Traumatic Brain Injury
Victims of Traumatic Brain Injury come from all ages and sectors of society, from football players to marines to victims of car accidents, to divers. Very little headway has been made when it comes to treating traumatic brain injury, and preventing it from getting worse.
The expression of the ASPA gene is pivotal for both Canavan patients and traumatic brain injury patients. Thus, adjusting the expression of the ASPA gene is key to stopping further neurodegenerative damage in both TBI patients and Canavan Patients. Developing a neuroprotective therapy in a model of TBI by expressing ASPA in neurons (normally only expressed in oligos) in order to provide an unlimited source of NAA, or better its metabolites such as acetate and aspartate in neurons to fuel mitochondrial function when needed. In other words, create NAA in order to give energy to the brain to fuel its work.
More on the relationships between TBI+ Canavan:
N-acetylaspartate (NAA) is one of the most abundant brain metabolites and is highly concentrated in neurons, but it remains to be determined why neurons synthesize so much of this particular acetylated amino acid. Other early investigations connected NAA to carbon transport and energy metabolism in neuronal mitochondria. Subsequently it was discovered that mutations in the gene for the enzyme that deacetylates NAA, known as aspartoacylase or ASPA, lead to the fatal neurodegenerative disorder known as Canavan disease. After more than two decades of research the precise connection between the inability to deacetylate NAA and the pathogenesis of Canavan disease remains a matter of ongoing investigation. One line of research has focused on the lack of catabolism leading to a toxic buildup of NAA in the brain as the primary etiological component. Another line of research has suggested that the lack of catabolism results in an acetate deficiency in oligodendrocytes during brain development that subsequently limits acetyl coenzyme A (acetyl CoA) availability during this critical period of myelination. There is experimental support for both mechanisms, and it is possible that both are operative.
Acetylaspartate is by far the most concentrated acetylated metabolite in the human brain, and its concentration is exquisitely responsive to brain injury. One possible explanation for the rapid and substantial drop in NAA levels immediately after injury is that NAA is providing local acetate as one of the mechanisms of response to depleted acetyl CoA that occurs due to injury-related energy depletion and metabolic depression.
Continuing work on NAA over the last two decades has focused almost exclusively on the utility of NAA measurements in various neuropathological conditions using proton magnetic resonance spectroscopy (MRS). NAA provides the largest single peak on proton MRS spectra of the healthy human brain, and brain NAA levels are found to be reduced in a majority of neuropathologies including traumatic brain injury (TBI). The loss of NAA after TBI is paralleled by a loss of ATP, acetyl CoA, and other metabolites associated with energy metabolism (Vagnozzi et al., 2007) indicating a substantial impact on neuroenergetics. The connections between NAA and brain energy metabolism are not entirely clear, but it seems likely that they involve acetyl CoA generation and utilization (Ariyannur et al., 2010a). Acetyl CoA is at the crossroads of energy derivation, storage, and utilization, and is also involved in cellular control of protein function and gene transcription through acetylation reactions. NAA is synthesized from acetyl CoA and aspartate, and because of the exceptionally high concentration in the human brain (~10 mM) some proportion of acetyl CoA must be utilized to maintain NAA levels, and that proportion may change with brain injury. Signoretti and colleagues have shown that severe brain injury results in a very rapid drop in NAA levels that is paralleled by a similar reduction in ATP levels, suggesting that NAA is utilized rapidly in response to injury. Indeed, NAA levels are reduced by over 20% within 1 min of severe TBI in rats at a time when ATP levels are only reduced by ~10% (Signoretti et al., 2001). These investigators also found that over time after injury, recovery of NAA levels “has been observed only in concert with restoration of ATP” (p. 988) further linking NAA with post-injury neuroenergetics. As such, the study of NAA metabolism may provide unique insights into how the brain’s energy systems respond to injury and recover throughout the healing process.
Traumatic brain injury results in the disruption of brain energy metabolism and the resultant energy deficit is proportional to the degree of damage (Marklund et al., 2006). The levels of NAA and ATP are reduced immediately after brain injury and remain depressed for hours, days or weeks depending on injury severity (Signoretti et al., 2001; Tavazzi et al., 2005; Vagnozzi et al., 2005; Arun et al., 2010a). These reductions are indicative of metabolic impairment and the depletion of energy stores in the brain, and it is very likely that the reduction in NAA levels is tied to the loss of the immediate precursor, acetyl CoA, after brain injury (Vagnozzi et al., 2007).
Traumatic brain injury results in disrupted lipid metabolism, oxidative damage to, and degradation of mitochondrial phospholipids (Adibhatla et al., 2006; Singh et al., 2006), damage to subcortical white matter and delayed axonal degeneration throughout the brain (Hall et al., 2005; Park et al., 2008). Because NAA-derived acetate is one of the building blocks for myelin lipid synthesis in the brain, and that NAA levels are substantially reduced after TBI, we have pursued the concept that a potent source of acetate which can cross the blood brain barrier would be useful for the treatment of brain injuries.
The exceptionally high level of NAA in the nervous system, coupled with the fact that NAA diverts some acetyl CoA from other potential uses, suggests that NAA serves as an acetyl group (carbon) storage molecule that is synthesized when glucose is in excess of minimal system needs. The stored acetate can be reclaimed by the action of ASPA, followed by the action of AceCS1 or AceCS2 to regenerate acetyl CoA. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872778/)