Abstract
CSP-1103 (formerly CHF5074) has been shown to reverse memory impairment and reduce amyloid plaque as well as inflammatory microglia activation in preclinical models of Alzheimer’s disease. Moreover, it was found to improve cognition and reduce brain inflammation in patients with mild cognitive impairment. Recent evidence suggests that CSP-1103 acts through a single molecular target, the amyloid precursor protein intracellular domain (AICD), a transcriptional regulator implicated in inflammation and apoptosis. We here tested the possible anti-apoptotic and neuroprotective activity of CSP-1103 in a cell-based model of post-ischemic injury, wherein the primary mouse cortical neurons were exposed to oxygen-glucose deprivation (OGD). When added after OGD, CSP-1103 prevented the apoptosis cascade by reducing cytochrome c release and caspase-3 activation and the secondary necrosis. Additionally, CSP-1103 limited earlier activation of p38 and nuclear factor κB (NF-κB) pathways. These results demonstrate that CSP-1103 is neuroprotective in a model of post-ischemic brain injury and provide further mechanistic insights as regards its ability to reduce apoptosis and potential production of pro-inflammatory cytokines. In conclusion, these findings suggest a potential use of CSP-1103 for the treatment of brain ischemia.
Highlights
IntroductionThere are no clinically effective therapies for stroke recovery, and current treatments offer only limited benefits, making ever more urgent the need to develop new therapies
Stroke is one of the major causes of mortality and disability worldwide [1]
A secondary necrosis was revealed by the progressive release of cellular lactate dehydrogenase (LDH) that became clearly detectable in the culture medium 24 h after the oxygen-glucose deprivation (OGD) [22,23]
Summary
There are no clinically effective therapies for stroke recovery, and current treatments offer only limited benefits, making ever more urgent the need to develop new therapies. Apoptosis and necrosis are key mechanisms that lead to cell death after cerebral ischemia. In the ischemic core in particular, most of the cells die of necrosis, while apoptosis is mainly involved with the penumbra, the border of the ischemic area, where the levels of energy and oxygen are sufficient to support apoptotic processes [2,3,4]. CSP-1103 (1-(3 ,4 -dichloro-2-fluoro (1,1 -biphenyl)-4-yl)-cyclopropanecarboxylic acid) is an orally bioavailable, brain penetrating, non-steroidal anti-inflammatory drug (NSAID) derivative with markedly reduced cyclooxygenase (COX) inhibitory activity [9], in contrast to classic NSAIDs such as ibuprofen, in development for the treatment of Alzheimer’s disease (AD) and other neurodegenerative disorders by CereSpir Incorporated
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