Xenon prevents early neuronal loss and neuroinflammation in a rat model of traumatic brain injury

Traumatic brain injury (TBI) is a complex and heterogeneous disorder. Potentially preventable ‘secondary injury’ develops after trauma and is believed to underlie the functional impairments seen in TBI patients. Current TBI treatment is mainly supportive and no specific neuroprotective drugs are available. Over-activation of N-methyl-d-aspartate (NMDA) receptors after TBI is thought to play a crucial role in secondary injury development. Xenon, a general anaesthetic and a competitive inhibitor at the glycine site of the NMDA receptor,1 is neuroprotective in models of brain ischaemia. We recently showed that xenon was neuroprotective after TBI in mice.2 3 In this work, we evaluate xenon's short-term neuroprotective efficacy using the reproducible and well-established controlled cortical impact TBI model. Adult Sprague–Dawley male rats (n=22) were fixed in a stereotactic frame under anaesthesia and underwent a right parietal cortical impact. Sham animals underwent an identical procedure, but no craniotomy or impact was done. The core body temperature was maintained at 37°C throughout using a feedback-controlled heating pad. Animals were randomly assigned to control (75% N2:25% O2) or xenon treatment groups (50% Xe:25% O2, balanced with N2). Treatment was given for 3 h, starting 30 min after TBI. Histological outcomes were measured at 15 min (contusion volume) and 24 h (contusion volume, neuronal and microglial cell count) by researchers blinded to treatment. Statistical significance was assessed with Kruskal–Wallis test, except for the contusion volume and secondary injury volume, where a Mann–Whitney test was used. Xenon reduced secondary injury development by 34% at 24 h after injury. In control TBI animals, neuronal cell number was significantly decreased in the ipsilateral retrosplenial cortex and contralateral motor cortex (P<0.05), and microglial cells were significantly increased in the ipsilateral somatosensory cortex (P<0.01) at 24 h. Interestingly, neuronal cell counts in xenon-treated animals were no different to uninjured shams, and microglial cell proliferation was reduced when compared with control animals. Our results show for the first time xenon neuroprotection after TBI in rats. We demonstrate that xenon treatment after TBI prevents neuronal cell loss and reduces inflammation in functionally relevant brain regions. These findings support the idea that xenon can be a realistic first-line treatment for patients with blunt TBI. MRC (MR/N0277361/1), NIAA, AAGBI, ESA, The Gas Safety Trust, Royal British Legion Centre for Blast Injury Studies, Royal Centre for Defence Medicine. References1.Dickinson R, Peterson BK, Banks P, et al. Anesthesiology 2007; 107: 756–672.Campos-Pires R, Armstrong S, Sebastiani A, et al. Crit Care Med 2015; 43: 149–583.Campos-Pires R, Hirnet T, Valeo F, et al. Br J Anaesth 2019; 123: 60–73