Broadly Neuroprotective Drug for TBI

Summary

Principal Investigator: Fernando Gomez Pinilla
Abstract: DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (15) Translational Science, and Specific Challenging Topic 15-NS-103 as our proposal is a "Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. The application may also apply to the Broad Challenge Area (03) Biomarkers discovery and validation, and Specific Challenging Topics: 03-NS-102 Standardization and validation of neurological biomarkers, as we are examining levels of BDNF and synaptic plasticity markers that can be implemented as biomarkers for traumatic brain injury 03-DK-105 Nutrient biomarkers, as our proposal is related to the identification and validation of sensitive and predictive biomarkers to evaluate status of a specific nutrient (curcumin derivative). Traumatic brain injury (TBI) affects more than 1,500,000 Americans every year, making TBI one of the most common causes of disability for the general population. The treatment of TBI is exceptionally complex as TBI can result from a large variety of insults and mechanisms to broad brain areas that compromise neural function with long-term cognitive implications. Therefore, proper treatment of TBI should require therapies that can properly address the multiple weaknesses, particularly those related to long-term neuronal function and plasticity underlying the cognitive and behavioral impairment. To address the need for broadly neuroprotective drugs, we have identified a potent synthetic derivative of curcumin, namely CNB-001, that may comprehensively normalize several of the neuronal processes that are disrupted after TBI. The natural product curcumin, which is the precursor of CNB-001, has shown excellent efficacy in counteracting dysfunction in several models of neurodegenerative diseases such as Alzheimer's, cerebral ischemia, promoting neurogenesis in the adult hippocampus, and in our hands, counteracting learning impairment resulting after TBI. CNB-001 has the advantage to be several times more potent than curcumin, orally active with rapid absorption into the blood and to the brain. CNB-001 has both neuroprotective and neuronal function enhancing properties, suggesting CNB-001 as a unique candidate drug for treating TBI and other neurodegenerative disorders. To assay the efficacy of our compound CNB-001, we will use the fluid percussion injury model (FPI) for TBI that produces a closed head wound characterized by marked physiological changes with a relative paucity of histological damage under moderate injury. The goal of this project is to explore the therapeutic potential of CNB-001 for TBI and to determine potential mechanisms for these actions. Specifically, we will evaluate the ability of CNB-001 supplemented in the diet to restore synaptic plasticity and energy metabolism disrupted after TBI, in conjunction with CNB-001 effects on counteracting cognitive, mood disorders, and motor dysfunction. It is noteworthy that our comprehensive study of CNB-001 efficacy considers the analysis of motor behavior beyond the brain. Our preliminary data are very exciting to demonstrate that CNB-001 counteracts a reduction in BDNF levels in the spinal cord after TBI. These data are very exciting and relevant to help understanding gait dysfunction common in TBI patients, and offering the possibility for developing a therapy. In addition, given preliminary evidence showing the potential of CNB-001 to affect BDNF activity, and the capacity of BDNF to modulate synaptic plasticity and energy metabolism, we will evaluate the role of BDNF mediating some of the actions of CNB-001. We will study molecular mechanisms in conjunction with their relationship to behavior, expecting to provide evidence for applying CNB-001 as a therapeutic for treating TBI patients. Based on all above consideration, our specific challenges are: 1) to develop a clinically effective drug for treating TBI with the capacity to protect neurons to damage in response to multiple stresses, and to support synaptic function and energy supply to cells;2) to deliver the drug to the brain in a minimally invasive fashion for optimal applicability even before the insult/challenge. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the therapeutic potential of a broad-spectrum drug for TBI and to determine its potential mechanisms using fluid percussion injury model in rats. We have a comprehensive approach to evaluate the ability of CNB-001 to restore synaptic plasticity and energy metabolism in conjunction with counteracting dysfunction in cognition, mood, and locomotion, in the brain and spinal cord. We expect to generate valuable pre-clinical information that will entitle us to initiate the steps for seeking IND approval.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing
    Q Ding
    Department of Integrative Biology and Physiology, UCLA Brain Injury Research Center, University of California, Los Angeles, CA 90095, USA
    Neuroscience 192:773-80. 2011
  2. pmc The influence of exercise on cognitive abilities
    Fernando Gomez-Pinilla
    Department of Integrative Biology and Physiology, UCLA and Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, California, USA
    Compr Physiol 3:403-28. 2013
  3. pmc A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma
    Sandeep Sharma
    Department of Integrative Biology and Physiology, University of California, LA, CA 90095, USA
    Exp Neurol 226:191-9. 2010
  4. pmc The combined effects of exercise and foods in preventing neurological and cognitive disorders
    Fernando Gomez-Pinilla
    Dept of Integrative Biology and Physiology, and Dept of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA
    Prev Med 52:S75-80. 2011
  5. pmc Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma
    Aiguo Wu
    University of California at Los Angeles, Los Angeles, CA, USA
    Neurorehabil Neural Repair 25:332-42. 2011
  6. pmc The influence of naturalistic experience on plasticity markers in somatosensory cortex and hippocampus: effects of whisker use
    Fernando Gomez-Pinilla
    Department of Integrative Biology and Physiology, UCLA Brain Injury Research Center, University of California, Los Angeles, CA 90095, USA
    Brain Res 1388:39-47. 2011
  7. pmc The influence of dietary factors in central nervous system plasticity and injury recovery
    Fernando Gomez-Pinilla
    Department of Neurosurgery, University of California Los Angeles Brain Injury Research Center, Los Angeles, CA 90095, USA
    PM R 3:S111-6. 2011

Scientific Experts

Detail Information

Publications7

  1. pmc Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing
    Q Ding
    Department of Integrative Biology and Physiology, UCLA Brain Injury Research Center, University of California, Los Angeles, CA 90095, USA
    Neuroscience 192:773-80. 2011
    ..These results indicate that the effects of exercise on hippocampal plasticity are dependent on BDNF processing and subsequent TrkB signaling, with important implications for neuronal function...
  2. pmc The influence of exercise on cognitive abilities
    Fernando Gomez-Pinilla
    Department of Integrative Biology and Physiology, UCLA and Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, California, USA
    Compr Physiol 3:403-28. 2013
    ..Therefore, exercise and dietary management appear as a noninvasive and effective strategy to counteract neurological and cognitive disorders...
  3. pmc A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma
    Sandeep Sharma
    Department of Integrative Biology and Physiology, University of California, LA, CA 90095, USA
    Exp Neurol 226:191-9. 2010
    ....
  4. pmc The combined effects of exercise and foods in preventing neurological and cognitive disorders
    Fernando Gomez-Pinilla
    Dept of Integrative Biology and Physiology, and Dept of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA
    Prev Med 52:S75-80. 2011
    ..New evidence indicates that exercise, in combination with dietary factors, exerts its effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity...
  5. pmc Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma
    Aiguo Wu
    University of California at Los Angeles, Los Angeles, CA, USA
    Neurorehabil Neural Repair 25:332-42. 2011
    ..Moreover, there are no current efficient treatments that can counteract the broad pathology associated with TBI...
  6. pmc The influence of naturalistic experience on plasticity markers in somatosensory cortex and hippocampus: effects of whisker use
    Fernando Gomez-Pinilla
    Department of Integrative Biology and Physiology, UCLA Brain Injury Research Center, University of California, Los Angeles, CA 90095, USA
    Brain Res 1388:39-47. 2011
    ..The critical action of experience on molecular substrates of plasticity seems to provide molecular basis for the design of experienced-based rehabilitative strategies to enhance brain function...
  7. pmc The influence of dietary factors in central nervous system plasticity and injury recovery
    Fernando Gomez-Pinilla
    Department of Neurosurgery, University of California Los Angeles Brain Injury Research Center, Los Angeles, CA 90095, USA
    PM R 3:S111-6. 2011
    ..Therefore, exercise and dietary management appear as a noninvasive and effective strategy to help counteract neurologic and cognitive disorders...