outcome. These include neuroin ammation, microthrombosis, cortical spreading depolarizations, disrupted blood-brain barrier (BBB) integrity, microvascular dysfunction and metabolic derangement [9][10][11][12] .…”

Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH)

“…One or more steps of this energy metabolism pathway seem to be disturbed. In this context, Lilla et al demonstrated for the first time a reduction in pyruvate dehydrogenase (PDH) activity following aSAH, independent of the supply of substrates [ 9 ]. As PDH is the key enzyme of the citric acid cycle, its activity reduction could be an independent factor contributing to a derangement of oxidative metabolism, a failure of oxygen utilization and secondary brain damage.…”

“…While the underlying mechanism is not cleared up yet, it may be worth having a closer look at the cellular level of metabolic disturbances. As Lilla et al suggested, the inactivation of PDH could play a critical role in EBI after aSAH, so that preventing this inactivity may act as a neuroprotective factor [ 9 ]. Dichloroacetate (DCA) is a small molecule that crosses the BBB and stimulates PDH activity by the inhibition of PDH kinase [ 177 ].…”

“…Several mechanisms during the acute phase of SAH contribute to DCI and poor outcome. These include neuroinflammation, microthrombosis, cortical spreading depolarizations, disrupted integrity of the blood–brain barrier (BBB), microvascular dysfunction and metabolic derangement [ 6 , 7 , 8 , 9 ].…”