Postischemic treatment of neonatal cerebral ischemia should target autophagy

Abstract

The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia.

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

“…Western blot analysis also has shown that the expression of LC3-II and cathepsin B (a main lysosomal protease of the brain parenchyma) are increased in the ischemic cortex [17] . These observations are also supported by Rami et al, who showed that a dramatic elevation in Beclin1 and LC3 levels in the penumbra of rats challenged by tMCAO [15] , and by Puyal et al, who indicated that lysosomal and autophagic activities are increased in the ischemic neurons after transient focal cerebral ischemia [16] .…”

“…In addition, autophagy is induced under starvation, differentiation, and normal growth control to maintain homeostasis and survival [1][2][3] ; however, it is also involved in neurodegenerative disorders and can trigger a form of programmed cell death (Type II death) distinct from apoptosis in neurons [4][5][6][7] . Accumulating evidence indicates that autophagy is activated and may be involved in the regulation of neuronal death in different animal models of ischemic brain injury, including hypoxiaischemia (HI) and global and focal ischemia [7][8][9][10][11][12][13][14][15][16][17] . Recently, using a permanent focal cerebral ischemia model of stroke and an oxygen and glucose deprivation (OGD) model in primary cultured astrocytes, the authors show that autophagy is activated in ischemic astrocytes and contributes to astrocytic cell death [18] .…”

Acute spinal cord injury could cause activation of autophagy in dorsal root ganglia

“…However, in the model of neonatal cerebral ischemia, inhibition of autophagy decreased the area of ischemic penumbra and neuroprotective efficacy. 31 In the current study, we detected activation of autophagy in DRGs after acute SCI. Expression of LC3 was increased in DRGs after injury, and changed over time, appearing at 8 h, peaking at 3 days and gradually decreasing from 7 days.…”

Autophagic cell death exists

“…In fact, numerous studies report that the blockade of autophagy (by pharmacological inhibitors, or by RNAi knockdown or conditional knockout or mutation of autophagy genes) can prevent or delay the death of cells manifesting enhanced autophagy. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] Doubts can be raised about the specificity of the inhibitors, and the possibility that autophagy proteins may have additional functions other than in autophagy, 20 but the convergent results from multiple approaches have convinced most specialists that autophagy can promote the death of cells. 5,8,10,20,21 However, the recent Editor's Corner article goes beyond the new recommendations, in requiring two additional criteria.…”

“…First, pure cases of ACD seem to be relatively rare in mammals. A review of cell death in development covering the literature up to 1989 concluded that ACD (morphologically defined) was the predominant type of cell death in metamorphosing insects and amphibians, but found only one case in mammals; 3 and more recent evidence indicates that, even though autophagy does contribute to cell death in mammals, 7,8,14 this often involves a complex interaction between multiple death pathways rather than pure ACD. 8,22 Second, dividing and recently postmitotic cells tend to be so sensitive to apoptosis that pure, nonapoptotic ACD may be unable to occur in most cases.…”