The Autophagy Signaling Pathway in Necroptosis-Dependent Cerebral Ischemia/Reperfusion Injury

Cerebral ischemia/reperfusion (I/R) is a complicated brain disease involving severe inflammation, autophagy, apoptosis and necroptosis. Hippocampal CA1 neuron death in cerebral I/R injury has been proven to be a form of necroptosis that is regulated by the connection of receptor interacting protein kinase (RIP) 1 and RIP3. The RIP3 substrate molecule is mixed lineage kinase domain-like protein (MLKL). The downstream of this signal pathway triggers mitochondrial permeability transition pore (mPTP) channel opening. The occurrence of mitochondrial membrane potential disappearance and the reduction of ATP facilitate reactive oxygen species (ROS) generation. The high level of ROS is essential for engulfing damaged organelles and proteins. In many conditions, autophagy has a decisive function in determining cell outcome through intricate signaling pathway interactions with other cell death signaling mechanisms. Necroptosis also been demonstrated to be responsible for the induction of autophagy. Studies have confirmed that cyclophilin D (CypD), as a regulator of mPTP, has effects on the course of necroptosis, autophagy and apoptosis. Preliminary treatment with cyclosporine-A (CsA), an effective inhibiting agent of CypD, has partial but valid negatively regulated function in necroptosis-associated molecule markers. Administration of CsA is also attributed to inhibiting autophagy-related molecular marker expression. Cerebral I/R injury widely increased the expression levels of autophagy-associated proteins, such as light chain 3-II (LC3-II) and extracellular signal-regulated kinase (ERK), while a small molecule inhibitor of RIP1, necrostatin-1 (Nec-1) functions as a negative regulator to them. The molecular mechanisms and the interaction between necroptosis and autophagy might represent a promising therapeutic target for cerebral I/R injury.