Review Article

Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

Table 1

Components of continuum-programmed necrosis pathway in neonatal HI models.

ComponentFinding(Year) Researchers

AIFTranslocation from mitochondria to nucleus produces DNA condensation. ↑ is correlated with ↑ infarct size (Rat model)(2003) Zhu et al. [46]
AIF effect on DNA is nitric oxide independent (Rat Model)(2004) Zhu et al. [47]
Hsp-70 translocation of AIF to the nucleus (Mouse model)(2005) Matsumori et al. [48]
TAT-Bcl-xL AIF translocation to nucleus and caspase activation providing neuroprotection post HI (Rat model)(2006) Yin et al. [49]
↑ nuclear translocation in males associated with ↑ injury Female mice show greater caspase 3 activity. (Mouse model)(2006) Zhu et al. [50]
Hypothermia AIF translocation. (Rat model)(2011) Askalan et al. [51]

Calpainsm-calpain but not μ-calpain cleaves caspase-3 (Rat model)(2001) Blomgren et al. [52]
Calpain inhibition (using MDL28170) provides neuroprotection and necrosis (Rat model)(2005) Kawamura et al. [53]
Prolonged hypothermia calpain activation (Rat Model)(2005) Ohmura et al. [54]
Polyphenols (pomegranate) provide neuroprotection and decrease calpain activation (Mouse model)(2007) West et al. [55]
Inhibition produced by inhibition of JNK (using D-JNKI1) (Rat model)(2009) Ginet et al. [56]
TAT-mGluR1 blocks the calpain cleavage site of mGluR1α and provide neuroprotection (Rat model)(2009) Zhou et al. [57]
Inhibition of JNK (using TAT-JBD) prevents calpain-mediated brain injury after HI (Rat model)(2010) Nijboer et al. [41]
Calpain modulates the in Bcl-2 following HI (Rat model)(2010) Zhu et al. [58]
Ethyl pyruvate is neuroprotective via inhibition of calpain activation and Ca2+ dysregulation. (Rat model)(2010) Shen et al. [59]

CathepsinsPropidium ioidide + cells in cortex and hippocampus were + for cathepsin B after HI suggesting necrosis (Rat model)(2007) Carloni et al. [60]
Cathepsin D ↑ at 6 h and 24 h post-HI (Rat model)(2009) Ginet et al. [56]

FADDExpression is independent of gluthatione levels and hydrogen peroxide accumulation (Mouse model)(2007) Payton et al. [61]
Inhibition of RIP-1 kinase activity restores the RIP-3/FADD interaction (Mouse model)(2011) Northington et al. [7]

Fas-DR↑ in the thalamus following HI along with ↑ cleavage of caspase 8. (Rat model)(2001) Northington et al. [62]
↑ after HI and genetic deletion provides neuroprotection to cortex (Mouse model)(2004) Graham et al. [63]

Hsp-90No in vivo HI studies

Hsp-70Hsp-70 overexpression provide protection against apoptosis (Mouse model)(2005) Matsumori et al. [48]
↑ FLIP levels, caspase-8 and 9 cleavage, and cytochrome C translocation to cytosol (Mouse model)(2006) Matsumori et al. [64]

JNKActivated after HI. Genetic deletion brain tissue loss. Activates c-JUN, ATF-2, Bim/PUMA (Mouse model)(2007) Pirianov et al. [65]
Inhibition (using D-JNKI1), caspase-3 activation. (Rat model)(2009) Ginet et al. [56]
Inhibition (using TAT-JBD) injury, improves outcomes, and preserves IAP (via inhibition of Smac/DIABLO). (Rat model)(2010) Nijboer et al. [41]

p53↑ in mitochondria→↑ cytochrome C and Smac/DIABLO translocation. p53 → infarct (better outcomes). (Rat model)(2011) Nijboer et al. [66]

PARP-1Activation after HI but NAD+ only in male mice and genetic deletion affords neuroprotection in males. (Mouse model)(2004) Hagberg et al. [26]
Simvastatin PARP-1 activation and IL-1β expression and provides neuroprotection (Rat model)(2006) Carloni et al. [67]
Immunoreactivity (IHC) peaks at 30 min and then again at 12 h post HI (Rat model)(2005) Martin et al. [68]

RIP1/RIP3 complex (necrosome) formation by necrostatin after HI affords neuroprotection, oxidation and FLIP (Mouse model)(2011) Northington, et al. [7]

TNFRNF-κB inhibition brain damage and switches the HI-induced TNF-R profile from ↑ TNF-R1 to ↑ TNF-R2. (Rat model)(2009) Nijboer et al. [69]

TRADDNo in vivo HI studies

AIF: apoptosis inducing factor; FADD: Fas-associated protein; Fas-DR: Fas death receptor; FLIP: (Fas-associated death-domain-like IL-1β converting enzyme)-inhibitory protein; HI: Hypoxia-ischemia, Hsp: heat shock protein; IAP: inhibitor of apoptosis JNK, Jun N-terminal kinase; NFκB: nuclear factor-kappa B; PARP-1: Poly [ADP-ribose] polymerase-1; RIP: receptor interacting protein; TNFR: tumor necrosis factor receptor; TRADD: TNFR-associated death domain.