Table 1.
Drug and nondrug conjunctive treatments to lengthen thrombolytic therapy for acute ischemic stroke
| Agent | Species and stroke model | tPA dose, mode and time of treatment | Timing of outcome evaluation | Result | Reference |
|---|---|---|---|---|---|
| Ascorbic acid (500 mg, p.o.) 5 h poststroke | Male rats MCA cauterization | 1 mg/kg, i.v., 5 h poststroke | 48 h poststroke | Decreased infarct volume, brain edema, and brain permeability Decreased MMP-9 Improved sensorimotor functions |
[15] |
| Atorvastatin (first dose: 20 mg/kg 4 h after stroke, second dose: 20 mg/kg at 24 h after the first dose, s.c.) | Male Wistar rats; embolic | 10 mg/kg, i.v., 6 h poststroke | 7 h 30 h poststroke |
Reduced HT, infarct volume Improved neurological functions Increased thrombolysis and vascular patency Reduced expression of ICAM-1, PAR-1, Collagen IV Increased MMP-9 |
[16] |
| Batimastat (MMP inhibitor; 50 mg/kg; i.p., 3 and 6 h after stroke) | Male spontaneously hypertensive rats; embolic | 10 mg/kg, i.v., 6 h poststroke | 24 h poststroke | Decreased HT, infarct volume and mortality Improved neurological functions |
[17] |
| Bryostatin (PKC modulator; 2.5 mg/kg., i.v., alongside tPA) | Female SD rats, 18-20 months old; embolic | 5 mg/kg, i.v., 6 h poststroke | 24 h poststroke | Decreased HT Decreased MMP-9 Infarct volume, MMP-2, PKCα, PKCδ not changed Increased PKCɛ |
[18] |
| Candesartan (AT1R blocker; 1 mg/kg, i.v., 3 h after stroke) | Male Wistar rats (330-350 g); embolic | 10 mg/kg., i.v., 6 h poststroke | 24 h poststroke | Decreased HT Decreased MMP-3, NF-κB, TNF-α, p-eNOS Infarct volume, MMP-9, MMP-2 not changed |
[19] |
| Cilostazol (PDEIII-inhibitor; 10 mg/kg, i.p., before tPA) | 10 mg/kg., i.v., 6 h poststroke, before reperfusion | Male ddY (22-26 g) 4 weeks old; intraluminal filament/reperfusion | 18 h postreperfusion 7 d poststroke | Decreased HT and infarct volume Decreased MMP-9 Increased claudin 5 Improved locomotor behavior |
[20] |
| Agent | Species and stroke model | tPA dose, mode and time of treatment | Timing of outcome evaluation | Result | Reference |
| DDFPe nanodroplets 0.3 ml/kg, i.v. 1 h after stroke, and 5 additional doses at 90 min intervals | 0.9 mg/kg tPA | New Zealand male or female rabbits; 3.4 to 4.7 kg/between; embolic 9 h after last DDFPe dose | 24 h poststroke | Decreased infarct volume Improved neurological functions |
[21] |
| Fasudil (ROCK inhibitor; 3 mg/kg, i.p., before tPA) | Male SD rats (250-330 g); intraluminal filament/reperfusion | 10 mg/kg., i.v., 6 h poststroke, after reperfusion | 18 h postreperfusion 7 d post stroke | Decreased HT Decreased MMP-9 Infarct volume not changed Improved locomotor behavior |
[22] |
| G-CSF (300 µg/kg, i.v., alongside tpa) | Male SD rats, (200-250 g) 9-10 wk old; intraluminal filament/reperfusion | 10 mg/kg., i.v., poststroke, before reperfusion | 24 h post-drug treatment | Decreased HT Infarct volume not changed Improved neurological functions Increased Ang-2, CD34, eNOS, VEGFR2, vWF |
[23] |
| GM6001 (MMP inhibitor; 100 mg/kg, i.p., alongside tPA) | Male ddY mice (22-30 g) 4 weeks old; intraluminal filament/reperfusion | 10 mg/kg., i.v., 6 h poststroke, after reperfusion | 48 h poststroke/reperfusion | Decreased HT Decreased MMP-9 Claudin not changed Enhanced occludin, ZO-1 |
[24] |
| Imatinib (PDGFR-α antagonist | C57BL/6J mice, 10 weeks old, photothrombotic induction of MCAO | 10 mg/kg, i.v., 5 h after stroke | 24 h poststroke | Decreased HT | [25] |
| Agent dosage, mode, and time of treatment | Species and stroke model | tPA dose, mode, and time of treatment | Timing of outcome evaluation | Result | Reference |
| IMM-H004 (Coumarin derivative; 6 mg/kg, i.v., alongside tPA) | Male SD rats (300-320 g); embolic Male SD rats (260-280 g); intraluminal filament/reperfusion |
10 mg/kg, i.v., poststroke | 18 h poststroke 24 h poststroke 1,2,3 d poststroke 24 h poststroke 1-7 d poststroke 24 h poststroke/reperfusion 7 d poststroke/reperfusion | Decreased HT Decreased infarct volume Improved neurological functions Decreased HT and infarct volume Improved neurological functions Decreased pro-MMP-9 and Akt, occludin Increased Ang-1, CD31, CD31+Ki67, Tie2 |
[26] |
| Minocycline (antibiotic; 3 mg/kg, i.v., 4 h after stroke) | Male SHR; embolic | 10 mg/kg., i.v., 6 h poststroke | 24 h poststroke | Decreased HT, infarct volume Decreased MMP-9 (plasma) |
[27] |
| Neural stem cells (1 day poststroke) + minocycline | Aged mice Intraluminal filament model | 10 mg/kg, i.v., 6 h poststroke | 48 h posstroke | Improved neurological functions Reduced mortality | [28] |
| Normobaric oxygen (100% O2) | Male Sprague-Dawley rats (290-320 g) suture occlusion, and reperfusion |
10 mg/kg, i.v., 5 and 7 h poststroke, 15 min before reperfusion | 24 h poststroke | Decreased HT, infarct volume, brain edema, neurological deficits, mortality Reduced BBB disruption, MMP-9 Increased occluding, claudin-5 | [29] |
I.v.: Intravenous, TPA: Tissue plasminogen activator, MMP: Matrix metalloproteinase, HT: Hemorrhagic transformation, ICAM-1: Intercellular adhesion molecule-1, PKC: Protein kinase C, TNF- α: Tumor necrosis factor-α, NF-κB: Nuclear factor kappa-B, VEGFR: Vascular endothelial growth factor, BBB: Blood-brain barrier, DDFPe: Dodecafluoropentane emulsion, SHR: Spontaneously hypertensive rat, PAR-1: Protease-activated receptor 1