Article Figures & Data
Figures
- Fig 1.
Schematic of the ischemic cascade. The numbers 1–12 correspond to the numbers 1–12 at each class of therapy in Table 2. When the presynaptic neuron becomes ischemic, it depolarizes, opening sodium (Na) and potassium (K) channels (1, 2). This leads to opening of calcium (Ca) channels and influx of calcium (3). The presynaptic cell releases glutamate that activates NMDA, AMPA, and MGLURs (4–6), which permits calcium entry in the postsynaptic cell. NAALADase inhibitors limit the amount of glutamate available for release (7). GABA agonists inhibit depolarization and prevent calcium entry (8). During reperfusion, upregulated adhesion molecules attract inflammatory cells that contribute to vessel occlusion and cytotoxin production (9). MMPs degrade the basement membrane around vessels, enhancing inflammation and edema (10). Inflammatory cells, ischemic neurons, and glia produce free radicals that contribute to cell damage and death (11). HMG-CoA reductase inhibitors (statins) stabilize the endothelium through upregulation of endothelial nitric oxide synthase (NOS, 12).
Tables
Stage of Research Pitfalls Experimental trials Therapies are not tested by multiple investigators with different stroke models. In experimental trials, outcomes focus on disease and are evaluated early after injury, whereas late, behavioral measures are used in clinical investigations. Translational problems Drug doses used in experimental models produce adverse side effects in patients. The therapeutic window is too small to be feasibly applied to most patients. Therapies are targeted to pathologic mechanisms identified in animal models but not in many patients. Whereas experimental animals are bred for genetic homogeneity, genetic differences among patients may alter their therapeutic response. Clinical investigations Patients with different types of stroke (gray vs white matter, large vs small vessel) are combined in the same study, and therapies may work on one stroke type but not the other. Outcome measures are not standardized, sensitive, or well defined. Some therapies may be influenced by sex, age, and other individual differences. Drug Type of Trial Results Reference No. 1. Na channel blockers 59 Phenytoin Exp + Clin − Carbamazepine Exp + Lamotrignine Exp + Sipatrigine Exp + Clin −− Riluzole Exp + 2. K channel blockers BMS-204352 Exp + 71 Clin − 72 3. Ca channel blockers 73 (S)-emopamil Exp +/− 75 Nimodipine Exp +/− Clin +/− Dantrolene Exp +/− Flunarizine Clin − 4. NMDA antagonists 89 MK-801 Exp +/− Clin −− Aptiganel Exp + Clin −− CP101,606 Exp + 100 Eliprodil Exp + Clin − NPS-1506 Exp + Clin + 103 Magnesium Exp + 113 Clin IP 5. AMPA antagonists YM-872 Exp + 106 Clin IP 6. MGLUR modulators BAY 36-7620 Exp +/− 111 7. NAALADase Inhibitors 109 GPI5232 Exp + 2-PMPA Exp + 8. GABA Agonists Clomethiazole Exp + 114 Clin − 115 Diazepam Clin IP 9. Anti adhesion molecules Enlimomab Exp +/− 136 Clin −− 135 10. MMP Inhibitors 116 Batimistat Exp + KB-R7785 Exp + BB-1101 Exp + 138 11. Free Radical Scavengers 116 PBN Exp +/− Ebselen Clin IP MCI-186 Exp + NXY-059 Exp + Clin +, IP PEG-SOD Clin + Tirilazad Exp + Clin +/− MDL 74,180 Exp + TEMPO Exp + Nicaraven Exp + Clin + 12. HMG-CoA reductase inhibitors 116 Mevastatin Exp + Atorvastatin Exp + Pravastatin Clin + Simvastatin Exp + Lovastatin Exp + Note.—Na indicates sodium; K, potassium; Ca, calcium; Exp, experimental study; Clin, clinical study; +, improved outcome; −, no effect; −−, worsened outcome; +/−, mixed results; IP, in progress.
The numbers 1–12 at each class of therapy correspond to the numbers 1–12 in Fig 1.
