Helping the Traumatized Brain Help Itself: A Novel Approach to the Restoration of Post TBI Brain Energy Metabolism
Abstract
Traumatic brain injury (TBI) results in a profound and prolonged disturbance in cellular brain energy metabolism that includes a depletion in the critical cellular substrate adenosine triphosphate (ATP), the primary energy source used by all brain cells. This ATP depletion is compounded by the loss of ATP metabolites necessary for ATP synthesis, such as adenosine, inosine, and hypoxanthine, from the brain into the blood and cerebrospinal fluid, and also by mitochondrial dysfunction. The post-TBI limitation of the brain to generate ATP contributes to acute and protracted brain energy metabolic impairment, giving rise to cell death and tissue loss in the immediate aftermath of TBI. Furthermore, the energy deficit leaves the brain vulnerable to TBI-associated secondary injuries including hypoxia, increased intracranial pressure, spreading depolarizations and seizure activity. These secondary sequelae are further drains on the brain's impoverished energy supply and contribute to worsening of clinical condition and prognosis. While previous approaches have targeted mitochondria through the provision of alternative fuel substrates such as lactate and pyruvate, recent studies suggest age-, time- and sex-dependent effects of these molecules, complicating the treatment algorithm under austere conditions. Moreover, they do not address the underlying issue of the depletion of the molecules necessary to create the ATP backbone. Here, we propose to provide the ATP precursor molecules, ribose and adenine, and allopurinol (RibAdeAll) acutely after TBI, to enhance the brain's ability to synthesize its own ATP. Importantly, these compounds are all clinically approved and used in different clinical contexts. Our previous data has shown that ribose and adenine restore cellular ATP levels to values found in vivo after an in vitro model of brain injury.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1216554
Entities
People
- Aviva J Symes
- Ibrahim Sartaj
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine