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

TBCLipids have essential structural roles in the central nervous system [CNS]. CNS injury induces
an activation of processes which destabilise membrane lipids such as the
glycerophospholipids, and induces deleterious oxidative changes [Nessel and Michael-Titus,
2021]. Lipid destabilisation is a consequence of the activation of phospholipases. It has been
suggested by us and others that inhibition of phospholipases could limit the impact of CNS
injury [Huang et al 2009; Sarkar et al; 2020]. However, there is still incomplete understanding
of the role of specific phospholipases and of changes in glycerophospholipids post-injury and
during recovery. Injury can also trigger tissue oxidation which induces chain-reaction
processes and large-scale membrane deterioration. Oxidation and neuroinflammation
synergise and increase tissue damage. The recent availability of deuterated lipids has made
it 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 specific
phospholipases, and 2. Use of deuterated fatty acids to block oxidation. The model used will
be a brain injury by cortical impact in mice and rats. We will determine lipid/metabolomic
changes ex vivo in tissue and assess in vivo cerebral metabolism and neuroinflammation
[Tremoleda et al., 2016] using imaging, and neurological outcome. We will characterize the
impact of cytosolic phospholipase A2, using selective inhibitors -collaboration Prof Matthias
Lehr, Germany - as compared with the use of an inhibitor with limited selectivity, e.g.
arachidonyl trifluoromethylketone, used previously. We will also analyse the oxidation of
tissue lipids and intervene post-injury with a partial replacement of dietary fatty acids with
deuterated forms and study the impact on recovery.
Professor Michael-Titus has expertise in neurotrauma and in particular the use of fatty acids
for protection and repair. Dr Lopez-Tremoleda has expertise in imaging.