Small Molecule Activators of the TRK Receptors for Neuroprotection
Posted August 24, 2011
Nicholas J. Webster, Ph.D., Veterans Medical Research Foundation of San Diego
Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity in children and young adult civilians as well as among active duty military personnel. TBI usually results in the loss of neurons within the region of the brain known as the hippocampus, an effect that can occur over a period of many days following the insult. Despite improvements in surgical treatment of the primary insult, there are currently no therapies that provide neuroprotection to mitigate this secondary or delayed damage subsequently leading to poor prognosis and chronic cognitive impairment. It is well-known that the neurotrophins acting through the nerve growth factor Trk receptors promote survival of multiple neuronal cell types and stimulate in vitro neuronal regeneration. Although preclinical and clinical findings suggest that neurotrophins are a promising therapy for TBI, they are not good drug candidates due to their poor pharmacokinetic behavior and bioavailability at the desired targets. So a lot of effort has been devoted to the search for novel small-molecule activators that will mimic the desired neuroregenerative responses of neurotrophins.
Dr. Webster, a recipient of an Intramural TBI Investigator-Initiated Research Award, is focusing on the development of neuroprotective drugs that will activate the Trk receptors to prevent the neuronal cell death following TBI and improve cognitive function. To date, Dr. Webster and his colleagues, Dr. Stan Krajewski at the Burnham Institute for Medical Research and Dr. Michael Pirrung at the University of California, Riverside, have (1) identified the lead drug, 5E5, and 38 other promising compounds based on their ability to activate the TrkB receptor, (2) completed an in vivo evaluation of the neuroprotective effects of 5E5 utilizing two mouse models of neurodegeneration, and (3) tested their lead drug 5E5 in a controlled cortical impact model for brain injury. The in vivo results indicated that treatment with 5E5 delayed the onset of cognitive impairments and improved the ability of the mice to learn spatial information when given before or after the onset of symptoms in both models of neurodegeneration. The drug also exerted a neuroprotective effect, reduced the magnitude of the brain injury as measured by a smaller contusion area, and improved motor skills in the cortical impact model of TBI. With funding from an FY09 Investigator-Initiated Research Award, Dr. Webster, Dr. Krajewski, and Dr. Pirrung will continue preclinical development studies of neuroprotective agents activating Trk receptors in the hope of identifying novel therapeutic modalities for TBI.
Link:
Technical Abstract: Small Molecule Activators of the TRK Receptors for Neuroprotection
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Virtual Reality Exposure Therapy to Battle PTSD
Posted August 16, 2011
Gregory Gahm, Ph.D., and Greg Reger, Ph.D., The Geneva Foundation
Prolonged Exposure Therapy (PE) is one of the most effective treatments for post-traumatic stress disorder (PTSD). However, PE requires the patient to revisit their traumatic memory in an emotionally engaging way. Soldiers face unique barriers to care compared to civilian populations. Following combat deployments, many Soldiers suffering from PTSD are emotionally detached and avoid the painful memories associated with the traumatic event, which can limit their ability to engage in the PE treatment process. In addition, some Soldiers report concerns about stigma associated with seeking help through traditional "talk therapies." Virtual Reality Exposure Therapy (VRET) holds the potential to provide effective therapy for PTSD and to improve access to care for Soldiers who might otherwise avoid treatment due to stigma. VR works by immersing a participant in a realistic computer-generated world that simulates the sources of combat stress. By revisiting the traumatic event in a sensory-rich environment, the investigators hypothesize that participants may experience heightened physiological arousal, and clinical outcomes may be significantly improved compared to those from traditional PE. Dr. Gregory Gahm and Dr. Greg Reger are conducting a randomized clinical trial comparing VRET to traditional PE in the treatment of combat-related PTSD in OIF/OEF Soldiers. Returning Soldiers diagnosed with PTSD will be randomized to receive 10 sessions of either VRET or PE or a waitlist control group (that will wait several weeks to be placed in a treatment group). The study will compare the efficacy of the two treatments and will also compare psychophysiological arousal during VRET and PE treatment sessions. This data will help demonstrate whether the multi-sensory nature of VRET increases arousal and whether increased arousal contributes to better treatment outcomes. Perceptions of stigma, patient satisfaction, and treatment adherence will be evaluated for the two treatments. The investigators hope that Soldiers will find the gaming aspect of VRET appealing and lessen the stigma associated with seeking help. The study is in collaboration with the Department of Psychology at Madigan Army Medical Center and is currently recruiting Soldiers from that facility. In addition, the investigators are planning to extend the study to Soldiers at Womack Army Medical Center at Fort Bragg, North Carolina.
Link:
Technical Abstract: The Army Behavioral Health Technology Office and Psychology Department at MAMC: A Tradition of Excellence in PTSD and Neuropsychological Research
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Spouse Telephone BATTLEMIND: A Telephone Support Program for Spouses to Help Soldiers Transition Home
Posted July 12, 2011
Linda Nichols, Ph.D. and Jennifer Martindale-Adams, Ed., VA Medical Center, Memphis, Tennessee
The BATTLEMIND Training System was originally developed by the Walter Reed Army Institute of Research to help soldiers reintegrate and adapt their combat skills back into civilian life. Although reintegration difficulties and mental health symptoms increase during the first year for returning veterans, face-to-face training for spouses of OEF/OIF service members has typically been offered on a one-time basis, which does not provide ongoing support as new reintegration challenges appear. Dr. Linda Nichols and Dr. Jennifer Martindale-Adams at the VA Medical Center in Memphis are expanding the Spouse BATTLEMIND training program into a year-long, telephone-based support group in order to investigate its effectiveness. The program provides telephone support group sessions to spouses that are designed to educate, build coping skills, improve access to services for veteran and family, and serve as a source of shared support. So far, 60 spouses have been enrolled in the feasibility trial, plus the recent addition of 26 Wounded Warrior Project spouses. Over the period of one year, each group of
6-10 spouses and a trained Group Leader have hour-long structured telephone sessions once a month. The content of the session includes ways the returning service member, spouse, and family may have changed during deployment, with emphasis placed on compromise and negotiation in personal relationships; strategies to reduce or eliminate reunion and reintegration difficulties; strategies to support the returning soldier; and cues to alert spouses when to seek mental health services for the soldier, children, or themselves. The investigators are evaluating participant satisfaction and changes in spouse self-report of depression, anxiety, relationship satisfaction, and family communication. If successful, the investigators hope to disseminate the program for use across the Department of Defense and the Department of Veterans Affairs. The Army's recent change from the BATTLEMIND rubric will provide more flexibility in session topics and in how sessions are scheduled, and in the future will be called Spouse READI (Resilience Education and Deployment Information.)
Link:
Public and Technical Abstracts: Reintegration: The Role of Spouse Telephone Battlemind
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