Necrosis calpain

Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates. Necrosis is characterized by marked dysregulation of ion homeostasis resulting in cell swelling, dilation of mitochondria and the ER and the formation of vacuoles in the cytoplasm [33], Proteases play important roles in the degradation of cells during necrosis. In contrast to apoptosis, where caspases are the key death proteases, calpains and lysosomal proteases (cathepsins B and D, in particular) are major players in necrosis. Caspases may be activated in response to mitochondrial damage and... 

Badalamente, M.A., and Stracher, A., 2000, Delay of muscle degeneration and necrosis in mdx mice by calpain inhibition, Muscle Nerve, 23, pp 106-111. 

Spencer, M.J., and Tidball, J.G., 1996, Calpain translocation during muscle fiber necrosis and regeneration in dystrophin-deficient mice, Exp Cell Res, 226, pp 264—272. 

Activation of calpain is usually associated with the progression of a necrotic type of cell death (Wang, 2000). However, neuronal necrosis and apoptosis occur in parallel after ischemic injury in vitro and in vivo (Charriaut-Marlangue et al., 1996). Retinal ischemia causes precocious necrosis of neurons in the ganglion cell layer (GCL) and INL, whereas apoptosis appears as the delayed component of neuronal death associated with transient retinal ischemia (Joo et al., 1999). 

Caspase and calpain function in cell death bridging the gap between apoptosis and necrosis, Ann. Clin. Biochem. 42, 415 31, 2005 Ho, P.K. and Hawkins, C J., Mammalian initiator apoptotic caspases, FEES J. 272, 5436-5453,2005 Fardeel, B. and Orrenius, S., Apoptosis a basic biological phenomenon with wide-ranging implications in human disease, J. Intern. Med. 258, 479-517, 2005 Cathelin, S R6be, C Haddaoui, L. et al Identification of proteins cleaved downstream of caspase activation in monocytes undergoing macrophage differentiation, J. Biol. Chem. 281, 17779-17788, 2006. 

How ever, it is important to acknowledge that apoptosis is not the only means for neurons to die. Death of adult neurons in response to pathological challenges also occurs by necrosis, the unregulated cell death mechanism. Necrosis is mediated by increase in intracellular calcium that catalyses activation of Ca + -dependent cystine proteases like, cathepsins and calpains, w hich primarily compromise lysosomal integrity. Subsequently, these cystine proteases in the company of released lysosomal enzymes dismantle structural netw ork of neuron. Additionally, the intracellular pH also plays a major role in necrosis (Syntichaki and Tavemarakis, 2003). 

Cd " is a well known necrosis inducer, especially at higher concentrations and/or in sensitive cell lines. In vivo necrosis by Cd " has been documented in the kidney, heart, liver, and testis. A wider variety of cell types have been employed for in vitro testing and have similarly shown both apoptosis and necrosis simultaneously or necrosis alone [359]. Using pharmacological inhibitors, Yang et al. could demonstrate a role for Ca ", calpains, mitochondrial membrane potential, ROS formation and NF-kB in necrosis of CHO cells. The authors suggested that cytosolic Ca " overload might be important in the execution phase of necrotic cell death while sustained depletion of Ca " stores in ER leads to apoptosis [511]. 

In a follow up study, necrostatin-1 is shown to be active in blocking Cd U induced necrosis by inhibiting A /m loss. Interestingly, necrostatin-1 + Cd " increased Ca " overload further over alone cells without a concurrent increase in calpain activity. In fact, necrostatin-I could attenuate Cd " induced calpain activity [512]. In line with their previous observations, necrostatin-1 restored Cd -induced decrease of NF-kB activity, indicating that this transcription factor is integral to the necrotic response. 

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