Table 1.
Strategies to attenuate delayed tPA-induced hemorrhagic transformation (HT)
| Strategy (dose, method and timing of treatment) | tPA dose, method & timing of treatment | Species & stroke Model | Parameter/ molecular Target | Outcome | Timing of evaluation | Ref. |
|---|---|---|---|---|---|---|
| Minocycline (antibiotic; 3 mg/kg, intravenous [i.v.], 4 hours after stroke) | 10 mg/kg., i.v., 6 hours post-stroke | Male SHR; embolic | HT | Decreased | 24 hours post stroke | [16] |
| Infarct volume | Decreased | |||||
| MMP-9 (plasma) | Decreased | |||||
| Cilostazol (PDEIII- inhibitor; 10 mg/kg, i.p., before tPA) | 0 mg/kg., i.v., 6 hours post-stroke, before reperfusion | Male ddY (22-26 g) 4 weeks old; intraluminal filament/reperfusion | HT | Decreased | 18 hours post-reperfusion | [14] |
| Infarct volume | Decreased | |||||
| MMP-9 | Decreased | |||||
| claudin 5 | Enhanced | |||||
| locomotor behavior | Improved | 7 days post stroke | ||||
| GM6001 (MMP inhibitor; 100 mg/kg, i.p., alongside tPA) | 10 mg/kg., i.v., 6 hours post-stroke, after reperfusion | Male ddY mic (22-30 g) 4 weeks old; intraluminal filament/reperfusion | HT | Decreased | 48 hours post-stroke/reperfusion | [23] |
| Infarct volume | Not examined | |||||
| MMP-9 | Decreased | |||||
| claudin (in vitro, in vivo) | Not changed | |||||
| occludin (in vitro, in vivo) | Enhanced | |||||
| ZO-1 (in vitro, in vivo) | Enhanced | |||||
| Fasudil (ROCK inhibitor; 3 mg/kg, i.p., before tPA) | 10 mg/kg., i.v., 6 hours post-stroke, after reperfusion | Male SD rats (250-330 g); intraluminal filament/reperfusion | HT | Decreased | 18 hours post-reperfusion | [13] |
| Infarct volume | Not changed | |||||
| MMP-9 (in vitro) | Decreased | |||||
| locomotor behavior | Improved | 7 days post stroke | ||||
| Candesartan (AT1R blocker; 1 mg/kg, i.v., 3 hours after stroke) | 10 mg/kg., i.v., 6 hours post-stroke | Male Wistar rats (330-350 g); embolic | HT | Decreased | 24 hours post stroke | [27] |
| Infarct volume | Not changed | |||||
| MMP-9 | Not changed | |||||
| MMP-2 | Not changed | |||||
| MMP-3 | Decreased | |||||
| NF-κB | Decreased | |||||
| TNF-α | Decreased | |||||
| p-eNOS | Decreased | |||||
| Bryostatin (PKC modulator; 2.5 mg/kg., i.v., alongside tPA) | 5 mg/kg, i.v., 6 hours post-stroke | Female SD rats, 18-20 months old; embolic | HT | Decreased | 24 hours post stroke | [31] |
| Infarct volume | Not changed | |||||
| MMP-9 | Decreased | |||||
| MMP-2 | Not changed | |||||
| PKCɛ | Increased | |||||
| PKCα | Not changed | |||||
| PKCδ | Not changed | |||||
| IMM-H004 (Coumarin derivative; 6 mg/kg, i.v., alongsidetPA) | 10 mg/kg, i.v., post-stroke | Male SD rats (300-320 g); embolic | HT | Decreased | 18 hours post-stroke | [36] |
| Infarct volume | Decreased | 24 hours post-stroke | ||||
| Neurological functions | Improved | 1,2,3 days post-stroke | ||||
| Male SD rats (260-280 g); intraluminal filament/reperfusion | HT | Decreased | 24 hours post-stroke | |||
| Infarct volume | Decreased | |||||
| Neurological functions | Improved | 1-7 days post-stroke | ||||
| pro-MMP-9 | Decreased | 24 hours post-stroke/reperfusion | ||||
| Akt (in vitro) | Decreased | |||||
| Ang-1 | Increased | |||||
| CD31CD31+Ki67 | Increased | 7 days post-stroke/reperfusion | ||||
| MMP-2 | Increased | |||||
| occludi | Not co-localized in astrocytes | |||||
| Tie2 | Decreased | |||||
| Increased | ||||||
| G-CSF (300 µg/kg, i.v., alongside tpa) | 10 mg/kg., i.v., post stroke, before reperfusion | Male SD rats, (200-250 g) 9-10 weeks old; intraluminal filament/reperfusion | HT | Decreased | 24 hours post-drug treatment | [38] |
| Infarct volume | Not changed | |||||
| Neurological functions | Improved | |||||
| Ang-1 | Not changed | |||||
| Ang-2 | Increased | |||||
| CD34 | Increased | |||||
| eNOS | Increased | |||||
| VEGFR2 | Increased | |||||
| vWF | Increased |
tPA, tissue plasminogen activator; SHR, spontaneously hypertensive rat; HT, hemorrhagic transformation; PDEIII; phosphodiesterase III; MMP, matrix metallopeptidase; ZO, zonula occludens; ROCK, Rho-associated protein kinase; SD, Sprague Dawley; AT1R, angiotensin II type 1 receptor, NF-κB; nuclear factor-κB; TNF-α, tumor necrosis factor; eNOS, endothelial nitric oxide synthase; PKC, protein kinase C; Akt or protein kinase B; Ang, angiotensin; CD, cluster of differentiation; Tie, tyrosine kinase with Ig and EGF; G-CSF, granulocyte-colony stimulating factor; VEGF2, vascular endothelial growth factor; vWF, Von Willebrand factor.