Dynamics of lipids and cerebral metabolism after injury and during recovery in the central nervous system

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TBCLipids have essential structural roles in the central nervous system [CNS]. CNS injury inducesan activation of processes which destabilise membrane lipids such as theglycerophospholipids, and induces deleterious oxidative changes [Nessel and Michael-Titus,2021]. Lipid destabilisation is a consequence of the activation of phospholipases. It has beensuggested by us and others that inhibition of phospholipases could limit the impact of CNSinjury [Huang et al 2009; Sarkar et al; 2020]. However, there is still incomplete understandingof the role of specific phospholipases and of changes in glycerophospholipids post-injury andduring recovery. Injury can also trigger tissue oxidation which induces chain-reactionprocesses and large-scale membrane deterioration. Oxidation and neuroinflammationsynergise and increase tissue damage. The recent availability of deuterated lipids has madeit possible to investigate the impact of blocking oxidation through their use as antioxidants -results reported in neurodegeneration models are promising [Raefsky et al, 2018].We will focus on: 1. Changes in glycerophospholipids and targeting of specificphospholipases, and 2. Use of deuterated fatty acids to block oxidation. The model used willbe a brain injury by cortical impact in mice and rats. We will determine lipid/metabolomicchanges ex vivo in tissue and assess in vivo cerebral metabolism and neuroinflammation[Tremoleda et al., 2016] using imaging, and neurological outcome. We will characterize theimpact of cytosolic phospholipase A2, using selective inhibitors -collaboration Prof MatthiasLehr, Germany - as compared with the use of an inhibitor with limited selectivity, e.g.arachidonyl trifluoromethylketone, used previously. We will also analyse the oxidation oftissue lipids and intervene post-injury with a partial replacement of dietary fatty acids withdeuterated forms and study the impact on recovery.Professor Michael-Titus has expertise in neurotrauma and in particular the use of fatty acidsfor protection and repair. Dr Lopez-Tremoleda has expertise in imaging.