Arundic Acid (ONO-2506) Ameliorates Delayed Ischemic Brain Damage by Preventing Astrocytic Overproduction of S100B

Abstract

After focal cerebral ischemia, the infarct volume increases rapidly within acute infarct expansion (initial 12 to 24 h) and continues slowly during delayed infarct expansion (25 to 168 h). While acute infarct expansion represents progressive necrosis within the ischemic core, delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border, which gradually coalesces to form a larger infarct. Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events. Specifically, the calcium binding protein S100B exerts detrimental effects on cell survival through activation of various intracellular signaling pathways, resulting in altered protein expression. Arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506] is a novel agent that inhibits S100B synthesis in cultured astrocytes. In the rodent ischemia model, this agent was shown to inhibit both the astrocytic overexpression of S100B and the subsequent activation of signaling pathways in the peri-infarct area. Concurrently, delayed infarct expansion was prevented, and neurologic deficits were promptly ameliorated. The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression.

Targeting Astrocytes for Stroke Therapy

“…In this screening, AA was found to effectively diminish expression and release of S-100␤ in astrocyte cultures. 13 Rodent stroke models confirmed that AA diminished S-100␤ abundance in CSF 24 hours after permanent focal ischemia or transient focal ischemia models in rodents, when administered immediately after stroke. 77 Immediate treatment with AA also diminished ischemic stroke volume and improved functional outcome 7 days after stroke onset.…”

“…Several expert reviews discuss these numerous aspects of astrocyte function and death during stroke. 4,[7][8][9][10][11][12][13][14][15] Here, we will briefly review mechanisms of astrocyte cell death during stroke, but focus most of the discussion on the adaptive and pathological roles of astrocytes during ischemia. Where applicable, we will discuss the potential for targeting astrocyte function to reduce cell death during stroke and so improve functional recovery.…”

“…27 When ischemia was applied for a longer time frame (90 minutes), however, the infarct damage was maximal within 24 hours after stroke. 27 More typically, a delayed increase in stroke volume is much more subtle or absent in rodent models 13,28,29 ; however, a notable increase in infarct growth may be observed when neuroprotective mechanisms are impaired in the brain, an illustration of the tenuous nature of cell viability in the penumbra. 28,29 Factors such as the presence of edema, peri-infarct depolarizations, 30 -32 inflammatory changes, [33][34][35] or the amount of collateral blood flow likely determine the fate of the penumbra.…”

“…In addition, expression and release of neuroprotective or harmful substances in response to ischemia are also likely determinants of cell death. 13,29,35 Given that astrocytes modulate blood flow, contribute to water homeostasis, participate in inflammatory responses, maintain ion homeostasis, and release a number of substances that may be either neuroprotective or harmful, they undoubtedly contribute to determining the viability of this vulnerable tissue.…”

“…For example, release of potentially toxic factors (e.g., S-100␤) or participation in inflammatory processes could contribute to stroke growth. 13 After some ischemic insults, such as permanent MCAO and transient global ischemia, reactive astrocytes express inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO), a known neurotoxin. 36 The induction of iNOS occurs within a time frame when delayed growth in infarct volume is typically observed.…”