Assessment of Functional Recovery and Reduced Tauopathy Following ALPHA-1062 Administration in a Repetitive Blast TBI Model in Rodents
Abstract
Traumatic brain injury (TBI) is a significant health concern among the general population and is an especially important health problem for U.S. military Service Members and Veterans. For Veterans of Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OED/OND), TBI accounts for the majority of combat casualties, with more than 85% diagnosed as mild-TBIs (mTBIs). Importantly, unlike civilians (including sports-related mTBIs), the vast majority of mTBIs among OIF/OED/OND Veterans are associated with exposure to high explosive detonations. Mild TBI due to blast has been termed the signature injury of OEF/OIF/OND. An assessment of 350,000 U.S. Veterans found that mTBI, most often resulting from blast injury, was associated with more than a two-fold increase in the risk of dementia diagnosis in later life. While blast exposure can be accompanied by impact to the head (e.g., flying shrapnel) and/or the head being propelled into other objects (e.g., ground or side of a vehicle), the intense primary supersonic shock waves generated by high explosives are also a source of injury to the brain, which is the case for the majority of Service Members and Veterans with mTBI. Compared to blunt impact-induced neurotrauma, blast-induced mTBI represents a distinct means of imparting injury. A growing body of evidence shows that aspects of the neuropathological lesions associated with blast also differ from those caused by repetitive impact mTBI. Thus, it is important that any clinical intervention aiming to treat mTBI in Service Members and Veterans be tested in the context of blast-induced mTBI. Regardless of the means by which the brain is injured (blast and/or impact) there is ample evidence proving that pathogenic processes are set in motion that are not easily arrested and lead to chronic behavioral and neurological problems. Scientists and physicians continue to grapple with questions about which aspects of mTBI best correspond to other neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and other brain diseases. Nonetheless, a strong case can be made that drugs originally tailored to treat AD need to be better investigated for their potential to treat mTBI. Over decades, a vast enterprise to find new treatments for AD has sadly met with limited success and a newly U.S. Food and Drug Administration (FDA)-approved treatment remains controversial. However, embedded within this long train of disappointment remain a number of positive results. One of them is galantamine, which is an acetylcholinesterase inhibitor (AChEI) that improves cognitive function and slows cognitive decline. While effective in treating dementia symptoms, galantamine is not without its limitations and drawbacks, which include common gastrointestinal side effects such as nausea, vomiting, and diarrhea. The considerations outlined above leads us to propose a novel set of experiments that will address the preclinical efficacy of a newly developed modified form of galantamine called ALPHA-1062. ALPHA-1062 gets into the brain more easily and by bypassing the gastrointestinal tract, possesses fewer side effects than standard oral galantamine. In this project, we will use a well-established, battlefield relevant mouse model of blast-induced mTBI to determine whether ALPHA-1062 reduces the cognitive, behavioral, and neuropathological consequences of repetitive blast exposure. Currently, there are no good pharmacologic treatments for those with blast-related mTBI. Successful completion of the aims of this project will greatly facilitate the path toward approval to test ALPHA-1062’s ability to prevent the cognitive and behavioral effects of mTBI and to prevent neurodegeneration in humans, and thereby offer new hope for those with Service-related mTBI. Reducing the neuropathology associated with mTBI offers the potential that the later life consequence of increased dementia risk will also be reduced.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310552
Entities
People
- Denis Kay
Organizations
- Seattle Institute for Biomedical and Clinical Research
- United States Army