Table 2.
Animal studies involving SDs and SAH
| Species | SAH method | Outcomes assessed | Major findings | Time course of findings | Ref |
|---|---|---|---|---|---|
| Observational | |||||
| Cat | Injection into the subarachnoid space | ECoG | Hemolyzed red blood cells injected into the subarachnoid space caused suppression of ECoG activity | Immediately after injection | [39] Levitt et al., 1971 |
| Cat | Autologous blood injection into subarachnoid space or micropuncture of cortical vessels |
Extracellular potassium DC ECoG AC ECoG |
Cortical SAH produced a neuronal depolarization wave | Immediately after the initiation of the SAH | [40] Hubschmann and Kornhauser, 1980 |
| Pig | Subarachnoid fresh blood or blood clots |
DC ECoG AC ECoG Infarction |
Subarachnoid blood clots caused clusters of SDs and infarction of a circumscribed cortex around the clots. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume | Immediately after (ECoG monitoring began after 5-10 min and the first spreading depolarization was observed after a median duration of 22 min (quartiles, 12, 30)) | [24] Hartings et al., 2017 |
| Rat | Perforation model | MR diffusion imaging (ADC) | ADC decrease in the somatosensory cortex appeared and spread over the hemisphere at SAH onset | Immediately after (within 2 min) | [41] Busch et al., 1998 |
| Rat | Perforation model | MR diffusion imaging (ADC) | ADC decrease in the somatosensory cortex appeared and spread over the hemisphere at SAH onset | Immediately after | [42] Beaulieu et al., 2000 |
| Rat | Perforation model |
DC, CBF NADH imaging histological damage |
12.5% of rats showed short-lasting spreading depolarization in acute phase and showed no histological damage | Immediately after (5.1 ± 2.2 min after initiation of SAH) | [43] Shimizu et al., 2018 |
| Rat | Perforation model | MRI (DWI) DC | SDs were detected in 2 animals in acute phase | Immediately after (This SD occurred after repolarization from the ischemic depolarization) | [44] van den Bergh et al., 2002 |
| Mouse | Cisternal injection |
DC ECoG AC ECoG Infarction |
Cisternal injection of blood did not show any spontaneous SD | No spontaneous SD during observation period (up to 72 h) | [45] Oka et al., 2017 |
| Mechanistic studies | |||||
| Rat | SAH-mimicking model |
DC potential CBF (LDF) Oxygen free radical production |
Combination of basal potassium rise and nitric oxide (NO) decline made by Hb or L-NA) showed severe hypoperfusion in response to SD (i.e., inverse neurovascular coupling, spreading ischemia). Nimodipine transformed spreading ischemia from the SAH-mimicking model back into a spreading hyperemia. | [46] Dreier et al., 1998 | |
| Rat | SAH-mimicking model |
DC potential CBF (LDF) Histology |
Spreading ischemia in the presence of Hb combined with either a high concentration of K+ or a low concentration of glucose in ACSF in the subarachnoid space led to cortical infarction | [47] Dreier et al., 2000 | |
| Rat | SAH-mimicking model |
DC potential CBF (LDF) Na+/K+ ATPase activity |
The combination of oxyhemoglobin (NO-lowering agents) and endothelin-1 triggered spreading ischemia | [48] Petzold et al., 2003 | |
| Rat |
SAH-mimicking model (vivo) Rat and human brain slices (vitro) |
DC potential CBF (LDF) Ko OIS and SD susceptibility in vitro |
Elevated baseline [K]o reduces the efficacy of NMDAR antagonists on SD and spreading ischemia. Pharmacosensitivity of SDs to NMDAR antagonists may be lower in metabolically compromised zones | [49] Petzold et al., 2005 | |
| Rat |
SAH-mimicking model (vivo) Rat and human brain slices (vitro) |
DC potential CBF (LDF) NO level and SD susceptibility in vitro |
Reduced NO levels may render the brain more susceptible to SDs | [50] Petzold et al., 2008 | |
| Rat | SAH-mimicking model |
DC potential CBF (LDF) |
Flow responses to SD (hyperemia and ischemia) resemble between rat and human | [51] Offenhauser et al., 2011 | |
| Rat | Perforation model |
MRI (T2) Histology Functional examination Mortality Subarachnoid hemorrhage severity |
Induced SD by KCL increased the tissue injury after SAH | [52] Hamming et al., 2016 | |
| Rat |
SAH-mimicking model (vivo) Rat brain slices (ex vivo) |
DC potential CBF (LDF) Ko |
Basal K+ rise leads to a downregulation of α1/α2 Na,K-ATPase activity, which results in an increased uptake of Ca2+ into intracellular stores and causes spreading ischemia when NO availability is reduced | [53] Major et al., 2017 | |
| Therapeutic studies | |||||
| Rat | SAH-mimicking model |
DC potential CBF (LDF) |
NO donor and NO independent vasodilator papaverine caused spreading ischemia to revert to normal hemodynamic response to SD | [54] Dreier et al., 2001 | |
| Rat | SAH-mimicking model |
DC potential CBF (LDF) |
Spreading ischemia induced by RBC products is antagonized by nimodipine or moderate volume expansion/hemodilution | [55] Dreier et al., 2002 | |
| Rat | Perforation model |
MRI (T2) Histology Functional examination Mortality Subarachnoid hemorrhage severity |
Valproate treatment significantly reduced brain lesion growth after KCl application | [56] Hamming et al., 2017 | |
| Rat | SAH-mimicking model |
DC potential CBF (LSF) |
Duration of spreading ischemia was shortened by cilostazol | [57] Sugimoto et al., 2018 | |