Neuroprotective effect of FK506, an immunosuppressant, on transient global ischemia in gerbil

Tokime, Tomoo; Nozaki, Kazuhiko; Kikuchi, Hiroe

doi:10.1016/s0304-3940(96)12438-1

Cited by 64 publications

(24 citation statements)

References 15 publications

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“…In the gerbil, a single injection of FK506 (1.0 mg/ kg) ip did not prevent ischemia-induced CA1 cell death. In contrast, the same dose given daily for four days provided neuroprotection, without hypothermia during the 24 h following FK506 administration (8,9). In rats, FK506 prevented ischemia-induced brain damage without reducing core temperature when given daily for 4 (10) or 14 days (19).…”

Section: Resultsmentioning

confidence: 95%

“…The importance of immunophilins in the development of neuroprotectors emerged from observations that compound FK506 provides neuroprotection against glutamate-induced neurotoxicity in vitro (5), and in the rodent model of focal cerebral ischemia employing intracerebrally applied endothelin-1 (6). These findings have been extended to models of transient global forebrain ischemia (7)(8)(9)(10). FK506 is a fungal-derived macrolide exhibiting a potent immunosuppressant action, and has been recently introduced in clinical practice to prevent allograft rejection.…”

Section: Introductionmentioning

confidence: 94%

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

Giordani

Benetolli

Favero-Filho

et al. 2003

Braz J Med Biol Res

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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.

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Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 94%

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

Giordani

Benetolli

Favero-Filho

et al. 2003

Braz J Med Biol Res

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“…Inflammation plays a role in propagating cerebral ischemic injury and, consequently, immunosuppressive agents improve outcome in experimental models of stroke (1)(2)(3)(4). Most available immunosuppressive agents, however, have systemic side effects that would limit therapeutic use in stroke.…”

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confidence: 99%

Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia

Becker

McCarron

Ruetzler

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

145

108

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Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor ␤1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor ␤1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.

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“…It is observed that tacrolimus (FK506), a fungal-derived macrolide, has potent immunosuppressant effects which can provide neuro-protection against glutamate-induced neurotoxicity in animal models of focal (8)(9)(10) or transient, global forebrain ischemia (11,12). Many studies have shown that FK506 reduces hippocampal pyramidal cell death after TGCI in the gerbil (11,12) and rat two-vessel occlusion (2-VO) models (13). This effect is due to the interaction of FK506 with the immunophilin FKBP12 (FK506-binding protein) by inhibiting phosphatase calcineurin (14).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Background:Behavioral studies on animals demonstrated that hippocampal damage could produce learning and memory impairments particularly spatial learning. It has been shown that ischemic damage restricted to only 50% of the CA1 cells of the hippocampus exceed the threshold for production of a behavioral impairment. Objectives: In this study we seek to evaluate the effect of FK506 (tacrolimus) on spatial learning of rats subjected to 20-min global transient ischemia/reperfusion. Material and Methods: In treatment group 2, FK506 (1mg/kg) was given intravenously (IV) 20 minutes before ischemia and in treatment group 3 rats were treated with the same dose of tacrolimus (IV) at the beginning of reperfusion. Morris water maze tests were performed 1 week after ischemia for 4 days. Brain tissue proceeded to TUNEL staining. Results: Our data showed; 1) No statistically significant differences were seen between the treatment group 2 and the control (intact) group thus, this suggests that treatment of ischemia with tacrolimus can improve spatial learning and memory. 2) Tacrolimus treatment ameliorated the increase of TUNEL-positive cells induced by cerebral ischemia indicating the neuro-protective properties of FK506. Conclusions: These results suggest that tacrolimus may reduce cognitive impairment and may be a good candidate for treatment of ischemic brain damage.

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Neuroprotective effect of FK506, an immunosuppressant, on transient global ischemia in gerbil

Cited by 64 publications

References 15 publications

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

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

Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia

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

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