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      Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA B1 receptor expression in transient focal cerebral ischemia in rats

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          Abstract

          Aim:

          Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) provides neuroprotection against apoptosis in a transient middle cerebral artery occlusion (MCAo) model. This study was to further investigate the anti-apoptotic effect of FA during reperfusion after cerebral ischemia.

          Methods:

          Rats were subjected to 90 min of cerebral ischemia followed by 3 or 24 h of reperfusion after which they were sacrificed.

          Results:

          Intravenous FA (100 mg/kg) administered immediately after middle cerebral artery occlusion (MCAo) or 2 h after reperfusion effectively abrogated the elevation of postsynaptic density-95 (PSD-95), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine, and cleaved caspase-3 levels as well as apoptosis in the ischemic cortex at 24 h of reperfusion. FA further inhibited Bax translocation, cytochrome c release, and p38 mitogen-activated protein (MAP) kinase phosphorylation. Moreover, FA enhanced the expression of gamma-aminobutyric acid type B receptor subunit 1 (GABA B1) in the ischemic cortex at 3 and 24 h of reperfusion. In addition, nitrotyrosine-positive cells colocalized with cleaved caspase-3-positive cells, and phospho-p38 MAP kinase-positive cells colocalized with nitrotyrosine- and Bax-positive cells, indicating a positive relationship among the expression of nitrotyrosine, phospho-p38 MAP kinase, Bax, and cleaved caspase-3. The mutually exclusive expression of GABA B1 and nitrotyrosine revealed that there is a negative correlation between GABA B1 and nitrotyrosine expression profiles. Additionally, pretreatment with saclofen, a GABA B receptor antagonist, abolished the neuroprotection of FA against nitric oxide (NO)-induced apoptosis.

          Conclusion:

          FA significantly enhances GABA B1 receptor expression at early reperfusion and thereby provides neuroprotection against p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion.

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          Most cited references 41

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          Reversible middle cerebral artery occlusion without craniectomy in rats.

          To develop a simple, relatively noninvasive small-animal model of reversible regional cerebral ischemia, we tested various methods of inducing infarction in the territory of the right middle cerebral artery (MCA) by extracranial vascular occlusion in rats. In preliminary studies, 60 rats were anesthetized with ketamine and different combinations of vessels were occluded; blood pressure and arterial blood gases were monitored. Neurologic deficit, mortality rate, gross pathology, and in some instances, electroencephalogram and histochemical staining results were evaluated in all surviving rats. The principal procedure consisted of introducing a 4-0 nylon intraluminal suture into the cervical internal carotid artery (ICA) and advancing it intracranially to block blood flow into the MCA; collateral blood flow was reduced by interrupting all branches of the external carotid artery (ECA) and all extracranial branches of the ICA. In some groups of rats, bilateral vertebral or contralateral carotid artery occlusion was also performed. India ink perfusion studies in 20 rats documented blockage of MCA blood flow in 14 rats subjected to permanent occlusion and the restoration of blood flow to the MCA territory in six rats after withdrawal of the suture from the ICA. The best method of MCA occlusion was then selected for further confirmatory studies, including histologic examination, in five additional groups of rats anesthetized with halothane. Seven of eight rats that underwent permanent occlusion of the MCA had resolving moderately severe neurologic deficits (Grade 2 of 4) and unilateral infarcts averaging 37.6 +/- 5.5% of the coronal sectional area at 72 hours after the onset of occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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            Apoptotic mechanisms after cerebral ischemia.

            Traditionally, cell death after cerebral ischemia was considered to be exclusively necrotic in nature, but research over the past decade has revealed that after a stroke, many neurons in the ischemic penumbra will undergo apoptosis. This brief review provides a general overview and update of various signaling pathways in the development of apoptosis in ischemic lesions. Cerebral ischemia triggers two general pathways of apoptosis: the intrinsic pathway, originating from mitochondrial release of cytochrome c and associated stimulation of caspase-3; and the extrinsic pathway, originating from the activation of cell surface death receptors, resulting in the stimulation of caspase-8. Although many of the key apoptotic proteins have been identified, our understanding of the complex underlying mechanisms remains poor and hence treatment of stroke patients by manipulating apoptotic pathways remains a daunting task. However, recent advances in the field have helped broaden our knowledge of apoptosis after cerebral ischemia. Further to the simplistic concept that stroke-induced apoptosis occurs predominantly in neurons and is caspase-dependent, accumulating evidence now indicates that apoptosis is prevalent in nonneuronal cells and that caspase-independent mechanisms also play a key role. Although the ischemic penumbra is under threat of infarction, it is potentially salvageable and thus represents an opportunity for therapeutic intervention.
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              Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.

              N-methyl-D-aspartate receptors (NMDARs) mediate ischemic brain damage but also mediate essential neuronal excitation. To treat stroke without blocking NMDARs, we transduced neurons with peptides that disrupted the interaction of NMDARs with the postsynaptic density protein PSD-95. This procedure dissociated NMDARs from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurological function. This approach circumvents the negative consequences associated with blocking NMDARs and may constitute a practical stroke therapy.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                August 2010
                19 July 2010
                : 31
                : 8
                : 889-899
                Affiliations
                [1 ]Graduate Institute of Acupuncture Science, China Medical University 40402, Taichung, Taiwan, China
                [2 ]Acupuncture Research Center, China Medical University 40402, Taichung, Taiwan, China
                [3 ]School of Chinese Medicine, China Medical University 40402, Taichung, Taiwan, China
                [4 ]Department of Chinese Medicine, China Medical University Hospital 40447, Taichung, Taiwan, China
                [5 ]Graduate Institute of Integrated Medicine, China Medical University 40402, Taichung, Taiwan, China
                Author notes
                Article
                aps201066
                10.1038/aps.2010.66
                4007809
                20644551
                Copyright © 2010 CPS and SIMM
                Categories
                Original Article

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