Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia

Doğgan, Aclan; Rao, A. Muralikrishna; Başkaya, Mustafa K.; Rao, Venkat K.; Rastl, Jane; Donaldson, David; Dempsey, Robert J.

doi:10.3171/jns.1997.87.6.0921

Cited by 42 publications

(19 citation statements)

References 38 publications

(41 reference statements)

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“…12,13 However, the bases of the neuroprotective action of these drugs at cellular and synaptic level are still unknown. To our knowledge, this study represents the first demonstration that NR2B subunit antagonists block postischemic LTP, favoring the recovery of activitydependent LTP in the ischemic penumbra.…”

Section: Discussionmentioning

confidence: 99%

NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

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et al. 2006

Stroke

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Background and Purpose-We characterized the differential effect of the NR2B subunit antagonist ifenprodil in the induction of activity-dependent long-term potentiation (LTP) and of postischemic LTP as well as in the neuronal damage induced by focal ischemia. Methods-Intracellular recordings were obtained from rat corticostriatal slice preparations. High-frequency stimulation of corticostriatal fibers was used as a LTP-inducing protocol. In vitro ischemia was induced by oxygen and glucose deprivation. In vivo ischemia was induced by permanent middle cerebral artery occlusion. Intracellular recordings were also performed in the ischemic penumbra. Results-Antagonists selectively targeting N-methyl-D-aspartate receptors containing the NR2B subunit blocked postischemic LTP without affecting activity-dependent LTP. In a model of focal ischemia, blockade of NR2B subunit in vivo caused reduction of brain damage, amelioration of neurological outcome, and normalization of the synaptic levels of NR2B subunits. Moreover, the antagonism of NR2B subunit was able to rescue the activity-dependent LTP in the ischemic penumbra. Conclusions-We suggest that NR2B subunits contribute to the striatal damage caused by in vivo and in vitro ischemia and play a critical role in the induction of postischemic LTP as well as in the suppression of activity-dependent LTP in the ischemic penumbra.

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Section: Discussionmentioning

confidence: 99%

NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

Picconi

Tortiglione

Barone

et al. 2006

Stroke

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“…In animal neuroprotection studies, ifenprodil is commonly used at a dose of 10 mg/ kg (Dogan et al, 1997); we found that doses of 20-30 mg/kg of ifenprodil were need to control prolonged SE in 28% of animals. As mentioned, ifenprodils dose-response curve was flat, with incremental doses causing limited effect.…”

Section: Discussionmentioning

confidence: 99%

A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus

2004

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Three different classes of NMDA receptor antagonists were compared for their effectiveness in terminating prolonged status epilepticus (SE), induced by continuous hippocampal stimulation. Animals were treated after 150 min of SE by intraperitoneal administration of increasing doses of 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), MK-801 (dizocilpine), ifenprodil, or saline. EEG recordings were used to determine seizure termination. The first experiment (n = 57 animals) determined the most effective anticonvulsant dose of each agent by determining its ability to terminate SE within the next 300 min. Five control rats treated with normal saline after 150 min of SE continued to exhibit continuous seizures for the next 300 min. All drugs were administered after 150 min of SE. CPP terminated seizures with an ED 50 of 6.4 mg/kg; the maximal effective dose was 15 mg/kg. MK-801 has an ED 50 of 1.4 mg/kg; the maximal effective dose was 2 mg/kg. Ifenprodil was maximally effective at 30 mg/kg. However, an ED 50 could not be calculated. In a subsequent experiment, the NMDA antagonists were compared for their ability to terminate prolonged SE within 60 min of their administration at the most effective dose. MK-801 (2.0 mg/kg) terminated SE in 6 of 10 animals within 60 min, CPP (15 mg/kg) terminated it in 1 of 9 animals; ifenprodil (30 mg/kg) did not terminate it in any of 9 animals treated. In the 300 min following administration, CPP (6/9) and MK-801 (6/10) were equally efficacious in terminating SE but ifenprodil (2/7) was less effective (P = 0.065, chi-square test). The results indicate that the non-competitive NMDA receptor antagonist MK-801 was superior to the competitive antagonist CPP and the pH-sensitive site antagonist ifenprodil, in terminating prolonged experimental SE.

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“…Brain water content as an indicator of brain edema was measured at 24 h after TBI according to the previous report (Dogan et al, 1997). As shown in Fig.…”

Section: Fty720 Provided Neuroprotection After Tbimentioning

confidence: 99%

Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720

et al. 2015

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FTY720 is a synthetic compound produced by modification of metabolite from Isaria sinclairii. It is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues, thereby causing peripheral lymphopenia. Growing evidences have suggested that apoptosis and autophagy were involved in the secondary brain injury after traumatic brain injury (TBI) although FTY720 exerted neuroprotective effects in a variety of neurological diseases except TBI. The present study was aimed to investigate the role of FTY720 in a mouse model of TBI. In experiment 1, ICR mice were divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + FTY720 group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 administration after TBI improved neurobehavioral function, alleviated brain edema, accompanied by modulation of apoptotic indicators such as Bcl-2, Bcl-xL, Bax, and cytochrome c. In experiment 2, ICR mice were also divided into four groups: sham group, TBI + vehicle group, TBI + FTY720 group, and TBI + FTY720 + inhibitors group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 increased the expression of phospho-protein kinase B (AKT) and some autophagy markers such as LC3 and Beclin 1. In addition, the apoptosis inhibition effect of FTY720 was partly abrogated by the phosphatidylinositide 3-kinases (PI3K)/AKT pathway inhibitor LY294002 and autophagy inhibitor 3-methyladenine. Collectively, our data provide the first evidence that FTY720 exerted neuroprotective effects after TBI, at least in part, through the activation of PI3K/AKT pathway and autophagy.

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Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia

Cited by 42 publications

References 38 publications

NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus

Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720

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