Metabolism and inflammation: implications for traumatic brain injury therapeutics

ABSTRACT

Introduction: Traumatic Brain Injury (TBI) is a leading cause of death and disability in young people, affecting 69 million people annually, worldwide. The initial trauma disrupts brain homeostasis resulting in metabolic dysfunction and an inflammatory cascade, which can then promote further neurodegenerative effects for months or years, as a ‘secondary’ injury. Effective targeting of the cerebral inflammatory system is challenging due to its complex, pleiotropic nature. Cell metabolism plays a key role in many diseases, and increased disturbance in the TBI metabolic state is associated with poorer patient outcomes. Investigating critical metabolic pathways, and their links to inflammation, can potentially identify supplements which alter the brain’s long-term response to TBI and improve recovery.

Areas covered: The authors provide an overview of literature on metabolism and inflammation following TBI, and from relevant pre-clinical and clinical studies, propose therapeutic strategies.

Expert opinion: There is still no specific active drug treatment for TBI. Changes in metabolic and inflammatory states have been reported after TBI and appear linked. Understanding more about abnormal cerebral metabolism following TBI, and its relationship with cerebral inflammation, will provide essential information for designing therapies, with implications for neurocritical care and for alleviating long-term disability and neurodegeneration in post-TBI patients.

KEYWORDS:

• Inflammation
• lactate pyruvate ratio (LPR)
• metabolic dysfunction
• metabolism
• supplementation
• traumatic brain injury (TBI)

Article highlights

• Traumatic Brain Injury patients have no standard therapies to address the metabolic or inflammatory effects of their disease in the short or long term.

• Metabolic dysfunction – identified by a high lactate/pyruvate ratio despite adequate brain glucose and oxygenation, has been characterized as occurring in a subset of patients.

• Inflammatory system activation can continue for months or years post-TBI, needing both acute and long-term pharmacological interventions. Inflammation immediately post-TBI is difficult to manage due to complex pleiotropic nature of the signaling molecules, cytokines, and chemokines.

• Links between inflammatory cell actions and their metabolism have been found in cell culture models of neuronal and non-neuronal cells. The further study of these links in both single cell and ‘whole brain’ is needed to tease out the specific metabolism/inflammation pathways and links.

• Metabolic supplementation is a potential to impact on inflammation and solve the energy crisis in the brain. Glucose control is important for clinical outcome, although strict control of such levels increase metabolic crisis. Succinate has potential to ameliorate metabolic stress, however, only in adequately oxygenated environments. Other supplementation candidates are also emerging, yet further research is needed.

Declaration of interest

PJA Hutchinson is a Director of Technicam, which manufactures a triple lumen cranial access device used for microdialysis catheter insertion. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

MJ Killen is supported through a Cambridge Australia Oliphant Scholarship in partnership with the Cambridge Trust while S Giorgi-Coll is supported by National Institute for Health Research Biomedical Research Centre, Cambridge. Furthermore, PJA Hutchinson has received support from: a National Institute for Health Research (NIHR) Research Professorship, an Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and the National Institute for Health Research Biomedical Research Centre, Cambridge while KLH Carpenter is supported by the National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Finally, the authors declare that their cerebral metabolism studies were funded by the Medical Research Council (Grant No. G1002277, ID98489) while their cytokine studies were supported by a joint Medical Research Council/Royal College of Surgeons of England Clinical Research Training Fellowship (G0802251), which was awarded to A Helmy.