Traumatic brain injuries (TBIs) constitute a significant and growing percentage of injuries in the veteran population; sequelae of explosions, motor vehicle accidents and falls. TBI is also a major cause of death and disability in the general population of the US, particularly in those under 40. Approximately 2% of the population is living with a chronic TBI-related disability. There are currently no effective protective or restorative therapies available clinically. In severl models of CNS trauma, administration of a neurotrophin (e.g. BDNF, NGF) protects tissues acutely and promotes longer term recovery. However, the neurotrophins are poor drugs as they are labile, exhibit poor CNS penetration and may augment cell death and pain pathways. These properties are due to their polypeptide composition and the stimulation of intersecting signalling pathways through the activation of multiple receptors. These problems may be at least partially circumvented through the use of recently discovered small, stable, non-peptidyl drug-like compounds (designated LM22) that promote neuronal survival through selective interactions with the Trk neurotrophin receptors (LM22A-4 with TrkB and LM22B-10 with TrkB and TrkC). The compounds inhibit neuronal death, promote neural progenitor cell proliferation and differentiation and augment functional and morphologic neuroplasticity. We hypothesize that the LM22 compounds will: increase neural progenitor survival and differentiation through distinct mechanisms involving activation of specific Trk-coupled survival and differentiative signalling pathways; that increasing TrkB signaling following TBI will promote early neuronal and neural progenitor survival and longer term plasticity, with effects on neuronal processes and spines; that activation of TrkB and TrkC together will be more effective than either alone, and; that while the compounds should improve behavioral outcomes, prolonged or excessive increased plasticity may be detrimental.
Specific Aims are to: 1. Determine LM22 compound effects on hippocampal progenitors in vitro: A) Examine the effects of LM22A-4 and LM22B-10 on proliferation, survival, neuro- and/or gliogenic differentiation and morphology of hippocampal neural progenitor cells in vitro, in comparison with neurotrophin protein ligands; B) determine the Trk specificity of the compounds for these effects using selectively inhibitable tyrosine kinase mutants of TrkB, TrkC or both receptors and; C) determine the role of PI3K/AKT, ERKs 1, 2 and 5, PLC, miRNA9 and NRSF/REST in compound effects, using selective chemical inhibitors, miRNA-mediated downregulation and viral construct-mediated enforced expression; 2. Determine LM22 compound effects on cellular responses relative to dose and timing of administration in the rat controlled cortical impact (CCI) model of TBI: assess A) neuronal and neural progenitor cell death; B) Trk activation and downstream signaling; C) neuro/gliogenesis and neuronal morphology and; D) inflammation, and; 3. Determine LM22 compound effects on behavior following rat CCI: Examine A): spatial/hippocampal memory (Morris Water Maze); B) anxiety/depression (open field testing, elevated plus maze) and; C) motor learning (rotorod/gait analysis) These studies will provide information important for the eventual application of these or related compounds to clinical head trauma, and will advance our knowledge of the roles of TrkB and TrkC in pathologic states. The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions.
Brain injuries constitute a significant and perhaps growing percentage of injuries in modern combat and the veteran population, due to explosions, motor vehicle accidents and falls. Current therapies have limited effectiveness, and new pharmacologic and cell-based approaches are needed. This proposal, to test a two promising new nerve cell-survival-promoting compounds (called LM22A-4 and LM22B-10) in models of brain trauma addresses this need directly. The proposed experiments will determine whether delayed-early treatment is effective, and whether treatment long after the injury will improve symptoms. In addition, they will provide insight into the question of whether the compound's main effects are due to improving cell survival, increasing regeneration or both and examine some of the mechanisms of these effects. If the results are positive, treatment with compounds of this type could represent an important advance in the development of new therapies for preserving and recovering tissue and function following brain trauma.
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