Tacrolimus (FK506) reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study

Abstract

The neuroprotective effect of the immunosuppressant agent FK506 was evaluated in rats after brain ischemia induced for 15 min in the 4-vessel occlusion model. In the first experimental series, single doses of 1.0, 3.0 or 6.0 mg FK506/kg were given intravenously (iv) immediately after ischemia. In the second series, FK506 (1.0 mg/kg) was given iv at the beginning of reperfusion, followed by doses applied intraperitoneally (ip) 6, 24, 48, and 72 h post-ischemia. The same protocol was used in the third series except that all 5 doses were given iv. Damage to the hippocampal field CA1 was assessed 7 or 30 days post-ischemia on three different stereotaxic planes along the septotemporal axis of the hippocampus. Ischemia caused marked neurodegeneration on all planes (P<0.001). FK506 failed to provide neuroprotection to CA1 both when applied iv as a single dose of 1.0, 3.0 or 6.0 mg/kg (experiment 1), and after five iv injections of 1.0 mg/ kg (experiment 3). In contrast, the repeated administration of FK506 combining iv plus ip administration reduced CA1 cell death on all stereotaxic planes both 7 and 30 days post-ischemia (experiment 2; P£0.01). Compared to vehicle alone, FK506 reduced rectal temperature in a dose-dependent manner (P£0.05); however, this effect did not alter normothermia (37ºC). FK506 reduced ischemic brain damage, an effect sustained over time and apparently dependent on repeated doses and on delivery route. The present data extend previous findings on the rat 4-vessel occlusion model, further supporting the possible use of FK506 in the treatment of ischemic brain damage.

Effects of FK506 on Hippocampal CA1 Cells Following Transient Global Ischemia/Reperfusion in Wistar Rat

“…Our findings also confirm with the previous finding which reported that a single IV injection of FK506 provided no protection, but this result does not correlate with the study which reported that a single-dose injected (3 or 10 mg/kg) IV has neuroprotective effect on pyramidal cells of robust when injected immediately after ischemia [47, 48]. …”

Neuroprotective Treatment With FK506 Reduces Hippocampal Damage and Prevents Learning and Memory Deficits After Transient Global Ischemia in Rat

“…demonstrated that FK506 is effective when it has been administrated 2 to 3 h after focal brain ischemia, but some studies have been shown that this therapeutic time (1 h) for FK506 is shorter (10,25). In this study, the neuroprotective effect of FK506 was maintained for at least 2 weeks, this finding agrees with previous studies showing that the neuroprotective effect of FK506 persists up to 45 (26) or 30 days after transient global ischemia (27).…”

A novel version of the 8-arm radial maze: effects of cerebral ischemia on learning and memory

“…The severe hippocampal lesions observed in most animals are unlikely to be due to ischemia-induced fever, since the animals were normothermic (36.8-37.5 • C), at least during the period of measurement (figure not shown). The development of hyperthermia during the subsequent post-ischemic hours is also improbably on the basis of previous studies (Drake et al, 1996;Giordani et al, 2003). However, we cannot exclude an exacerbating effect of possibly elevated glycemia, since the animals were not food deprived overnight before ischemia.…”