Selegiline treatment after transient global ischemia in gerbils enhances the survival of CA1 pyramidal cells in the hippocampus (original) (raw)
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Journal of Neural Transmission, 2000
Ϫ)Deprenyl (selegeline) is a monoamine oxidase B (MAO-B) inhibitor, but it also exerts several effects independent of MAO-B inhibition. For example, it has been shown to improve neuronal survival in different neurodegenerative models. In the present study, we have tested whether (Ϫ)deprenyl attenuates the neuronal damage in the hippocampus that is induced in a model of transient global ischemia in gerbils. (Ϫ)Deprenyl was administered 1) at a low daily dose starting two weeks before occlusion, 2) at a single high dose administered 3 h after occlusion, or 3) at a low daily dose for one or two weeks after occlusion. A nonsignificant trend of reduced neuronal damage in the hippocampal CA1 area was seen in all experimental groups treated with (Ϫ)deprenyl, regardless of the timing of treatment. The results together with previous evidence suggest that (Ϫ)deprenyl may protect CA1 neurons from ischemia-induced delayed death by several possible mechanisms, including the suppression of oxidative stress and apoptotic processes.
Neuroprotectionby MK-801 following cerebral ischemia in Mongolian gerbils
Archives of Biological Sciences, 2008
Global cerebral ischemia in Mongolian gerbils is an established model in experimental research on cerebral ischemia, which is characterized morphologically by selective neuronal damage in the hippocampus, striatum, and cortex. Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of dizocilpine malate �MK-80��, a non-competitive glutamate antagonist, in the model of �0-min gerbil cerebral ischemia. Gerbils were given MK-80� �3 mg/kg i.p.� or saline immediately after the occlusion. On day 4 after reperfusion, neuronal damage was examined in the hippocampus �30 μm� and striatum slices �5 μm� stained with hematoxylin/eosin, fluorescent Nissl staining and membrane tracer DiI. The striatum and C3 regions of the hippocampus were analyzed by confocal microscopy. Neuroprotection was determined by quantifying the degree of cell loss, reduction of morphologically damaged cells, and the degree of preservation of recognizable neuroanatomical pathways after the ischemic insult. Our results demonstrate that the neuronal damage induced by sustained ischemia is related to abnormalities in glutamatergic function associated with NMDA receptors. MK-80� significantly prevented neuronal loss in the tested brain structures. All of this contributes to a better understanding of the given pathophysiological process causing ischemic neuronal damage.
Journal of Biomedical Science, 2014
Background: Stroke is one of the leading causes of neuronal death. Sesamin is known for neuroprotection by its antioxidant and anti-inflammatory properties but it lacks blood-brain barrier (BBB) activity. A panel of sesamin derivatives was screened and 3-bis (3-methoxybenzyl) butane-1,4-diol (BBD) was selected for high BBB activity and tested for its neuroprotective effect. Methods: The focal cerebral ischemia of Sprague-Dawley rats and hypoxia models of murine BV-2 microglia or PC12 cells under oxygen/glucose deprivation were used for in vivo and in vitro test, respectively. Lipid peroxidation and superoxide dismutase (SOD) activity from the ischemic brain were tested and reactive oxygen species (ROS), cytokine production, prostaglandin (PGE 2) and related signaling pathways from hypoxic cells were examined by ELISA or Western blot assay, respectively. Results: BBD showed a protective effect when given 90 min after the focal cerebral ischemia. It also reduced lipid peroxidation and preserved SOD activity from the ischemic brain. The mechanism of BBD was further confirmed by attenuating ROS, cytokine production, and PGE 2 release from hypoxic BV-2 or PC12 cells. BBD significantly reduced hypoxia-induced c-Jun N-terminal kinases (JNK) and modulated AKT-1 and caspase-3 (survival and apoptotic pathways) in BV-2 cells, and inhibited hypoxia-induced JNK and cyclooxygenase-2 activation in PC12 cells. Conclusions: The neuroprotective effect of BBD on ischemia/hypoxia models was involved with antioxidant and anti-inflammatory effects. The result would help the development of new CNS drug for protection of ischemia/ hypoxia injury.
Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid, 1993
In the model of transient brain ischemia of 6-min duration in gerbils we have estimated: 1. The concentration of brain gangliosides: A significant decrease to about 70% of control was observed selectively in the hippocampus at 3 and 7 d after ischemia. 2. The activity of Na+,K(+)-ATPase: The enzyme activity was not affected in either hippocampus nor in cerebral cortex. 3. The malonaldehyde (MDA) concentration: The levels of MDA had increased at 30 min after ischemia up to 123 and 129% of control in hippocampus and cerebral cortex, respectively. 4. Immunoreactivity of protein kinase C detected by Western blotting: In hippocampus the early translocation toward membranes was followed by a decrease in total enzyme content at 6, 24, 72, and 96 h of postischemic recovery. Also, a sharp increase of 50 kDa isoform (PKM) was noticed immediately and at the early recovery times. The behavior of these biochemical markers of ischemic brain injury in the hippocampus after the short (6 min) insult...
Journal of Neuroscience Research, 2002
An ischemia-induced gene was screened using a differential display technique in mouse transient forebrain ischemia. One of the ischemia-responsive clones was found to encode mouse hsp40. HSP40 has a critical regulatory function in the HSC70 ATPase activity. Expression of hsp40 mRNA was low in the nonischemic mouse hippocampus, but it was significantly upregulated 4 hr after ischemia by Northern blot analysis. In situ hybridization analysis revealed hsp40 mRNA induction in the neuron. HSP40 protein expression was also enhanced in the pyramidal and dentate granular neurons from 2 to 4 days after ischemia. The temporal expression and distribution profile of HSC70 protein was similar to that of HSP40, and both proteins were colocalized in ischemic hippocampal neurons. In the gerbil transient forebrain ischemia model, both HSP40 and HSC70 proteins were expressed strongly in ischemia-resistant CA3 neurons and dentate granule cells 1 day after 5 min ischemia, but were not expressed in vulnerable CA1 neurons. However, both proteins were in parallel expressed in the tolerance-acquired CA1 neurons. Based on the current observation that both HSP40 and HSC70 proteins were synergistically expressed in the ischemiaresistant and tolerance-acquired neurons, cochaperone HSP40 may play a significant role against postischemic neuronal response and lead to cell survival through interaction with simultaneously induced HSC70.
Archives italiennes de biologie, 2010
In this study, transient forebrain ischemia was induced in male Wistar rats with subsequent 3 days of reperfusion (ischemia/reperfusion group) or 2 days of reperfusion followed by 5 min ischemia and another 1 day of reperfusion (postconditioning group) to assess an effect of delayed postconditioning applied two days after a previous lethal ischemic attack. We have examined immunoreactivity of antioxidant enzymes (MnSOD, CuZnSOD) and proteins related to apoptosis development (Bcl-2, Bax). Results of microdensitometric measurements from the vulnerable hippocampal CA1 region and relatively resistant dentate gyrus were compared to sham controls and identically, results of postconditioning group were compared to ischemic one. Our findings show protective effects of postconditioning in both brain regions examined, include increased expression of antioxidant enzymes, mainly CuZnSOD, what can be demonstrated by microdensitometric results: CuZnSOD density after ischemia and reperfusion was 6...
Stroke, 1988
Sixty-five male gerbils were exposed to 30 minutes of cerebral ischemia induced by a bilateral carotid artery occlusion. One group of 15 gerbils received a single injection of 25 /xl of 5 ftM cyclohexyladenosine into the cerebral ventricle 15 minutes after release of the occlusion. Another group of 45 gerbils received a similar injection of the vehicle. Five days after ischemia, the hippocampal histology was examined under light microscopy. In the gerbils treated with the adenosine receptor agonist JV-6-cyclohexyladenosine, the CA1 region of the hippocampus showed significant quantitative pyramidal cell preservation (p<0.01, Mann-Whitney U test). Qualitatively, substantial destruction of CA1 neurons was present in all hippocampi of the vehicle-injected gerbils. The CA1 neurons in the cyclohexyladenosinetreated gerbils did not differ from those seen in the five nonischemic controls. The precise mechanism of the protective action of cyclohexyladenosine is unknown, although it has been demonstrated that adenosine agonists reduce presynaptic glutamate release in vitro. It is possible that postischemic administration of cyclohexyladenosine decreases the release of this neurotransmitter in the intact brain as well. The concomitant reduction of the neurotoxic effect of glutamate may, therefore, result in better histologic preservation of the pyramidal cells in the postischemic CA1.
Ischemic preconditioning protects the hippocampal CA1 neurons by inhibiting synaptic activity in rat
Journal of Cerebral Blood Flow and Metabolism, 2005
Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic injury by activating specific mechanisms. In this study, we tested the hypothesis that IPC attenuates postischemic neuronal death via heme oxygenase-1 (HO-1). Animals used in this study were randomly assigned to 4 groups; sham-operated group, ischemia-operated group, IPC plus (þ) sham-operated group and IPCþ ischemia-operated group. IPC was induced by subjecting gerbils to 2 min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in pyramidal neurons of the hippocampal CA1 region (CA1) in the ischemia-operated groups at 5 days postischemia. In the IPC þischemia-operated groups, CA1 pyramidal neurons were well protected. The level of HO-1 protein and its activity increased significantly in the CA1 of the IPCþ sham-operated group, and the level and activity was maintained in all the time after ischemia-reperfusion compared with the ischemia-operated groups. HO-1 immunoreactivity was induced in the CA1 pyramidal neurons in both IPC þsham-operatedand IPCþ ischemiaoperated groups. We also found that levels or immunoreactivities of superoxide anion, 8-hydroxy-2 0deoxyguanosine and 4-hydroxy-2-nonenal were significantly decreased in the CA1 of both IPCþ shamoperated-and IPC þischemia-operated groups. Whereas, treatment with zinc protoporphyrin IX (a HO-1 inhibitor) into the IPC þischemia-operated groups did not preserve the IPC-mediated increase of HO-1 and lost beneficial effects of IPC by inhibiting ischemia-induced DNA damage and lipid peroxidation. In brief, IPC protects CA1 pyramidal neurons from ischemic injury by upregulating HO-1, and we suggest that Contents lists available at ScienceDirect