Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial.

BACKGROUND: Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations. METHODS: IMN patients with SRNS (age 16-75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2-3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks. RESULTS: Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3-1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications. CONCLUSION: CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2-3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.

Vascular dysfunction and impaired insulin signaling in high-fat diet fed ovariectomized mice.

The metabolic syndrome, characterized by conditions such as obesity and insulin resistance, is more prevalent in postmenopausal women than in premenopausal women, and increases the risk of cardiovascular disease and type 2 diabetes. The main objective of the present study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HFD) on metabolic parameters, vascular function and glucose homeostasis in mice. After OVX or sham operation (Sham), mice were fed with either a normal diet (ND) or a HFD. Mice were divided into ND+Sham, ND+OVX, HFD+Sham, and HFD+OVX groups. After 4weeks, HFD+OVX mice developed marked increases in body weight and plasma insulin levels, but not blood glucose levels. The area under the glucose tolerance curve (Δ AUC(glucose)) following an oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR) revealed that HFD+OVX mice had higher values than any other group. Concomitantly with these metabolic disturbances, decreased tail skin blood flow and augmented tail skin flushing, a marker of hot flashes, were observed in HFD+OVX mice. These vascular modulations likely result from vasomotor dysfunction. Furthermore, we investigated whether OVX and HFD affect the insulin signaling pathway in mice. Insulin-induced Akt phosphorylation in the livers of HFD+OVX mice was significantly downregulated compared with ND+Sham and HFD+Sham mice. Thus, the HFD+OVX mice used in the present study constitute an experimental animal model of postmenopausal metabolic syndrome. Herein, we provide experimental evidence that vascular dysfunction and impaired insulin signaling may contribute to the pathogenesis of postmenopausal metabolic syndrome.

Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1.

The blood-brain barrier (BBB) is the interface that separates the central nervous system (CNS) from the peripheral circulation. An increase in blood-borne substances including cytokines in plasma and brain affects BBB function, and this is associated with the development of pathogenesis of a number of diseases. Plasminogen activator inhibitor (PAI)-1 regulates the plasminogen activator/plasmin system as a serpin in the periphery and the CNS. We investigated whether PAI-1 alters BBB function using in vitro models of the BBB consisting of rat primary brain endothelial cells (RBECs) alone and co-cultured with pericytes. We found that PAI-1 increased the tightness of the brain endothelial barrier in a time- and dose-dependent manner, as shown by an increase in the transendothelial electrical resistance (TEER) and a decrease in the permeability to sodium fluorescein (Na-F). RBECs responded equally to PAI-1 in the blood-facing and brain-facing sides of the brain, leading to a decrease in Na-F permeability. In addition, RBECs constitutively released PAI-1 into the blood-facing (luminal) and brain-facing (abluminal) sides. This release was polarized in favor of the luminal side and facilitated by serum. The neutralization of PAI-1 by an antibody to PAI-1 in RBEC/pericyte co-culture more robustly reduced TEER of RBECs than in RBEC monolayers. These findings suggest that PAI-1 derived from the neurovascular unit and peripheral vascular system participates as a positive regulator of the BBB in facilitating the barrier function of the endothelial tight junctions.

Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia.

The blood-brain barrier (BBB) is formed by brain capillary endothelial cells, astrocytes, pericytes, microglia, and neurons. BBB disruption under pathological conditions such as neurodegenerative disease and inflammation is observed in parallel with microglial activation. To test whether activation of microglia is linked to BBB dysfunction, we evaluated the effect of lipopolysaccharide (LPS) on BBB functions in an in vitro co-culture system with rat brain microvascular endothelial cells (RBEC) and microglia. When LPS was added for 6 h to the abluminal side of RBEC/microglia co-culture at a concentration showing no effects on the RBEC monolayer, transendothelial electrical resistance was decreased and permeability to sodium-fluorescein was increased in RBEC. Immunofluorescence staining for tight junction proteins demonstrated that zonula occludens-1-, claudin-5-, and occludin-like immunoreactivities at the intercellular borders of RBEC were fragmented in the presence of LPS-activated microglia. These functional changes induced by LPS-activated microglia were blocked by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, diphenyleneiodonium chloride. The present findings suggest that LPS activates microglia to induce dysfunction of the BBB by producing reactive oxygen species through NADPH oxidase.

Medication use as a risk factor for inpatient falls in an acute care hospital: a case-crossover study.

AIMS: The present study aimed to evaluate the associations between medication use and falls and to identify high risk medications that acted as a trigger for the onset of falls in an acute care hospital setting. METHODS: We applied a case-crossover design wherein cases served as their own controls and comparisons were made within each participant. The 3-day period (days 0 to -2) and the 3-day periods (days -6 to -8, days -9 to -11 and days -12 to -14) before the fall event were defined as the case period and the control periods, respectively. Exposures to medications were compared between the case and control periods. Odds ratios (OR) and 95% confidence intervals (CI) for the onset of falls with respect to medication use were computed using conditional logistic regression analyses. RESULTS: A total of 349 inpatients who fell during their hospitalization were recorded on incident report forms between March 2003 and August 2005. The initial use of antihypertensive, antiparkinsonian, anti-anxiety and hypnotic agents as medication classes was significantly associated with an increased risk of falls, and these ORs (95% CI) were 8.42 (3.12, 22.72), 4.18 (1.75, 10.02), 3.25 (1.62, 6.50) and 2.44 (1.32, 4.51), respectively. The initial use of candesartan, etizolam, biperiden and zopiclone was also identified as a potential risk factor for falls. CONCLUSIONS: Medical professionals should be aware of the possibility that starting a new medication such as an antihypertensive agent, including candesartan, and antiparkinsonian, anti-anxiety and hypnotic agents, may act as a trigger for the onset of a fall.

Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells.

The present study was designed to elucidate the involvement of tumor necrosis factor-alpha (TNF-alpha) release from activated microglia in the induction of blood-brain barrier (BBB) dysfunction in an in vitro co-culture system with mouse brain capillary endothelial cells (MBEC4) and microglia. Lipopolysaccharide (LPS)-activated microglia increased the permeability of MBEC4 cells to sodium-fluorescein, and this hyper-permeability was blocked by a neutralizing antibody against TNF-alpha. LPS stimulated microglia to facilitate TNF-alpha release. These findings suggested that TNF-alpha released from activated microglia is attributable to BBB dysfunction.

[Development of clinical trial education program for pharmaceutical science students through small group discussion and role-playing using protocol].

The acquirement of basic knowledge of clinical trials and professional attitude in their practices is a general instructional objective in the Model Core Curriculum for Pharmaceutical Education. Unfortunately, the previous program of clinical trial education was not effective in the acquirement of a professional attitude in their practices. Then, we developed the new clinical trial education program using protocol through small group discussion (SGD) and roll-playing. Our program consists of 7 steps of practical training. In step 1, the students find some problems after presentation of the protocol including case and prescription. In step 2, they analyse the extracted problems and share the information obtained in SGD. In steps 3 and 5, five clinical case scenarios are presented to the students and they discuss which case is suitable for entry to the clinical trial or which case corresponds to the discontinuance criteria in the present designed protocol. In steps 4 and 6, the roll-playing is performed by teachers and students as doctors and clinical research coordinators (CRC) respectively. Further, we conducted a trial practice based on this program for the students. In the student's self-evaluation into five grades, the average score of the skill acquisition level in each step was 3.8-4.7 grade. Our clinical trial education program could be effective in educating the candidates for CRC or clinical pharmacists.

Selective serotonin reuptake inhibitors fluvoxamine and paroxetine restore forced exercise-induced temperature dysregulation in ovariectomized mice.

Hot flushes are one of the most frequent symptoms in menopausal women. Selective serotonin reuptake inhibitors (SSRIs) are considered to be first-line therapy for the treatment of hot flushes in women for whom hormone therapy is contraindicated. Recently, we have proposed forced exercise-induced flushing of tail skin in ovariectomized mice as a new experimental model of temperature dysregulation in menopausal hot flushes. In the present study, to validate this animal model as a tool for testing potential compounds for the treatment of menopausal hot flushes, we examined the effects of two SSRIs (fluvoxamine and paroxetine) on forced exercise-induced flushing of tail skin in ovariectomized mice, and compared it with that of estradiol replacement (1 mg/kg/week for 3 weeks, i.m.). Treatment with fluvoxamine (20 mg/kg, i.p.) or paroxetine (10 mg/kg, i.p.) completely inhibited forced exercise-induced flushing of tail skin in ovariectomized mice, and the effect of each was comparable to that of estradiol replacement. It is believed that the present findings provide the first experimental evidence to support the anti-flushing effects of SSRIs, such as fluvoxamine and paroxetine, in a clinical setting. An animal model with forced exercise probably serves as a useful experimental tool for evaluating the effects of different agents on hot flushes.

Oncostatin M induces functional and structural impairment of blood-brain barriers comprised of rat brain capillary endothelial cells.

Oncostatin M (OSM), a member of the interleukin-6 family, is produced by monocytes and macrophages in the peripheral blood and microglia in the brain. The present study aimed to elucidate a regulatory role of OSM in the functions of blood-brain barrier (BBB) comprised of rat brain capillary endothelial cells (RBECs). OSM decreased the transendothelial electrical resistance of RBEC monolayers in a concentration- and time-dependent manner. Immunocytochemical observations of ZO-1 and claudin-5 in OSM-treated RBECs showed a zipper-like and/or zigzag shape along the junctions between cells, in contrast with the smooth and linear shape in vehicle-treated cultures. When RBECs were pre-treated with anti-OSM antibody, OSM failed to evoke these changes. The cellular constituents producing OSM in the brain and peripheral blood could be implicated in the functional and structural impairment of the BBB.

DRESS Syndrome Caused by Cross-reactivity Between Vancomycin and Subsequent Teicoplanin Administration: A Case Report.

BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening syndrome comprising severe skin eruption, fever, eosinophilia, lymphadenopathy, and involvement of internal organs. Here, we describe a case of DRESS syndrome caused by cross-reactivity between vancomycin and subsequent teicoplanin administration. CASE REPORT A 79-year-old male was admitted to our hospital for the treatment of injuries incurred in a traffic accident. Eosinophilia and lung dysfunction appeared after vancomycin administration. These symptoms were improved temporarily by withdrawal of vancomycin and administration of corticosteroid, but exacerbated by subsequent teicoplanin administration. These symptoms disappeared after discontinuation of teicoplanin. Based on comprehensive assessment of the overall clinical course, we judged that DRESS syndrome was induced by cross-reactivity between vancomycin and subsequent teicoplanin administration. Using the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system, we categorized DRESS syndrome related to vancomycin and teicoplanin as "probable." We describe, for the first time, DRESS syndrome (defined using the RegiSCAR scoring system) caused by cross-reactivity between vancomycin and subsequent teicoplanin administration. CONCLUSIONS Clinicians should be aware that DRESS syndrome can be induced by cross-reactivity between vancomycin and teicoplanin.

The statins fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals.

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3mg/kg/day for 7days, p.o.) significantly ameliorated the flushing of tail skin in ovariectomized mice, and the effect of each statin was comparable with that of estrogen replacement (1mg/kg/week for 3weeks, i.m.). In phenylephrine-pre-contracted rat-tail arteries, ovariectomy inhibited acetylcholine-induced relaxation, but augmented sodium nitroprusside-induced relaxation. These ovariectomy-altered vasodilator responses were restored by fluvastatin treatment as well as by estrogen replacement. Nitrite/nitrate levels in the plasma of ovariectomized animals showed significantly lower values than those in sham-operated animals; this ovariectomy-reduced production of nitric oxide was improved by fluvastatin treatment. These data provide the first experimental evidence that statins such as fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Thus, therapeutic methods that target improvement of vasomotor dysfunction could be novel strategies for reducing menopausal hot flushes.

Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice.

AIMS: Cyclosporin A, a calcineurin inhibitor, produces neurotoxicity with relatively high frequency in organ-transplanted patients. The aim of the present study was to clarify whether acute liver failure (ALF) simulated to the transient liver dysfunction at an early phase after liver transplantation increases the susceptibility to cyclosporin A-induced neurotoxicity through the blood-brain barrier (BBB) dysfunction. MAIN METHODS: The right internal, left lateral and left internal lobes in male ddy mice were surgically excised under sodium pentobarbital anesthesia. Effect of cyclosporin A on harmine-induced tremors was examined and BBB permeability to (3)[H]cyclosporin A was assessed in partially (70%) hepatectomized mice at postoperative days 1, 3 and 7. KEY FINDINGS: Patrial hepatectomy aggravated harmine-induced tremors. Cyclosporin A (50mg/kg, i.p.) markedly augmented harmine-induced tremors in partially hepatectomized mice at postoperative day 1. Consistent with these behavioral findings, the brain uptake of (3)[H]cyclosporin A in mice injected with (3)[H]cyclosporin A into the jugular vein at postoperative day 1 was significantly increased by partial hepatectomy compared with sham operation. SIGNIFICANCE: Our results indicate that ALF increases BBB permeability to cyclosporin A by lowering the function of P-glycoprotein and tight junctions, consequently leading to augmentation of cyclosporin A-induced neurotoxicity. The possibility that cyclosporin A increases the risk of neurotoxicity including tremors at an early phase of liver transplantation must be considered.

Disruption of the blood-brain barrier in collagen-induced arthritic mice.

Patients with rheumatoid arthritis (RA) are at higher risk of developing pathological cardiovascular and cerebrovascular events than non-RA subjects. Vascular endothelial dysfunction is involved in the induction of cardiovascular events and this process is also observed in patients with RA. Endothelial dysfunction impairs the integrity of the blood-brain barrier (BBB); this phenomenon also underlies brain damage in cerebrovascular diseases. This study was aimed at evaluating the influence of a chronic inflammatory state on BBB integrity in RA using collagen-induced arthritis (CIA), an animal model of RA. CIA was induced by intradermal injection of type II collagen emulsified with Freund's complete adjuvant at the base of the tail of DBA/1 mice. Cerebrovascular permeability was assessed by measurement of sodium fluorescein (Na-F) content in the brains of CIA mice. The expression level of tight junction proteins was investigated by immunoblotting and immunofluorescence of occludin and zonula occludens-1 (ZO-1). Cerebrovascular permeability to Na-F in the brain was increased in CIA mice. This CIA-induced BBB hyperpermeability was more remarkable in the advanced stage than that in the persistent stage of the arthritis. The expression of occludin, but not that of ZO-1, was decreased by CIA. Our results indicate that the integrity of the BBB could be impaired in the inflammatory pathophysiology of RA.

Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function.

Cyclosporin A, a potent immunosuppressant, can often produce neurotoxicity in patients, although its penetration into the brain is restricted by the blood-brain barrier (BBB). Brain pericytes and astrocytes, which are periendothelial accessory structures of the BBB, can be involved in cyclosporin A-induced BBB disruption. However, the mechanism by which cyclosporin A causes BBB dysfunction remains unknown. Here, we show that in rodent brain endothelial cells, cyclosporin A decreased transendothelial electrical resistance (TEER) by inhibiting intracellular signal transduction downstream of adrenomedullin, an autocrine regulator of BBB function. Cyclosporin A stimulated adrenomedullin release from brain endothelial cells, but did not affect binding of adrenomedullin to its receptors. This cyclosporin A-induced decrease in TEER was attenuated by exogenous addition of adrenomedullin. Cyclosporin A dose-dependently decreased the total cAMP concentration in brain endothelial cells. A combination of cyclosporin A (1microM) with an adenylyl cyclase inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536; 10microM), or a protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89; 1microM), markedly increased sodium fluorescein permeability in brain endothelial cells, whereas each drug alone had no effect. Thus, these data suggest that cyclosporin A inhibits the adenylyl cyclase/cyclic AMP/PKA signaling pathway activated by adrenomedullin, leading to impairment of brain endothelial barrier function.

Gender differences in tail-skin flushing induced by nitrates and phosphodiesterase type 5 inhibitors in a climacteric mouse model.

Flushing is one of the most common vasodilation-related adverse effects associated with both nitrates and phosphodiesterase type 5 (PDE5) inhibitors. The present study aimed to investigate the effects of orchidectomy and ovariectomy on isosorbide dinitrate-, sildenafil-, vardenafil- and tadalafil-induced flushing of tail-skin in mice. Both orchidectomy and ovariectomy markedly increased the tail-skin temperature, a good parameter of flushing, induced by isosorbide dinitrate (500 microg/kg, i.p.). These observations suggest that both testosterone withdrawal and estrogen withdrawal are risk factors for isosorbide dinitrate-induced flushing. In contrast, sildenafil (100 mg/kg, p.o.)-, vardenafil (10 mg/kg, p.o.)- and tadalafil (40 mg/kg, p.o.)-induced flushing of tail-skin in mice was aggravated by ovariectomy but not by orchidectomy. Orchidectomized male mice, but not ovariectomized female mice, showed significantly lower levels of PDE5 mRNA expression in tail artery compared with those of sham-operated mice. The present findings suggest that estrogen withdrawal, but not testosterone withdrawal, is a risk factor for PDE5 inhibitor-induced flushing. These gender differences in the vascular adverse reactions of PDE5 inhibitors may be interpreted as occurring due to differences in the levels of PDE5 mRNA expression in peripheral arteries.

An inhibitory role of nitric oxide in the dynamic regulation of the blood-brain barrier function.

1. The present study aimed at elucidating the effect of nitric oxide (NO) on blood-brain barrier (BBB) function with mouse brain capillary endothelial (MBEC4) cells.2. Histamine (20-100 microM) evoked NO production (1.6-7 microM) in MBEC4 cells in a dose-dependent manner.3. The permeability coefficient of sodium fluorescein for MBEC4 cells and the cellular accumulation of rhodamine 123 in MBEC4 cells were increased dose-dependently by the addition of NO solutions (14 and 28 microM) every 10 min during a 30-min period.4. The present study demonstrated that NO increased the permeability and inhibited the P-glycoprotein efflux pump of brain capillary endothelial cells, suggesting that NO plays an inhibitory role in the dynamic regulation of the BBB function.

Protective action of indapamide, a thiazide-like diuretic, on ischemia-induced injury and barrier dysfunction in mouse brain microvascular endothelial cells.

The aim of the present study was to elucidate the effects of indapamide on ischemic damage to the blood-brain barrier (BBB) in vitro. The ischemia/reperfusion conditions employed here significantly decreased the viability of mouse brain capillary endothelial (MBEC4) cells, an effect ameliorated by indapamide. Ischemia increased the permeability of MBEC4 cells to two cellular transport markers, sodium fluorescein and Evan's blue-albumin. Indapamide reduced the ischemia-induced hyperpermeability of cells. These results suggest that indapamide may have a protective role against ischemia-induced injury and dysfunction of the BBB.

Inhibition of transforming growth factor-beta production in brain pericytes contributes to cyclosporin A-induced dysfunction of the blood-brain barrier.

: 1. The present study was designed to clarify whether brain pericytes and pericyte-derived transforming growth factor-beta1 (TGF-beta1) participate in cyclosporin A (CsA)-induced dysfunction of the blood-brain barrier (BBB).2. The presence of brain pericytes markedly aggravated CsA-increased permeability of MBEC4 cells to sodium fluorescein and accumulation of rhodamine 123 in MBEC4 cells.3. Exposure to CsA significantly decreased the levels of TGF-beta1 mRNA in brain pericytes in pericyte co-cultures. Treatment with TGF-beta1 dose-dependently inhibited CsA-induced hyperpermeability and P-glycoprotein dysfunction of MBEC4 cells in pericyte co-cultures.4. These findings suggest that an inhibition of brain pericyte-derived TGF-beta1 contributes to the occurrence of CsA-induced dysfunction of the BBB.

Adverse effect of cyclosporin A on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro.

Hypoxia and post-hypoxic reoxygenation induces disruption of the blood-brain barrier (BBB). Alterations of the BBB function after hypoxia/reoxygenation (H/R) injury remain unclear. Cyclosporin A (CsA), a potent immunosuppressant, induces neurotoxic effects by entering the brain, although the transport of CsA across the BBB is restricted by P-glycoprotein (P-gp), a multidrug efflux pump, and tight junctions of the brain capillary endothelial cells. The aim of this study was to evaluate whether the BBB after H/R damage is vulnerable to CsA-induced BBB dysfunction. We attempted to establish a pathophysiological BBB model with immortalized mouse brain capillary endothelial (MBEC4) cells. The effects of CsA on permeability and P-gp activity of the MBEC4 cells were then examined. Exposure to hypoxia for 4 h and reoxygenation for 1 h (H/R (4 h/1 h)) produced a significant decrease in P-gp function of MBEC4 cells, without changing cell viability and permeability for sodium fluorescein and Evan's blue-albumin at 7 days after H/R (4 h/1 h). CsA-induced hyperpermeability and P-gp dysfunction in MBEC4 monolayers at 7 days after H/R (4 h/1 h) were exacerbated. The possibility that CsA penetrates the BBB with incomplete functions in the vicinity of cerebral infarcts to induce neurotoxicity has to be considered.

Cyclosporin A aggravates electroshock-induced convulsions in mice with a transient middle cerebral artery occlusion.

1. To test whether an ischemic insult increases the susceptibility to cyclosporine A (CsA)-induced neurotoxicity, we examined the effect of CsA on the minimal electroshock-induced convulsions in mice treated with a transient middle cerebral artery occlusion (MCAO) for a short period (2 h). 2. This MCAO produced small to mid-sized infarcted regions in the cerebral hemisphere with increasing post-operative days. In MCAO mice, CsA (30 mg/kg, i.p.) elevated the incidence of minimal electroshock-induced convulsions to 90-100% over that in sham mice (20-30%) at 1-7 days but not 14 days post-surgery. 3. In light of these findings, the possibility that CsA increases the risk of convulsions in patients with cerebral infarction and/or at an early stage following focal cerebral ischemia would have to be considered.