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Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats.
Pharmacol Biochem Behav 2007; 88(1):28-38PB

Abstract

Transient, global cerebral ischemia (TGCI) leads to hippocampal damage and disruption of spatial learning and memory. The immunosuppressant, tacrolimus (FK506), prevents TGCI-induced hippocampal neurodegeneration, but its effectiveness in promoting the recovery of learning and memory performance after TGCI has been little investigated. Here, we use a confined version of the aversive, non-food rewarded radial maze to evaluate further the effects of FK506 on TGCI-induced learning and memory deficits. In the first experiment, rats were rendered ischemic (15 min 4-VO) and 20 days later were tested for acquisition of the radial maze task over 15 consecutive days (post-operative training). In the second experiment, naive rats were trained for 10 days and subjected to TGCI (pre-operative training); retention of task performance was assessed on days 31, 35 and 39 post-ischemia. Acquisition and retention performances were expressed as a) latency to find a goal box, b) number of reference memory errors, and c) number of working memory errors. Data are presented both across daily training sessions (15 days, 3-day blocks) and as a total value (summed over the 15 days). Histological examination was performed on the day after behavioral testing. In both experiments, FK506 (1.0 mg/kg) was given i.v. at the beginning of reperfusion, followed by doses applied intraperitoneally (i.p.) 6, 24, 48 and 72 h post-ischemia. TGCI markedly disrupted both acquisition and retention performance (p<0.0001-0.05). Treatment with FK506 did not prevent the TGCI-induced acquisition and retention deficits, independently of whether performances were quantified 'daily' or as a 'total' value. In contrast, FK506 reduced hippocampal damage significantly compared to the vehicle alone (p<0.001-0.05). We conclude that the present study did not confirm our earlier behavioral data, and suggest that FK506 is not effective in treating the behavioral outcomes of TGCI, despite its efficacy in reducing CA1, hippocampal damage. However, further studies including other behavioral tasks and more extensive neurohistological analysis, are needed to better elucidate the effectiveness of FK506 in promoting functional recovery in models of transient, global cerebral ischemia.

Authors+Show Affiliations

Department of Pharmacy and Pharmacology, Health Science Center, State University of Maringá, Maringá, 87020-900, Paraná, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17675223

Citation

Benetoli, Arcelio, et al. "Tacrolimus (FK506) Reduces Hippocampal Damage but Fails to Prevent Learning and Memory Deficits After Transient, Global Cerebral Ischemia in Rats." Pharmacology, Biochemistry, and Behavior, vol. 88, no. 1, 2007, pp. 28-38.
Benetoli A, Dutra AM, Paganelli RA, et al. Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats. Pharmacol Biochem Behav. 2007;88(1):28-38.
Benetoli, A., Dutra, A. M., Paganelli, R. A., Senda, D. M., Franzin, S., & Milani, H. (2007). Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats. Pharmacology, Biochemistry, and Behavior, 88(1), pp. 28-38.
Benetoli A, et al. Tacrolimus (FK506) Reduces Hippocampal Damage but Fails to Prevent Learning and Memory Deficits After Transient, Global Cerebral Ischemia in Rats. Pharmacol Biochem Behav. 2007;88(1):28-38. PubMed PMID: 17675223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats. AU - Benetoli,Arcelio, AU - Dutra,Aline Mara, AU - Paganelli,Ricardo Alexandre, AU - Senda,Dalton Makoto, AU - Franzin,Simone, AU - Milani,Humberto, Y1 - 2007/07/10/ PY - 2007/03/29/received PY - 2007/06/29/revised PY - 2007/07/03/accepted PY - 2007/8/7/pubmed PY - 2007/11/6/medline PY - 2007/8/7/entrez SP - 28 EP - 38 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol. Biochem. Behav. VL - 88 IS - 1 N2 - Transient, global cerebral ischemia (TGCI) leads to hippocampal damage and disruption of spatial learning and memory. The immunosuppressant, tacrolimus (FK506), prevents TGCI-induced hippocampal neurodegeneration, but its effectiveness in promoting the recovery of learning and memory performance after TGCI has been little investigated. Here, we use a confined version of the aversive, non-food rewarded radial maze to evaluate further the effects of FK506 on TGCI-induced learning and memory deficits. In the first experiment, rats were rendered ischemic (15 min 4-VO) and 20 days later were tested for acquisition of the radial maze task over 15 consecutive days (post-operative training). In the second experiment, naive rats were trained for 10 days and subjected to TGCI (pre-operative training); retention of task performance was assessed on days 31, 35 and 39 post-ischemia. Acquisition and retention performances were expressed as a) latency to find a goal box, b) number of reference memory errors, and c) number of working memory errors. Data are presented both across daily training sessions (15 days, 3-day blocks) and as a total value (summed over the 15 days). Histological examination was performed on the day after behavioral testing. In both experiments, FK506 (1.0 mg/kg) was given i.v. at the beginning of reperfusion, followed by doses applied intraperitoneally (i.p.) 6, 24, 48 and 72 h post-ischemia. TGCI markedly disrupted both acquisition and retention performance (p<0.0001-0.05). Treatment with FK506 did not prevent the TGCI-induced acquisition and retention deficits, independently of whether performances were quantified 'daily' or as a 'total' value. In contrast, FK506 reduced hippocampal damage significantly compared to the vehicle alone (p<0.001-0.05). We conclude that the present study did not confirm our earlier behavioral data, and suggest that FK506 is not effective in treating the behavioral outcomes of TGCI, despite its efficacy in reducing CA1, hippocampal damage. However, further studies including other behavioral tasks and more extensive neurohistological analysis, are needed to better elucidate the effectiveness of FK506 in promoting functional recovery in models of transient, global cerebral ischemia. SN - 0091-3057 UR - https://www.unboundmedicine.com/medline/citation/17675223/Tacrolimus__FK506__reduces_hippocampal_damage_but_fails_to_prevent_learning_and_memory_deficits_after_transient_global_cerebral_ischemia_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(07)00211-0 DB - PRIME DP - Unbound Medicine ER -