Neuroprotective Mechanism of DMF/MMF Associated with CAA-Related Pathology After TBI
Abstract
The goal is to investigate the potential intervention and mechanism to limit cerebral amyloid angiopathy (CAA) complications following traumatic brain injury (TBI). CAA is characterized by infiltration of the brains blood vessels with amyloid and has been reported to be an independent risk factor for Alzheimer’s disease (AD) and dementia. The overlap between classic AD and vascular brain pathology in dementia has been difficult to separate, given that both are associated with aging and the relative risk of dementia for those with CAA has been difficult to ascertain. The overall objectives are to determine the impact of CAA after TBI in at-risk models and test potential intervention to prevent such complications. Thus, the proposal has wide spectrum impact with potential benefits to the military, Veteran, and civilian communities. CAA and neurological deficits are some of the commonly reported problems associated with TBI and are likely exacerbated following TBI. After trauma, some endogenous repair/processes are initiated. One such mechanism includes Nrf2-dependent pathway. This transcriptional factor, Nrf2, a known key intracellular regulator, up-regulates a significant number of endogenous antioxidant and anti-inflammatory proteins. Since TBI is a complex neurodegenerative condition, using a unidirectional therapy, for example, using only a free radical scavenger or an anti-inflammatory agent alone is likely not sufficient to significantly disrupt the pathophysiological cascades following TBI. Most researchers adhere to the idea that devastative secondary injury cascade can be interrupted through a multifaceted pharmacological intervention. Since Nrf2 exhibit such multifaceted neuroprotective effects, we will use fumaric acid esters (di- and monomethyl fumarate; DMF and MMF) as Nrf2 activator. Given the significant reported differences between DMF and its metabolite MMF, comparisons between DMF and MMF need to be investigated. Our recent results show that DMF and Nrf2 are most effective in various acute brain injury models. DMF not only alleviates oxidative stress and inflammation, but also improves cell/tissue repaired/survival in central nervous system injuries. Preclinical studies raised questions, and it is unclear whether DMF has superior beneficial effects over MMF or vice versa. Thus, the proposal is aimed towards the identifying novel therapeutic targets and mechanisms of the pathogenesis. The overall rationale is that the effect of fumaric acid esters (DMF/MMF) on the CAA outcomes after TBI is postulated to be positive, though several discrepancies remain. Optimizing their respective effectiveness in both acute severe and mild repetitive head trauma is essential for the design of optimal clinical trials. Nrf2 is one of the master regulators of redox and inflammation. DMF and its metabolite MMF hold anti-oxidative and anti-inflammatory by activating Nrf2, and has been approved for multiple sclerosis and psoriasis. Thus, we expect that understanding the unique and respective roles of DMF and MMF on Nrf2 on CAA neuroprotection after TBI and it would strengthen their potential use in for the veterans and active military people. Preclinical studies raised questions, and it is unclear whether DMF has superior beneficial effects over MMF or vice versa. Furthermore, whether the therapeutic window would defer from acute TBI over a repetitive concussion like brain insults leading to CAA needs to be tested. Considering these knowledge gaps, it is essential to determine the optimal DMF and MMF therapeutic regiment and validate their respective effectiveness in CAA models. Aim 1: To determine whether DMF/MMF treatment attenuates CAA-like neurobehavioral and pathophysiological outcomes following TBI. Aim 2: To test whether the DMF/MMF-associated CAA neuroprotective mechanisms after TBI are mediated through the Nrf2 upregulation, using global Nrf2-/-. Aim 3: To further address which bra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910606
Entities
People
- Sylvain Doré
Organizations
- United States Army
- University of Florida