ABSTRACT
Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in different organs like the kidney, liver, heart, brain, etc., and may not only involve the ischemic organ but also cause systemic damage to distant organs. Oxygen-glucose deprivation in cells causes oxidative stress, calcium overloading, inflammation, and apoptosis. CREB is an essential integrator of the body's various physiological systems, and it is widely accepted that dysfunction of CREB signaling is involved in many diseases, including ischemia-reperfusion injury. The activation of CREB can provide life to a cell and increase the cell's survival after ischemia. Hence, GSK/CREB signaling pathway can provide significant protection to cells of different organs after ischemia and emerges as a futuristic strategy for managing ischemia-reperfusion injury. Different signaling pathways such as MAPK/ERK, TLR4/MyD88, RISK, Nrf2, and NF-κB, get altered during IR injury by the modulation of GSK-3 and CREB (cyclic AMP response element (CRE)-binding protein). GSK-3 (protein kinase B) and CREB are the downstream targets for fulfilling the roles of various signaling pathways. Calcium overloading during ischemia increases the expression of calcium-calmodulin-dependent protein kinase (CaMK), which subsequently activates CREB-mediated transcription, thus promoting the survival of cells. Furthermore, this review highlights the crosstalk between GSK-3 and CREB, promoting survival and rendering the cells resistant to subsequent severe ischemia.
Subject(s)
Brain Ischemia , Reperfusion Injury , Humans , Glycogen Synthase Kinase 3/metabolism , Calcium , Signal Transduction/physiology , Ischemia , Reperfusion Injury/metabolism , Brain Ischemia/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , ApoptosisABSTRACT
Caspases are intimately associated with altering various signaling pathways, resulting in programmed cell death or apoptosis. Apoptosis is necessary for the normal homeostasis of cells and their development. The untoward activation of apoptotic pathways indirectly or directly results in pathologies of various diseases. Identifying different caspases in apoptotic pathways directed the research to develop caspase inhibitors as therapeutic agents. However, no drug is available in the market that targets caspase inhibition and produces a therapeutic effect. Here, we will shed light on the role of caspases in the number of neuronal disorders and neurodegenerative diseases. The article reviews the findings about the activation of various upstream mechanisms associated with caspases in neurodegenerative disorders along with the recent progress in the generation of caspase inhibitors and the challenge faced in their development as therapeutic agents for neurological indications.