The role of Lysophosphatidic Acid in Traumatic Brain Injury outcomes
- Author(s): McDonald, Whitney S.;
- Advisor(s): Harris, Neil G;
- et al.
Over a century of research efforts have been devoted to developing a therapy to recover loss of function after Traumatic Brain Injury (TBI). Despite these efforts there is still no FDA approved treatment that promotes functional recovery after injury. Every year, millions of new TBI cases occur and many TBI patients have persistent loss of motor and cognitive function leaving them incapable of living independent of caregivers. There is an urgent need for a novel therapeutic that addresses the functional loss after TBI and anti-LPA therapeutic may prove effective in this regard. Progression of secondary injuries like excitotoxicity and inflammation is predictive of functional outcomes for TBI patients. Lysophosphatidic Acid (LPA) signaling is a potent mediator of the above secondary injures, despite these facts, no study has identified the role of LPA in outcomes after TBI in the adult. Fundamental issues regarding LPAs metabolic changes in the brain after injury, the effects of LPA signaling on neuroregeneration after TBI and ultimately whether intervening with Anti-LPA after TBI improves outcomes and functional recovery, require resolution in order to utilize LPA as a therapeutic target for TBI. The work herein is aimed toward gaining a more comprehensive understanding of the effects of LPA metabolism and signaling in TBI and to identify the effects of blocking LPA on injury outcomes.
The first study identified the spatial and temporal profile of LPA metabolism in the injured brain and associated those changes with markers of axonal injury (Beta-APP) and cell death (Fluro-JadeB) using MALDI mass spectrometry techniques. Within 3 hour after TBI there was an enhancement of LPAs bioactive unsaturated species, as well as an increase in LPAs intra- and extra-cellular precursors at the injury epicenter in association with blood. LPA metabolism was also increased in distal regions of the brain, throughout the white matter tracts and in the cerebellum. Intracellular precursor, PA, was increased in the peri-contusional cortical grey matter and ipsilateral thalamus within 1 hour after injury and intracellular LPA increased in at 3 hours after injury in association with neuronal death markers. Pronounced expression of LPA 20:1 species was observed in the sub-cortical white matter which correlated significantly with the spatial distribution of axonal injury marker beta-APP. The data provided evidence of an increase in bioactive phospholipid metabolism throughout the brain within 3 hour of injury and associated those changes with necrosis and axonal injury. The study also identified a critical window of intervention, to potentially attenuate the increase in LPA signaling. The data suggested that LPA metabolism is involved in the early pathogenic cascades of TBI.
The second study identified the effects of a one-time dose of Anti-LPA at 2 hours after injury, on secondary injury outcomes to underlie functional decline: cell death, axonal injury and inflammation. Anti-LPA intervention resulted in a reduction of white matter damage and inflammation, but had no significant neuroprotective effects and anti-inflammatory effects in the grey matter. Furthermore, anti-LPA treatment significantly improved sensorimotor function with some behavioral scores being insignificantly different from that of uninjured sham. The result suggested that a one-time dose of Anti-LPA reduces axonal injury and white matter inflammation but is insufficient on neuroprotection of the cortical grey matter. Since grey matter pathology is sensitive even to mild changes in the brain, additional treatments of Anti-LPA may be needed to provide adequate neuroprotective effects. Nevertheless, a one-time treatment of anti-LPA improved sensorimotor outcomes, likely through white matter preservation. Data obtained in parallel studies suggest a potential neurogenic mechanism may also be involved in improving outcomes.
The final study identified the effects of Anti-LPA treatment on the endogenous neurogenic response of the sub-ventricular zone (SVZ) and cortex to injury with a thymidine analog-labeling paradigm to identify acutely dividing cells between 1 and 7 days post injury (DPI) and the long-term fate of early dividing cells at 14 and 28 DPI. Anti-LPA treatment enhanced SVZ neurogenesis and reduced DCX+ neuroblasts populations in the cortex within 7 days of injury. However, at 28 days of injury there was a significant enhancement of dividing neuroblasts in the cortex of anti-LPA treated mice as compared to the vehicle group, with migratory patterning similar to neuroblast response in the uninjured sham group. Furthermore, there was enhanced neurogenesis with Anti-LPA treatment as characterized by NeuN+ dividing cells in the cortex although not statistically significant at 28 DPI. Lastly, at 28 DPI there was marked reduction in SVZ neuroblast populations as well as a reduction in activated microglia as characterized by morphology of Iba1+ cells. The results provide evidence of the potent effects of LPA signaling on acute and long-term neurogenic response of the cortex and SVZ. The results demonstrate that blocking post-injury LPA signaling enhances cortical survival of immature neurons likely by reducing long-term cortical excitotoxicity and consequently suggest that Anti-LPA intervention may enhance neurogenesis. Lastly, Anti-LPA treatment after injury acts as a potent anti-inflammatory in the SVZ, which correlated with a reduction in SVZ response at 28 DPI. Additional work on the dosage effects of Anti-LPA on outcomes and the longer-term effects of Anti-LPA treatment on neurogenesis is needed. However, the results herein provide significant evidence of Anti-LPA intervention as a potentially effective treatment that improves functional outcomes after TBI.