A Combined Treatment with Tacrolimus (FK506) and Recombinant Tissue Plasminogen Activator for Thrombotic Focal Cerebral Ischemia in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window

Abstract

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.

Systematic Review and Metaanalysis of the Efficacy of FK506 in Experimental Stroke

“…In response to our request for further relevant information one author provided unpublished data. This meta-analysis is therefore based on data from 24 full papers published between 1994 and 2004 (Sharkey and Butcher, 1994;Sharkey et al, 1996;Kuroda and Siesjo, 1996;Butcher et al, 1997;Aoyama et al, 1997;Takamatsu et al, 1998Takamatsu et al, , 2001Yoshimoto and Siesjo, 1999;Kuroda et al, 1999;Toung et al, 1999;Bochelen et al, 1999;Miyazawa et al, 2000;Aronowski et al, 2000;Arii et al, 2001;McCarter et al, 2001;Ebisu et al, 2001;Fredduzzi et al, 2001;Maeda et al, 2002;Brecht et al, 2003;Furuichi et al, 2003a, b;Nito et al, 2004;Chung et al, 2004;Shichinohe et al, 2004), four abstracts Toung et al, 1997;Janelidze et al, 1999;McGregor et al, 2001) and one personal communication (J Aronowski); it represents the work of 14 independent groups, and nine of 29 publications came from groups funded directly by the Fujisawa Chemical Company, the manufacturers of FK506. Within the 29 studies, 109 comparisons (see Materials and methods for definition) were identified.…”

Tacrolimus (FK506) Limits Accumulation of Granulocytes and Platelets and Protects against Brain Damage after Transient Focal Cerebral Ischemia in Rat

“…7) In addition to its immunosuppressive effects, tacrolimus has been reported to exert neuroprotective activity in a variety of animal models of cerebral ischemia. [8][9][10][11] The neuroprotective effect of tacrolimus has been explained by several mechanisms such as an anti-apoptotic effect via inhibition of cytochrome c release from mitochondria, an anti-inflammatory effect and so on. 12,13) However, the neuroprotective mechanism of tacrolimus has not been fully elucidated.…”

Tacrolimus, a Potential Neuroprotective Agent, Ameliorates Ischemic Brain Damage and Neurologic Deficits after Focal Cerebral Ischemia in Nonhuman Primates

“…Furthermore, the concentrations of tacrolimus in the blood and brain after administration of an effective dose at 0.1 mg/kg were comparable with those in rats given with effective doses of tacrolimus in focal ischemia models (Butcher et al, 1997;Furuichi et al, unpublished observations, 2002). Of interest, however, is the fact that the neuroprotective efficacy of tacrolimus in the present model ranks highly compared with other animal models (Furuichi et al, 2003;Maeda et al, 2002), with an 85% reduction of cortical infarction size at 24 hours and over a 50% reduction after 28 days. In addition to reducing infarct size, tacrolimus remarkably improved the motor system deficits and muscle coordination (Figs.…”

“…Previous studies have shown that tacrolimus has potent neuroprotective effects in a variety of rodent models of stroke, focal ischemia in rats (Bochelen et al, 1999;Butcher et al, 1997;Furuichi et al, 2003;Sharkey and Butcher, 1994), thrombotic focal ischemia in rats (Maeda et al, 2002;Takamatsu et al, 1998), and transient global ischemia in gerbils (Furuichi et al, 2003;Yagita et al, 1996). However, the predictive value of these models is limited given the numerous neuroprotectants that have failed in clinical trials.…”

“…The drug has been well-characterized to have neuroprotective action on ischemic brain damage in rodents (Bochelen et al, 1999;Furuichi et al, 2003;Maeda et al, 2002;Sharkey and Butcher, 1994;Yagita et al, 1996). Because the neuroprotective effect of tacrolimus was first demonstrated to be mediated by inhibition of calcineurin activity (Sharkey and Butcher, 1994), the mechanism for antiischemic effects of tacrolimus have been studied, and antiinflammatory actions (Tsujikawa et al, 1998;Wakita et al, 1998) and antiapoptotic actions (Herr et al, 1999;Wang et al, 1999) have been proposed.…”