Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection

•There are at least three different morphological types of cell death.•Each type is controlled by multiple death mechanisms, and there is cross-talk between them.•Inhibition of a single mechanism leaves the brain vulnerable to alternative ones.•This review analyzes the multiple death mechanisms in excitotoxicity and ischemic brain damage.•The importance of this multiplicity for attempts at neuroprotection is discussed.

There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death – apoptosis, autophagic cell death and necrosis – emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.