Apoptosis: Future Targets for Neuroprotective Strategies

Abstract

Focal permanent or transient cerebral artery occlusion produces massive cell death in the central core of the infarction, whereas in the peripheral zone (penumbra) nerve cells are subjected to various determining survival and death signals. Cell death in the core of the infarction and in the adult brain is usually considered a passive phenomenon, although events largely depend on the partial or complete disruption of crucial metabolic pathways. Cell death in the penumbra is currently considered an active process largely dependent on the activation of cell death programs leading to apoptosis. Yet cell death in the penumbra includes apoptosis, necrosis, intermediate and other forms of cell death. A rather simplistic view implies poor prospects regarding cell survival in the core of the infarction and therapeutic expectations in the control of cell death and cell survival in the penumbra. However, the capacity for neuroprotection depends on multiple factors, primarily the use of the appropriate agent, at the appropriate time and during the appropriate interval. Understanding the mechanisms commanding cell death and survival area is as important as delimiting the therapeutic time window and the facility of a drug to effectively impact on specific targets. Moreover, the detrimental effects of homeostasis and the activation of multiple pathways with opposing signals following ischemic stroke indicate that better outcome probably does not depend on a single compound but on several drugs acting in combination at the optimal time in a particular patient.

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…Apoptosis of nerve cells is a common event in stroke, according to a previous report (2). Apoptotic alterations of neurons, including the condensation of nuclei and the activation of caspases, are observed in the ischemic core in the early stage of focal cerebral ischemia (19,20). In rim of the ischemic core, neurons undergo a delayed neuronal death dependent or independent of caspases (19,20).…”

“…Apoptotic alterations of neurons, including the condensation of nuclei and the activation of caspases, are observed in the ischemic core in the early stage of focal cerebral ischemia (19,20). In rim of the ischemic core, neurons undergo a delayed neuronal death dependent or independent of caspases (19,20). The present study established an in vitro model of OGD/R that mimics the in vivo ischemia/reperfusion injury, and demonstrated that the apoptosis rate of SH-SY5Y cells was notably increased following OGD/R treatment with reduction of cell viability.…”

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…The failure of so many neuroprotectants in clinical trials represents a significant challenge and calls for novel treatment approaches, perhaps involving multiple therapeutic targets (for recent discussion see [3,125,126]). …”

Protease Omi cleaving Hax-1 protein contributes to OGD/R-induced mitochondrial damage in neuroblastoma N2a cells and cerebral injury in MCAO mice

“…As previously reported, apoptotic changes of neurons in the early stage of focal cerebral ischemia are presented in the ischemic core, including the condensation of nuclei and the activation of caspases, before they undergo necrosis [8] . In the ischemic penumbra, the rim of the ischemic core, neurons undergo both caspase-dependent and -independent apoptosis, which contributes to a delayed neuronal death [9] .…”