Epileptogenic effect of cyclosporine in guinea-pig hippocampal slices

Institut für Physiologie, Universität Münster, Robert-Koch-Strasse 27a, 48149, Münster, Germany.
Neuroscience (Impact Factor: 3.36). 02/2002; 115(4):993-7. DOI: 10.1016/S0306-4522(02)00507-9
Source: PubMed


Cyclosporine A (CsA) neurotoxicity is a common cause of seizures in transplant patients and others receiving immunosuppressive therapy. CsA at concentrations higher than the levels estimated for cerebrospinal fluid of the patients suffering from seizure attacks was ineffective to induce epileptiform field potentials (EFP) in in vitro brain-slice preparation. The aim of this study was to test the effect of CsA at lower concentrations on neuronal activity. Guinea-pig hippocampal slices were exposed to artificial cerebrospinal fluid containing CsA (0.1-2 microM). Furthermore, the effects of CsA (0.25-10 microM) were tested on EFP elicited by omission of Mg2+ from superfusate. Low concentrations of CsA (0.1-0.25 microM) induced EFP while higher doses (0.5-2 microM) failed to decrease the seizure threshold. CsA at concentrations of 0.25 and 1 microM had no significant effect on the low Mg2+-induced EFP. Higher CsA concentration (10 microM) strongly suppressed EFP. The results indicate that CsA at doses that are probably clinically relevant increases the neuronal excitability.

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    • "It was supposed that a breakdown of cortico-cortical interactions at any level might be reflected in abnormalities of glutamate N-Nitrosodimethylamine (NMDA) subreceptor function (Wong & Prince, 1990). Indeed , blocking of NMDA receptors lead to functional disruption of signal processing in epileptic neocortical tissues (Wong & Prince, 1990; Gorji et al., 2002, 2003). Furthermore , focal application of dopamine produced a short transient abnormal pattern of lateral conduction of epileptiform discharges in neocortical slices (Gorji et al., 2003). "
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    ABSTRACT: The effects of AMPA-type glutamate receptor as well as dopamine D1 and D2 receptors on the lateral propagation of epileptiform field potentials (EFP) were studied across adjacent areas of rat neocortical tissues. Epileptiform burst discharges were induced by superfusion of Mg(2+)-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer of the neocortex. The effects of AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), dopamine D1 receptor agonist SKF 81297, and dopamine D2 receptor agonist quinpirole on lateral propagation of burst discharges were investigated. CNQX, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. Focal application of SKF 81297 between recording sites increased the repetition rate of EFP, but reduced the amplitude as well as the duration of epileptic discharges. However, addition of SKF 81297 to the bath medium abolished EFP. Both local and systemic applications of quinpirole irreversibly enhanced repetition rate of epileptiform burst discharges. The results indicate the prerequisite of AMPA synaptic transmission for synchronized lateral propagation of Mg(2+)-free ACSF-induced epileptic activity and the modulatory effects of dopamine D1 and D2 receptors on both EFP initiation and propagation in epileptic tissues.
    Epilepsia 03/2008; 49(2):237-47. DOI:10.1111/j.1528-1167.2007.01385.x · 4.57 Impact Factor
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    • "Gorji et al., 2002). Different effects of calcineurin inhibitors and rapamycin on the neuronal excitability may be attributed to the different mechanism of action . "
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    ABSTRACT: Neurological complications are common in transplant recipients treated with immunosuppressant calcineurin inhibitors. Rapamycin, a macrolide antibiotic, was suggested as an alternative agent in patients who develop calcineurin inhibitor associated neurotoxicity, including seizure attacks. The aim of the present study was to test the effect of rapamycin on the bioelectrical activity and evoked field excitatory postsynaptic potentials (fEPSP) in CA1 area of hippocampal tissues and compare its effect with FK506, a calcineurin inhibitor agent. Application of rapamycin at different concentrations neither affected the bioelectrical activity nor changed fEPSP magnitude. In contrast, FK506 elicited epileptiform burst discharges and significantly enhanced fEPSP magnitude. This study supports the suggestion that rapamycin could be used as an alternative to calcineurin inhibitors in the event of neurotoxicity.
    Epilepsia 05/2007; 48(4):834-6. DOI:10.1111/j.1528-1167.2006.00976.x · 4.57 Impact Factor
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    ABSTRACT: Although ulcerative colitis and Crohn’s disease have traditionally been considered to be inflammatory diseases limited to the gastrointestinal tract, it has been shown that both pathologies are frequently accompanied by various extraintestinal disorders. There is an increasing evidence that they may also manifest in the nervous system, including the peripheral and the central parts. Although some of these neurological complications have been known for a long time, such as cerebrovascular disease, vasculitis and autoinmune processes including neuropathies and cerebral demyelination, others have been recently described. With the exception of some of this complications such as the thromboembolism, evidence for a casual relationship relies merely on single case reports or case series. In this article, we try to review the existing evidence on neurological manifestations of both variants of inflammatory bowel disease.
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