Repurposing of R-etodolac for Alzheimer's disease and related disorders

Repurposing of R-Etodolac for Alzheimer’s Disease and Related Disorders Summary The deposition of amyloid-β (Aβ) in cerebrovasculature can result in blood-brain barrier (BBB) dysfunction and the development of cerebral amyloid angiopathy (CAA). CAA is a pathological feature that presents concomitantly with Alzheimer’s disease (AD) at a high frequency, highlighting a potentially important role for vascular Aβ in AD. Currently, no treatment is available to slow or hold the progression of CAA or AD. Recent in vitro and in vivo findings from our laboratory demonstrated that treatment with etodolac, a non-steroidal anti- inflammatory drug (NSAID) used to treat pain and arthritis, restored the BBB function and rectified Aβ toxic effects. However, the long-term use of NSAIDs, especially in the elderly, is not recommended because of toxicities resulting from cyclooxygenase (COX) inhibition. Etodolac is a racemic drug with the S-enantiomer responsible for COX2 inhibition associated with adverse effects. R-etodolac, on the other hand, lacks the COX2-inhibitory effect. Thus, R-etodolac has the potential advantage of avoidance of COX2 inhibitory adverse effects observed with racemic etodolac. Preliminary in vitro data demonstrated that, like racemic etodolac, both enantiomers upregulate tight and adherens junction proteins, which are essential for BBB integrity. However, only R-etodolac upregulates β-catenin, which is required for full cellular control of endothelial permeability and junction stabilization. Based on these findings, this proposal aims to delineate the COX2-independent effect of R-etodolac on endothelium-BBB model integrity and function (R61 phase), and in vivo on BBB function, brain Aβ accumulation and related pathology, and memory function (R33 phase). We hypothesize that R-etodolac attenuates vascular Aβ pathogenesis by restoring the BBB function. In phase 1 (R61, Aim 1), we will investigate and compare the in vitro potency of racemic, R- and S-enantiomers of etodolac to improve the function of a cell- based endothelium-BBB model with Aβ pathology. Concentration-dependent studies will be performed to assess the compounds' effects on the endothelium-BBB model permeability and Aβ clearance, RNA transcriptional changes, and R-etodolac pharmacokinetics and brain disposition. In phase 2 (R33, Aim 2), we will investigate the in vivo efficacy of orally administered R-etodolac to rectify BBB integrity, improve learning and memory and reduce Aβ deposition and related pathology in a transgenic mouse model of CAA/AD. Following treatments, mice will be assessed for cognitive performance using a battery of cognitive tasks, for alterations in BBB permeability using gadolinium contrast agent magnetic resonance imaging (Gd-MRI), and for alterations in biomarkers of Aβ-related pathology. Successful completion of the project will pave the way for the repurposing of R-etodolac as a novel molecule to prevent and/or slow the progression of CAA and AD that can be rapidly translated to the clinic. The results will have a significant positive impact as R-etodolac does not possess COX2- mediated adverse effects making it safe to use for long term by the elderly.