PDE2a inhibition as a therapeutic target for the chronic effects of repetitive mild TBI

James A. Haley Va Medical Center, Tampa FL

Investigators

Abstract

Among surviving soldiers wounded in Iraq and Afghanistan, TBI accounts for a larger proportion of casualties (> 22%) than in other recent US wars, and accounts for a large proportion of the acute and long-term combat casualty care burden. The military loses thousands of man-years in experience, each year due to the effects of TBI in soldiers, including those prematurely returned to active duty as well as soldiers who cannot return to service and add to the already heavy burden on the VA healthcare system. Many young adults never regain premorbid skills or responsibilities after TBI despite intensive and comprehensive rehabilitation efforts on their behalf. The sequelae of TBI are a mixture of cognitive psychomotor and emotional (psychiatric) signs and symptoms, and the emotional and psychological burden on patients and caregivers can be enormous. Repetitive mild TBI (r-mTBI) is one of the most devastating outcomes of the recent conflicts. The diversity of etiology of human TBI poses problems for identification of valid therapeutic targets and the relevance of preclinical models is key. There is a clear need for improved and increased modeling of r-mTBI in the laboratory, to enable the dissection and evaluation of TBI-dependent molecular responses and identification of better approaches to mitigate the negative outcomes. We have developed several different mouse models of repetitive mild TBI, with different neurobehavioral, neuropathological and biochemical outcomes. They recapitulate features of human TBI and our clinical collaborators consider them to be of relevance as translational platforms. We have pioneered assessment at chronic timepoints, and delayed treatment approaches in order to better model the human situation. Our overarching hypothesis is that treatments showing efficacy with late treatment initiation in multiple different r-mTBI models will have most potential in clinical translation to address the vast heterogeneity inherent in the human r-mTBI patient population. We have recently completed a VA RR&D funded project in which we demonstrated improved neurobehavioral and neuropathological outcomes in two different mouse models of r-mTBI following delayed treatment with the anti-inflammatory compound anatabine. We also demonstrated positive outcomes in one of these models with immediate treatment with the putative anti-Alzheimer therapeutic Nilvadipine. Proteomic analysis on the brains of these mice identified phosphodiesterase 2a (PDE2a) as a critical molecule in r-mTBI pathogenesis, which was significantly upregulated in response to r-mTBI, as were PDE2a-containing molecular signaling pathways such as cAMP-mediated signaling and Protein Kinase A signaling. cAMP and cGMP mechanisms have both been identified as potential targets for Alzheimer’s Disease and related disorders, but have not previously been specifically addressed in relation to r-mTBI. Treatment with either anatabine or nilvadipine resulted in decreased expression of r-mTBI- induced PDE2a and/or mitigation of the r-mTBI-induced effects on the PDE2a signaling pathways. In a pilot study conducted since the original submission we have now demonstrated that PDE2a inhibition mitigates the subacute behavioral, biochemical and pathological consequences of r-mTBI. Thus, in this new project, we will focus on PDE2a inhibition to treat the chronic effects of r-mTBI. We will use two different mouse models – a 5 hit paradigm over 9 days (5r-mTBI) and a 20 hit paradigm over 28 days (20r-mTBI), all injuries being the same mild TBI administered on the midline of a closed skull. Using a well-characterized PDE2a inhibitor, we will determine if inhibition of PDE2a mitigates the chronic neurobehavioral, neuropathological and biochemical consequences of r-mTBI, as well as the most effective administration paradigms, and through single cell transcriptomic analyses we will identify specific mechanisms of action for PDE2a which will provide additional potential therapeutic targets.