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Table 1 Overview of in vivo Studies Investigating the Role of Zinc during Cerebral Ischemia

From: The Role of Zinc in Cerebral Ischemia

Species/Model Therapeutic Intervention Assessment Methods/Main Finding(s) Reference
Rat/Global ischemia; 4-VOa (20 min occlusion) TSQb & acid fuschin staining between 2 and 24 h post-ischemia/At 2 h: TSQ-stained somata in CA4, diminished TSQ-signal in mossy fibers; at 18 h: TSQ-stained cells corresponded to acidophilic cells. (9)
Rat/Focal ischemia; tMCAOc (60 min occlusion) ZnPPd (1–10 µg); topical application Brain edema (wet/dry weight method) assessed at 24 h post-ischemia/Modest but significant reduction in brain edema with ZnPP treatment. (24)
Rat/Global ischemia; 4-VO (20 min occlusion) Pre-txe & intra-txf hypothermia (29°C) started 1h prior and maintained for ischemia TSQ staining 2 h to 7 days post-ischemia/lschemia at 37°C: TSQ-stained CA3 neuronal bodies present at 2 to 24 h; ischemia at 29°C TSQ-stained cell bodies absent (10)
Rat/Focal ischemia; pMCAOg or tMCAO (2 h occlusion). ZnPP (50 mg/kg) i.p., pre-tx: 30 min (pMCAO & tMCAO); post-txh: 2 or 4 h (tMCAO). Infarct volume & brain edema assessed 24 h post-ischemia/ZnPP pre-tx in pMCAO: no effect; ZnPP post-tx in tMCAO: no effect; ZnPP pre-tx in tMCAO: dramatic neuroprotective effect reducing infarct volume & brain edema (26)
Rat/Global ischemia; 2-VOi (15 min occlusion) Ca-EDTA 300 mM (5 µL; i.c.v.), pre-tx: 30 min. TSQ & acid fuschin staining 72 h post-ischemia/Znl accumulation leads to degeneration; Ca-EDTA reduced Zn accumulation & degeneration of CA1 neurons. (11)
Rat/Focal ischemia; tMCAO (2 h occlusion) ZnCI2k (10 mg/kg; i.p.), PPl (48.5 mg/kg; i.p.). ZnPP (50 mg/kg; i.p.), pre-tx: 30 min. Infarct volume & brain edema assessed 24 h post-ischemia/ZnCI2 reduced infarct volume but had no effect on brain edema; ZnPP and PP: both significantly reduced infarct volume and brain edema (27)
Gerbil/Global ischemia; BCCAOm (3 min occlusion) ZnCI2 (20 mg/kg; s.c), pre-tx: 1 h, or 48 and 24 h. TUNELn and H-Eo at 3 and 4 days, respectively/1 h ZnCI2 pre-tx: no effect; 48 and 24 h ZnCI2 pre-tx: modest but significant protection of CA1 region (28)
Gerbil/Global ischemia; BCCAO (5 min occlusion) Examined ZnT-1 mRNA expression between 12 h to 1 week post ischemia/ZnT-1 mRNA expression was induced in CA1 neurons exhibiting Zn accumulation. Without subsequent ZnT-1 protein expression, these cells started to degenerate at 72 h. (12)
Rat/Focal ischemia; pMCAO   Neo-Timm stain to show synaptic Zn levels from 7 min to 7 days post-ischemia/Decrease in Zn staining at 7 min and continued throughout 7 days; at 1 h, Zn-positive cell bodies seen (31)
Rat/Global ischemia; 2-VO (15 min occlusion) Ca-EDTA 300 mM (3 µL; i.c.v.); pre-tx: 30 min. TFL-Znp and TUNEL staining 24, 48, and 72 h post-ischemia/Ca-EDTA markedly reduced Zn accumulation and degeneration of CA1 neurons at all time points. (14)
Rat/Global ischemia; 2-VO (12 min occlusion) Sodium Pyruvate (500 mg/kg; i.p.); pre-tx: 30 min; post-tx: 08, 0.5, 1, 2, 3 h. TFL-Zn & TUNEL staining 3, 15, and 30 days post-ischemia/Sodium pyruvate almost completely blocked neuronal injury when given within 1 h of ischemia (16)
Rat/Focal ischemia; tMCAO (30 min occlusion — mild ischemia) or (60 min occlusion — severe ischemia) Ca-EDTA 500 mM (5 µL; i.c.v.).; pre-tx: 15 min or post-tx: continuous infusion for 1 week (10–100 nmole/h) 1 µ/h; i.c.v. TSQ, H-E, acid fuschin, CMl-IHCr staining 3 h to 14 days post-ischemia/Ca-EDTA pre-tx reduced intracellular Zn accumulation, infarct volume, and degeneration at 3 days but protective effects lost at 14 days or if insult intensity increased (30 min occlusion to 60 min occlusion) and if Ca-EDTA was continuously infused for 7 days. (17)
Mouse/Global ischemia; BCCAO (20 min occlusion). Hypothermia (33°C) initiated at occlusion; continued 35 min TSQ & H-E staining 72 h post-ischemia/Hypothermia markedly reduced Zn accumulation and degeneration of CA1, CA2, and CA4 neurons. (18)
Mouse/Focal ischemia photothrombosis. Infarct volumes & ZnSeAMG s assessed 30 min to 24 h post-ischemia/Infarct core devoid of Zn by 0.5 h until 24 h; 20% increase in Zn in peri-infarct region up to 6 h; Lesions markedly larger at later (12 and 24 h) than at earlier (0.5–6 h) times. (33)
Rat/Focal ischemia; Embolic MCAO. ZnCI2 (80 µmol/kg; i.p.); Bicuculline (48.5 µmol/kg; i.p.) or the above in combination; pre-tx: 30 min Infarct volume & brain edema assessed 48 h post-ischemia/ZnCI2 alone or ZnCI2 and Bicuculline: dramatically increased infarct volume, increased brain edema and worsened neurological deficits; Bicuculline alone: no effect. (19)
Gerbil/Focal ischemia; right pMCAO. Micro-dialysis collected 0–3 h post-ischemia; analyzed with GF-AASt/Zn levels dropped 75% of baseline and never recovered in ipsilateral hemisphere and only minimally changed in contralateral hemisphere (35)
Gerbil/Global ischemia BCCAO (5 min occlusion) and Rat/Global ischemia 4-VO (10 min occlusion) Ca-EDTA 300 mM (5 µL; i.c.v.); pre-tx: 30 min or post-tx: 3, 6, 48, 60, or 72 h. GluR2 mRNA and protein expression, Caspase-3-activity, TSQ, TUNEL 48 h to 5 days post-ischemia/Ca-EDTA pre-tx: reduced Zn levels, GluR2 down-regulation, and early stages of apoptosis in CA1 cells; Ca-EDTA Post-tx between 48 and 60 h: rescued CA1 cells by blocking the later stages of apoptosis (DNA fragmentation). (22)
Rabbit/Global ischemia; inflatable neck tourniquet & systemic hypoperfusion (30 min occlusion) Micro-dialysis collected 4 to 6 h post-ischemia; analyzed with pZn meter/Ischemia induced immediate rise in extracellular Zn levels from baseline (19 nM) in hippocampus. Reperfusion induced greater rise in extracellular Zn levels (100 nM). Glutamate release was earlier and shorter in duration than Zn release (38)
Rat/Focal ischemia tMCAO (60 min occlusion) Ca-EDTA 100 mM (5 µL; i.c.v.); pre-tx: 30 min Infarct volume assessed 3,6, & 24 h post-ischemia/Ca-EDTA pre-tx: deleterious effect on early infarct development: larger infarct volumes at 3 and 6 h but similar to control at 24 h. (30)
Rat/Global ischemia 4-VO (30 min occlusion) TSQ staining 0 to 24 h post-ischemia/Zn accumulation in CA1 cells at 24 h but not before. Micro-dialysis collected 0 to 3h post-ischemia; analyzed with flameless AASU. Extracellular Zn levels in CA1 area increased to 600 nM within 15 min of occlusion, decreased during reperfusion, and returned to basal levels (300 nM). (36)
Rat/Focal ischemia tMCAO (60 min occlusion) Micro-dialysis collected 0 to 3 h post-ischemia; analyzed with flameless AAS/Extracellular Zn levels increased to 300 nM within 15 min of occlusion, decreased during reperfusion, and returned to basal levels (150 nM) (37)
  1. a4-VO, 4-vessel occlusion.
  2. bTSQ, N-(6-methoxy-8-quinolyl)-P-toluenesulfonamide.
  3. ctMCAO, transient middle cerebral artery occlusion.
  4. dZnPP, zinc protoporphyrin.
  5. epre-tx, pre-treatment.
  6. fintra-tx, intra-treatment.
  7. gpMCAO, permanent middle cerebral artery occlusion.
  8. hpost-tx, post-treatment.
  9. i2-VO, 2-vessel occlusion.
  10. jZn, zinc.
  11. kZnCI2, zinc chloride.
  12. lPP, protoporphyrin.
  13. mBCCAO, bilateral common carotid occlusion.
  14. nTUNEL, Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling.
  15. oH-E, hematoxylin and eosin stain.
  16. PTFL-Zn, N-(6-methoxy-8quinolyl)-P-carboxybenzoylsulfonamide.
  17. q’0’ hr refers to the time coinciding with the onset of reperfusion
  18. rCMl-IHC, antibody against activated caspase-3 immunohistochemistry.
  19. sZnSeAMG, zinc-selenium autometallography technique.
  20. tGF-AAS, graphite furnace atomic absorption spectroscopy.
  21. uAAS, atomic absorption spectroscopy.