Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.

Kinouchi, Hiroyuki; Imaizumi, Shin; Yoshimoto, Takashi; Motomiya, Masakichi

doi:10.1161/01.str.21.9.1326

Cited by 31 publications

(16 citation statements)

References 43 publications

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“…Because of its lipophilic nature, AA can act as autocrine and/or paracrine signaling molecule promoting a variety of biological effects that range from modulation of ion channels (Meves, 1994) to regulating cell growth, differentiation, and cell viability (Katsuki and Okuda, 1995). Noteworthy, AA levels are substantially up-regulated under various pathological conditions, and high micromolar levels of AA are found in brain under hypoxic/ischemic conditions, trauma, and seizures (Kinouchi et al, 1990). The role of pathological levels of free AA in the regulation of the activity of the astrocytic syncytium is still largely elusive.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Native and Recombinant P2X7-Mediated Calcium Signaling by Arachidonic Acid in Cultured Cortical Astrocytes and Human Embryonic Kidney 293 Cells

Alloisio¹,

Aiello²,

Ferroni³

et al. 2006

Mol Pharmacol

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Section: Discussionmentioning

confidence: 99%

Potentiation of Native and Recombinant P2X7-Mediated Calcium Signaling by Arachidonic Acid in Cultured Cortical Astrocytes and Human Embryonic Kidney 293 Cells

Alloisio¹,

Aiello²,

Ferroni³

et al. 2006

Mol Pharmacol

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“…In models of forebrian ischaemia, phenytoin protects hippocampal CAl neurones from a period of temperature-regulated cerebral ischaemia (Taft et al, 1989) and provides additive protection in the presence of other neuroprotective compounds (Hass & Alps, 1985). These protective effects appear to be related to the maintenance of ionic homeostasis and conservation of energy levels (Artru & Michenfelder, 1980;Kinouchi et al, 1990). Phenytoin does not appear to have any vascular interactions and has no significant effects on cortical blood flow (Kennedy et al, 1972) and does not interact with the NMDA receptor complex (Rogawski & Porter, 1990).…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia

Brown

Calder

Linton

et al. 1995

British J Pharmacology

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5 Agents with other mechanisms of action were also shown to have significant neuroprotection in this model. The non-competitive NMDA antagonist, MK 801, showed significant neuroprotection in the model when given at 0.5 mg kg-', i.p. 30 min pre-ischaemia with t.i.d. dosing for 7 days (P< 0.001). The dihydropyridine calcium antagonist, nimodipine was not protective when given using the same dosing protocol as MK 801, 0.5 mg kg-' 30 min pre-occlusion and three times daily for 7 days but showed significant protection when given at 0.05 mg kg-' 15 min post-ischaemia and three times daily for 7 days. The lipid peroxidation inhibitor, tirilazad (single dose 1 mg kg-', i.v.) showed significant neuroprotection when given 5 min post-ischaemia but not when the first dose was delayed for 4 h.

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“…amounts, but accumulates under adverse conditions such as cerebral ischemia (Bazan, 1970;Yoshida et al, 1980;Gardiner et al, 1981;Kinouchi et al, 1990). Release of the free fatty acid is attributable to breakdown of membrane phospholipids by activa tion of phospholipases (U memura et al, 1992).…”

mentioning

confidence: 99%

“…AA is a polyunsaturated lipid that mediates a variety of pathological processes, e.g., after conversion to prostaglandins, leukotrienes, or oxygen-derived free radicals (Wolfe, 1982). Free concentrations of AA of up to 0.5 mmollkg were found in brain tissue in cerebral ischemia (Kinouchi et al, 1990). Trau matic brain injury or seizures were also known to raise the concentration of free AA in the brain (Siesj6 et aI., 1982;Baethmann et aI., 1989).…”

mentioning

confidence: 99%

Swelling, Acidosis, and Irreversible Damage of Glial Cells from Exposure to Arachidonic Acid in vitro

Staub¹,

Winkler²,

Peters³

et al. 1994

J Cereb Blood Flow Metab

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Swelling and damage of C6 glioma cells and of primary cultured astrocytes were analyzed in vitro during incubation with arachidonic acid (AA; 20:4). The cells were suspended in a physiological medium supplemented with AA at concentrations of 0.001–1.0 m M. Cell swelling was quantified by flow cytometry with hydrodynamic focusing. Flow cytometry was also utilized for assessment of cell viability by exclusion of the fluorescent dye propidium iodide and for measurement of the intracellular pH (pHi) by 2′,7′-bis-(2-carboxyethyl)−5(and −6)carboxyfluorescein. Administration of AA caused an immediate dose-dependent swelling of C6 glioma cells, even at a concentration of 0.01 m M. At this level cell volume increased within 20 min to 105.0% of control, at 0.1 m M to 111.0%, while at 1.0 m M to 123.7%. Following a phase of rapid cell volume increase, swelling leveled off during the subsequent observation period of 70 min. Viability of the C6 glioma cells was 90% under control conditions. It remained unchanged after raising AA concentrations to 0.1 m M. At 0.5 m M, however, cell viability fell to 72.8%, and at 1.0 m M to 32.7%. pHi of the glioma cells was 7.3 under control conditions. In parallel with the early swelling phase, AA led to a dose-dependent decrease of the intracellular pH and an elevated lactate production of the cells. During incubation with 0.1 m M AA, pHi decreased to 7.06 after 5 min, but recovered to normal subsequently. In addition, swelling-inducing properties of linoleic (18:2) or stearic (18:0) acid were analyzed for evaluation of the specificity of glial swelling induced by AA. Whereas stearic acid (0.1 m M) failed to induce a swelling response, linoleic acid (0.1 m M) was found to be effective. The volume increase of the glial cells, however, was only half of that found during exposure to AA at the same concentration. Further, glial swelling from AA or linoleic acid was completely inhibited by the aminosteroid U-74389F, an antagonist of lipid peroxidation. Finally, omission of Na+ ions in the suspension medium with replacement by choline led also to inhibition of the cell volume increase by AA. Experiments using astrocytes from primary culture confirmed the swelling-inducing properties of AA at a quantitative level, whereas vulnerability of the cells to AA was increased. The present results demonstrate an important role of AA in cytotoxic swelling and irreversible damage of glial cells at concentrations that occur in vivo in cerebral ischemia or trauma. The damaging potential of AA might be enhanced by a concurrently evolving intracellular acidosis, stimulating the formation of oxygen-derived free radicals and lipid peroxidation.

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Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.

Cited by 31 publications

References 43 publications

Potentiation of Native and Recombinant P2X7-Mediated Calcium Signaling by Arachidonic Acid in Cultured Cortical Astrocytes and Human Embryonic Kidney 293 Cells

Potentiation of Native and Recombinant P2X7-Mediated Calcium Signaling by Arachidonic Acid in Cultured Cortical Astrocytes and Human Embryonic Kidney 293 Cells

Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia

Swelling, Acidosis, and Irreversible Damage of Glial Cells from Exposure to Arachidonic Acid in vitro

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