Table 2.
Inhibitors (pharmacological and genetic) and markers for the identification of various forms of neuronal cell death
| Type | Pharmacological Inhibition | Genetic Inhibition | Markers |
|---|---|---|---|
| Apoptosis extrinsic | Caspase-8 inhibitor: Z-IETD-fmk | Conditional caspase-8−/− | Caspase-8 and -3 cleavage tBid, TUNEL+, PS exposure on nonnecrotic cell |
| Apoptosis intrinsic | Pan-caspase inhibitors: Z-VAD-fmk, Q-VD-OPh | Caspase-3−/− | Bax NH2-terminal exposure and oligomerization, cytochrome c release, caspase-3 cleavage, TUNEL+, chromatin condensation, PS exposure on intact cell |
| Complex II/SDH stabilizer: compound A | Caspase-9−/− | ||
| Bax−/− | |||
| BH3-only protein-deficient mice | |||
| Necroptosis | RIP1 inhibitors: necrostatin-1s, GSK2982772 | RIP3−/− | MLKL phosphorylation and oligomerization at plasma membrane, accompanied by necrotic features |
| RIP3 inhibitors: GSK'872 (but can induce apoptosis) | MLKL−/− | ||
| MLKL inhibitor: necrosulfonamide (human) | RIP1 D138N kinase-null knock-in | ||
| RIP1 K45A kinase-null knock-in | |||
| Parthanatos | PARP inhibitors | PARP-1−/− | PARP activation, high PAR deposition, AIF release |
| AIF−/− | |||
| Ferroptosis | Iron chelators (deferoxamine) | Cysteinyl-tRNA synthetase knockdown | Excessive lipid peroxidation with necrotic features |
| Lipid ROS scavengers (ferrostatins, liproxstatin-1, vitamin E) | |||
| 5-Lipoxygenase inhibitor (zileuton) | |||
| Pyroptosis | Inflammasome inhibitors (MCC950) | Caspase-1−/− | Caspase-1 activation, accompanied by gasdermin-D cleavage and plasma membrane localization |
| Pan-caspase inhibitors | Gasdermin-D−/− | ||
| Caspase-1 inhibitor (Z-YVAD-FMK) | |||
| Autophagic | Autosis inhibitors (cardiac glycosides) | Conditional ATG family−/− | LC3+ve puncta in cytoplasm, autophagosomes by EM, morphological signature of autosis |
| Beclin-1−/− | |||
| Phagocytic | PS-inhibitors (PS blocking antibodies, annexin V, MFG-E8 D89E, cyclicRGD) | MerTK−/−, VNR−/− | Engulfed (NeuN+) neurons within phagocytes |
| CRT/LRP inhibitors (receptor-associated protein, blocking antibodies) | MFG-E8−/− | ||
| P2Y6−/− | |||
| CR3−/− | |||
| MitoPore | Cyclophilin D inhibitors (cyclosporine A) | Cyclophilin D−/− | Mitochondrial swelling (not selective) |
See text for definitions.