*2.1. Exhibition of Necroptosis, Apoptosis, and Related Processes in Neuronal Death*

Apoptosis can be defined as a type of programmed cell death that is mainly associated with the disintegration of deoxy ribonucleic acid (DNA) and the destruction of several nuclear and cytoskeletal proteins, which leads to immune cell-mediated phagocytosis. The protein caspases execute a chain of proteolysis, which ultimately results in cell death [29]. During the development of the central nervous system, excess neurons are removed by neuronal apoptosis, followed by acute insults that range from excited conditions to injuries [30]. The activation of caspase 8 by extrinsic pathway and caspase 9 via intrinsic pathway leads to the activation of death receptors and mitochondrial damage, respectively, and eventually converges to caspase 3, which ultimately initiates downstreaming of neuronal apoptosis. It was established in a published paper that mice that lack caspase 3 expressions present excessive neuronal cells at birth and significantly reduced apoptosis [31]. The damaged mitochondrion in neurons initiates apoptosis with the help of proapoptotic protein Bax, belonging to the bcl-2 family, by activation of the mitochondrial membrane and release of cytochrome C and further caspase 9 activation [32]. This pathway mainly regulates apoptosis of the neurons even when the chief stimuli has not impaired the functioning of mitochondria. This indicates that the permeability of mitochondria broadly contributes to the apoptosis of neurons. It has been discovered that the neurons that lack Bax protein display no activation of caspases and are strongly protected from neurodegeneration even after prolonged insults [33].

Necroptosis is a form of programmed cell death that is independent of caspases and has been recently discovered to explain cellular characteristics of necrosis. Interferons, tumor necrosis factor, toll-like receptors, and signaling of other proteins and infections act as stimuli and induce necroptosis [34]. Apart from apoptosis and necroptosis, several other pathways that cause cell death have also been identified, such as iron-independent necrosis, known as ferroptosis; lysosomal cell death, known as auto lysis; and death by self-eating, known as autophagy. All these mechanisms are interrelated and cause neuronal cell death.
