Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy

Furuichi, Yasuhisa; Katsuta, Kiyotaka; Maeda, Masashi; Ueyama, Noriko; Moriguchi, Akira; Matsuoka, Naoki; Goto, Toshio; Yanagihara, Takehiko

doi:10.1016/s0006-8993(02)04151-3

Cited by 71 publications

(39 citation statements)

References 30 publications

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“…Butcher et al (9). 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).…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…We chose FK506 to target calcineurin because there are no specific inhibitors of STEP. A 1 mg/kg intraperitoneal injection of FK506 has been shown to cross the blood-brain barrier and attenuate ischemia-induced neuropathology (Uchino et al, 2002;Furuichi et al, 2003;Noto et al, 2004). Systemic injection of FK506 (1 mg/kg) 15 min after pilocarpine injection (ϳ30 min before SE onset) significantly reduced cell death in the hilus 6 h after SE (Fig.…”

Section: Step Inhibition Decreases Se-induced Hilar Interneuron Cell mentioning

confidence: 88%

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Choi¹,

Lin²,

Lee³

et al. 2007

J. Neurosci.

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Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatalenriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatinimmunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death.

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“…Transient occlusion of the right MCA was induced by insertion of a nylon suture through the right internal carotid artery to the origin of the MCA as described previously (Furuichi et al, 2003). Rats were anesthetized with a mixture of 4.0% halothane and oxygen-nitrogen (30% oxygen and 70% nitrogen) and maintained with a mixture of 1.5% halothane and oxygen-nitrogen during the procedure.…”

Section: Downloaded Frommentioning

confidence: 99%

A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia

Iwashita

Tojo²,

Matsuura³

et al. 2004

J Pharmacol Exp Ther

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The activation of poly(ADP-ribose) polymerase-1 (PARP-1) after exposure to nitric oxide or oxygen-free radicals can lead to cell injury via severe, irreversible depletion of NAD. Genetic deletion or pharmacological inhibition of PARP-1 attenuates brain injury after focal ischemia and neurotoxicity in several neurodegenerative models in animals. FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a K i value of 35 nM. Here, we show that prevention of PARP activation by FR247304 treatment protects against both reactive oxygen species-induced PC12 cell injury in vitro and ischemic brain injury in vivo. In cell death model, treatment with FR247304 (10 Ϫ8 -10 Ϫ5 M) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after hydrogen peroxide (100 M) exposure. After 90 min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADPribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32 mg/kg i.p.) treatment, and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion. Whereas other PARP inhibitors such as 3-aminobenzamide and PJ34 [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylactamide] showed similar neuroprotective actions, they were less potent in in vitro assays and less efficacious in an in vivo model compared with FR247304. These results indicate that the novel PARP-1 inhibitor FR247304 exerts its neuroprotective efficacy in in vitro and in vivo experimental models of cerebral ischemia via potent PARP-1 inhibition and also suggest that FR247304 or its derivatives could be attractive therapeutic candidates for stroke and neurodegenerative disease.Activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP) promotes cell death through processes involving energy depletion. Reactive oxygen species (ROS)-mediated damage of DNA can activate PARP (Szabo et al., 1996;Eliasson et al., 1997) and consumes NAD and consequently ATP, culminating in cell dysfunction or necrosis (Ha and Snyder, 1999). In addition, PARP plays a central role in the caspase-independent apoptosis pathway mediated by apoptosis-inducing factor. Translocation of apoptosis-inducing factor from the mitochondria to the nucleus is dependent on PARP activation in neurons treated with various DNA-damaging stimuli, including hydrogen peroxide (Yu et al., 2002). This cellular suicide mechanism of both necrosis and apoptosis by PARP activation has been implicated in the pathogenesis of ischemic brain injury and neurodegenerative disorders, and PARP inhibitors have been shown to be effective in animal models of stroke, traumatic brain injury and Parkinson's disease (Cosi et al., 1996;Endres et al...

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Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy

Cited by 71 publications

References 30 publications

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

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

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia

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