Table 4.
Dose–response relationship and time window of ZK200775 in rodent models of ischemia and head trauma
| A MCAO |
Infarct volume (mm3; means ± SEM), n
|
|||
|---|---|---|---|---|
| Treatment | Vehicle | 1 mg/kg/h | 3 mg/kg/h | 10 mg/kg/h |
| Mouse, 1 d | 26.05 ± 1.55 (10) | – | 28.80 ± 3.01 (8) | 17.18 ± 1.44** (9) |
| Rat, 1 d | 160.79 ± 10.56 (25) | 142.07 ± 6.88 (9) | 122.92 ± 9.97* (16) | 113.64 ± 13.7* (12) |
| Rat, 7 d | 84.39 ± 9.95 (27) | 82.51 ± 9.70 (22) | 46.23 ± 7.45** (17) | – |
| B Time window, rat MCAO | ||||||||
|---|---|---|---|---|---|---|---|---|
| Treatment delay | 1 h | 2 h | 4 h | 5 h | 6 h | 7 h | 12 h | 24 h |
| Vehicle | 206.20 ± 16.36 | 194.57 ± 19.28 | 213.42 ± 15.66 | 236.59 ± 11.90 | 218.22 ± 16.91 | 210.06 ± 20.06 | 194.01 ± 18.57 | 216.42 ± 12.28 |
| (12) | (9) | (8) | (19) | (14) | (14) | (15) | (15) | |
| 3 mg/kg/h | 146.82 ± 16.43** | 144.32 ± 14.15* | 168.57 ± 8.80* | 190.65 ± 14.13* | 204.64 ± 13.92 | 208.66 ± 14.38 | 179.58 ± 15.08 | 199.27 ± 19.37 |
| (12) | (13) | (8) | (18) | (15) | (18) | (16) | (18) | |
| % protection | 28.80 | 25.83 | 21.01 | 19.42 | 6.22 | 0.67 | 7.44 | 7.92 |
| C Common carotid/middle cerebral artery occlusion (CCA/MCAO) | ||||
|---|---|---|---|---|
| Treatment | Vehicle | 0.01 mg/kg/h | 0.03 mg/kg/h | 0.1 mg/kg/h |
| Rat CCA/MCAO transient, 7 d | 115.10 ± 17.41 (12) | 114.92 ± 16.61 (13) | 112.14 ± 9.99 (11) | 63.33 ± 9.78** (13) |
| % protection | – | 0.16 | 2.57 | 44.98 |
| D Rat traumatic brain injury, 3 d |
Numerical density of pyramidal cells in the hippocampal CA3 subfield (NV; means × 106/mm3 ± SEM), n
|
||||
|---|---|---|---|---|---|
| Treatment | Vehicle | 0.03 mg/kg/h | 0.3 mg/kg/h | 1 mg/kg/h | 3 mg/kg/h |
| Ipsilateral side | 0.067 ± 0.004 (18) | 0.067 ± 0.010 (5) | 0.049 ± 0.013 (7) | 0.063 ± 0.010 (7) | 0.108 ± 0.009*** (8) |
Body temperature of NMRI mice (Schering AG), Fischer 344, or Wistar rats (Charles River, Sulzfeld, Germany/Iffa Credo, Arbresle, France) was kept at 37.5 ± 0.5°C; 24 h or 7 days after ischemia, the brains were stained with triphenyltetrazolium chloride or with vanadium acidic fuchsin, and the infarct size was determined stereologically by using image analysis. ZK200775 was administered i.v. over 6 h beginning immediately after MCAO or CCA/MCAO. For determination of therapeutic time window, ZK200775 was infused continuously i.v. in the dose of 3 mg/kg/h over 6 h beginning 1-24 h after MCAO. In trauma experiments, ZK200775 was infused i.v. over 6 h beginning 1 h after the head injury. Three days after traumatic brain injury, volume of damage in the cortex was determined by means of volumetry, and neuronal loss in the hippocampal subfield CA3 was assessed by using an unbiased stereological dissector technique (24). On the side contralateral to traumatic injury, numerical density (NV) of pyramidal cells in the CA3 subfield varied from 0.171 to 0.184 × 106/mm3. The differences in NV of pyramidal cells in the CA3 subfield between the damaged and nondamaged side were analyzed statistically by means of ANOVA.
*P < 0.05; **P < 0.01; ***P < 0.001 vs. vehicle-treated animals.