TABLE 9.
Cell death in preclinical models of iatrogenic preterm brain injury: caffeine and anesthetics.
| Species | Time of the insult | Model | Cell death markers(time post insult) | + Cell types | ROIs | Neuroprotectant | References |
| Rat | E20 | Propofol, maternal i.v. (8.0 mg/kg) + 1 h (1.2 mg/kg/min) | -c-CASP3 (6 h) | -NeuN | -CTX, TH, HTH | Dexmedetomidine | Li et al., 2016a |
| E14 | Sevoflurane, maternal (3.5%) for 2 h | -↑LC3-II, ↑BECLIN-1, ↓SQSTM1, ↓mTOR, TUNEL, ↓BCL2, (2 h, 12 h, 1 d, 2 d) |
-Nestin+ | Whole brain | 3-MA | Li X. et al., 2017 | |
| P3 | Caffeine, 1 × i.p. (80 mg/kg) | c-CASP3 (6 h) | n.d. |
Whole brain (Hipp, ST, TH, CTX) | – | Cabrera et al., 2017 | |
| P4 | Caffeine, 1 × /d i.p., for 3 d (10 mg/kg) | TUNEL (6 h, 12 h, 1 d) | n.d. | HTH, DG | – | Endesfelder et al., 2017a | |
| P6 | Caffeine, 1 × (10 mg/kg) | PARP-1, AIF (1 d or 2 d) | n.d. | Whole brain | – | Endesfelder et al., 2017b | |
| P3 | MgSO4, 1 × /h, for 3 h (4 × 250 mg/kg) | c-CASP3, apoptotic by EM | Neurons | CTX, STcn, STp, Hipp, TH, CB c | – | Dribben et al., 2009 | |
| E20 | Propofol, maternal i.v. (8.0 mg/kg) + 1 h (1.2 mg/kg/min) | -c-CASP3 (6 h) | -NeuN | -CTX, TH, HTH | Dexmedetomidine | Li et al., 2016a | |
| P4 |
Phenobarbital, 1 × /d i.p., for 3 d (50 mg/kg) |
-TUNEL (6 h, 12 h, 1 d) | -n.d. | Frontal CTX, retrosplenial CTX, HTH, TH, DG | – | Endesfelder et al., 2017a | |
| Mouse | E14 | Sevoflurane (2.5%), 2 h | -c-CASP3 | -n.d. | Whole brain | – | (Zheng et al., 2013) |
| P6 |
Sevoflurane (3%) or isoflurane (2%) or desflurane (4/8%), for 2 h/3 h or 6 h |
-c-CASP3, c-PARP, TUNEL (18 h) -c-CASP3, TUNEL (2 d) |
-n.d | -CX, Hipp, Am, TH, ST, CP -Hipp -Hipp |
- -Luteolin -Tanshinone IIA |
Kodama et al., 2011
Wang Y. et al., 2019 Xia et al., 2017 |
|
| P6 | Sevoflurane (3%), 1 × /d for 2 h, for 3 d | ↑LC3-II, ↓SQSTM1, | n.d | Hipp | 3-MA | Wang X. et al., 2019 | |
| P3 | -Midazolam, 1 × i.p. (6 mg/kg); ketamine, 1 × i.p. (40 mg/kg); fentanyl, 1 × i.p. (40 μg/kg) + caffeine (80 mg/kg) |
c-CASP3 (6 h) | n.d. | Whole brain (Hipp, ST, TH, CTX) | – | Cabrera et al., 2017 | |
| P5–P7 | Propofol, i.p. (50/100 mg/kg) | c-CASP3 | n.d. | STcn, CTX | – | Cattano et al., 2008 | |
| Rhesus macaque | 100–120 d ga |
Isoflurane (5 h) 3 h before preterm delivery |
c-CASP3 | MBP, NeuN | - ST, PT | – | Noguchi et al., 2018 |
| 120 d ga | Propofol, i.v. (5 h), 3 h before preterm delivery | c-CASP3 fractin (3 h) |
MBP, neurons | CTX, STcn, STp, Am, CB, infCOLL CSO, CC, iC |
– | Creeley et al., 2013 | |
| 120 d ga 100–120 d ga |
-Isoflurane, i.v. (0.7–1.5 vol%), 5 h, 3 h before preterm delivery - + caffeine (1 × 80 mg/kg, 1 × /d 20 mg/kg) |
-c-CASP3 (3 h) -↑ c-CASP3 |
-MBP, NeuN -MBP, NeuN |
CTX, STcn, STp, Am, CB, -CB, ST |
– – |
Creeley et al., 2014
Noguchi et al., 2018 |
|
| 120 d ga | Ketamine, i.v. (10 mg/kg) + 5 h (10–85 mg/kg/min) | c-CASP3 (3 h) | n.d. | CTX, STcn, STp, Am, GP, CB | – | Brambrink et al., 2012 | |
AIF = apoptosis-inducing factor; Am = amygdala, CB = cerebellum; CC = corpus callosum; c-CASP = cleaved caspase; CSO = centrum semiovale, CG = cingulum; CTX = cortex; Cyc = cytochrome c; d = day; DG = dentate gyrus; E = embryonic day; eC = external capsule; EM = electronic microscopy; EPO = erythropoietin; FB = forebrain; GP = globus pallidus; h = hours; Hipp = hippocampus; HTH = hypothalamus; iC = internal capsule, infCOLL = inferior colliculus NAcc = nucleus accumbens; n.d. = not defined; P = postnatal day; ROIs = regions of interest (i.e., where cell death is detected); SCWM = subcortical white matter; ST = striatum; STcn = striatal caudate nucleus; STp = striatal putamen; TH = thalamus; WM = white matter.