SUSTAIN BRAIN PROJECT- ongoing

Oral succinate administration

We are recruiting patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. Identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, we clinically classified as cerebral ‘mitochondrial dysfunction’ (MD). In patients with TBI and MD, we administer disodium succinate orally, recovering metabolites in blood serum and microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.
 

This is complimented by oral ongoing oral succinate pharmokinetics studies in healthy volunteers. 

Previous succinate studies by our group include, most recently, administered disodium 2,3-¹³C₂ succinate (12 mmol/L) by retrodialysis into the monitored region of the brain.

In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(−12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous ¹³C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.