tacrolimus and Status-Epilepticus

Tacrolimus is a macrolide immunosuppressant widely used to prevent rejection after solid organ transplantation. In general, adverse events of tacrolimus occur more often as the concentration of tacrolimus in the blood increases. We report the case of a 39-year-old man who developed a variety of adverse events despite in the therapeutic level of tacrolimus in the blood.. A 39-year-old man underwent liver transplantation for liver cirrhosis due to alcoholic liver disease. The postoperative immunosuppressant consisted of tacrolimus (5 mg) and mycophenolate (500 mg) twice daily. Five months after taking tacrolimus, he presented with talkativeness, which gradually worsened. Brain magnetic resonance imaging performed 10 months after tacrolimus administration revealed a hyperintense lesion affecting the middle of the pontine tegmentum on T2WI. The blood concentration of tacrolimus was 7.2 ng/mL (therapeutic range 5-20 ng/mL). After 21 months, he exhibited postural tremor in both the hands. Twenty-four months after taking tacrolimus, he showed drowsy mentality, intention tremor, and dysdiadochokinesia. Electroencephalography presented generalized high-voltage rhythmic delta waves; therefore, tacrolimus was discontinued in suspicion of tacrolimus-induced neurotoxicity, and anticonvulsive treatment was started. The level of consciousness gradually improved, and the patient was able to walk independently with mild ataxia.. This case shows that tacrolimus-induced neurotoxicity can occur even at normal concentrations. Therefore, if a patient taking tacrolimus exhibits psychiatric or neurologic symptoms, neurotoxicity should be considered even when the blood tacrolimus is within the therapeutic range.

Topics: Adult; Bipolar Disorder; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Status Epilepticus; Tacrolimus

A 58-year-old woman developed rapidly progressive neurological symptoms and finally loss of vigilance 5 weeks following primarily successful lung transplantation. A posterior reversible encephalopathy syndrome (PRES) under treatment with tacrolimus as well as hyperammonemia due to sepsis with Ureaplasma urealyticum could be identified as the causes. Infections with Ureaplasma, bacteria which produce ammonia as a product of metabolism, are increasingly being identified in immunocompromised people by specific PCR (polymerase chain reaction) procedures and should routinely be taken into consideration as the cause of unspecific neurological symptoms.

Topics: Brain Edema; Female; Humans; Hyperammonemia; Immunocompromised Host; Lung Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Status Epilepticus; Tacrolimus; Ureaplasma Infections; Ureaplasma urealyticum

To investigate the mechanisms underlying the neuroprotective effect of tacrolimus (FK506) on the hippocampal neurons of rats with status epilepticus (SE).. A total of 126 male Wistar rats were randomly and equally divided into the control group, the epilepsy group, and the epilepsy + FK506 group. The epilepsy group and the epilepsy + FK506 group were both injected with pilocarpine to establish SE models. The epilepsy + FK506 group was pretreated with FK506 at 24 h and 1 h prior to pilocarpine injection. The contents of nitric oxide (NO), nitric oxide synthase (NOS), malondialdehyde (MDA), and apoptosis-inducing factor (AIF) of the hippocampus were measured. The expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in the hippocampus was determined by immunohistochemistry. Mitochondrial membrane potential (MMP) and mitochondria size were also detected by flow cytometry.. FK506 could increase the survival of neurons in the hippocampus. Compared with the epilepsy group, the levels of NO, NOS (including nNOS and iNOS), and MDA were obviously decreased by FK506 (P < 0.05). Moreover, FK506 reversed the SE-induced MMP reduction and mitochondrial expansion (P < 0.05). Besides, compared with the epilepsy group, FK506 significantly increased the AIF level in the mitochondrial, but decreased that in the nuclear fractions, respectively (P < 0.05).. FK506 plays an important role in neuroprotection, possibly through suppressing oxidative stress and inhibiting the mitochondrial pathway of apoptosis.

Topics: Animals; Apoptosis; Epilepsy; Hippocampus; Male; Mitochondria; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Status Epilepticus; Tacrolimus

After status epilepticus (SE), actin cytoskeleton (F-actin) becomes progressively deconstructed in the hippocampus, which is consistent with the delayed pyramidal cell death in both time course and spatial distribution. A variety of experiments show that calcineurin inhibitors such as FK506 are able to inhibit the SE-induced actin depolymerization. However, it is still unclear what changes happen to the F-actin in the epileptic brain after FK506 treatment. A pilocarpine model of SE in mice was used to examine the effects of FK506 on the F-actin in the hippocampal neurons. The post SE (PSE) mice with or without FK506 treatment were monitored consecutively for 14 days to examine the frequency and duration of spontaneous seizures. The effects of FK506 on the activity of cofilin and actin dynamics were assessed at 7 and 14 d PSE by western blots. The organization of F-actin, neuronal cell death, and glial reactions were investigated by phalloidin staining, histological and immunocytochemical staining, respectively. As compared to the PSE + vehicle mice, FK506 treatment significantly decreased the frequency and duration of spontaneous seizures. Relative to the PSE + vehicle mice, western blots detected a partial restoration of phosphorylated cofilin and a significant increase of F/G ratio in the hippocampus after FK506 treatment. In the PSE + vehicle mice, almost no F-actin puncta were left in the CA1 and CA3 subfields at 7 and 14 d PSE. FK506-treated PSE mice showed a similar decrease of F-actin, but the extent of damage was significantly ameliorated. Consistently, the surviving neurons became significantly increased in number after FK506 treatment, relative to the PSE + vehicle groups. After FK506 treatment, microglial reaction was partially inhibited, but the expression of GFAP was not significantly changed, compared to the PSE + vehicle mice. The results suggest that post-epileptic treatment with FK506 ameliorated, but could not stop the deconstruction of F-actin or the delayed neuronal loss in the PSE mice.

Topics: Actin Cytoskeleton; Actins; Animals; Anticonvulsants; Calcineurin Inhibitors; Calcium-Binding Proteins; Cell Survival; Disease Models, Animal; Hippocampus; Male; Mice, Inbred ICR; Microfilament Proteins; Neuroglia; Neurons; Neuroprotective Agents; Pilocarpine; Random Allocation; Status Epilepticus; Tacrolimus

To determine if the activity-dependent trafficking of γ2 subunit-containing γ-aminobutyric acid type A receptors (GABAA Rs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age-dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity-dependent plasticity of these receptors.. The efficacy and potency of diazepam 0.2-10 mg/kg administered 3 or 60 min after the onset of a lithium/pilocarpine-induced seizure in postnatal day 15-16 rats was evaluated using video-electroencephalography (EEG) recordings. The surface expression of γ2 subunit-containing GABAA Rs was assessed using a biotinylation assay, and GABAA R-mediated miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch-clamp recording techniques from dentate granule cells in hippocampal slices acutely obtained 60 min after seizure onset (SE-treated). The effect of the protein phosphatase inhibitors FK506 and okadaic acid (OA) on the surface expression of these receptors was determined in organotypic slice cultures exposed to high potassium and N-methyl-d-aspartate (NMDA) or in SE-treated slices.. Diazepam terminated seizures of 3 min but not 60 min duration, even at the highest dose. In the SE-treated slices, the surface expression of γ2 subunit-containing GABAA Rs was reduced and the amplitude of the mIPSCs was diminished. Inhibition of protein phosphatases prevented the activity-induced reduction of the γ2 subunit-containing GABAA Rs in organotypic slice cultures. Furthermore, treatment of SE-treated slices with FK506 or OA restored the surface expression of the γ2 subunit-containing GABAA Rs and the mIPSC amplitude.. This study demonstrates that the plasticity of γ2 subunit-containing GABAA Rs associated with the development of benzodiazepine resistance in young and adult animals is similar. The findings of this study suggest that the mechanisms regulating the activity-dependent trafficking of GABAA Rs during SE can be targeted to develop novel adjunctive therapy for the treatment of benzodiazepine-refractory SE.

Topics: Animals; Animals, Newborn; Anticonvulsants; Cells, Cultured; Diazepam; Disease Models, Animal; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Hippocampus; Immunosuppressive Agents; In Vitro Techniques; N-Methylaspartate; Neurons; Okadaic Acid; Organ Culture Techniques; Phosphoric Monoester Hydrolases; Pilocarpine; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, GABA; Status Epilepticus; Tacrolimus

Calcineurin (CaN)-mediated excitotoxicity impairs γ-aminobutyric acid (GABA) transmission and induces neuronal apoptosis. Ca(2+)-dependent K(+)-Cl(-) cotransporter 2 (KCC2) participates in GABAergic inhibitory transmission. However, the mechanism by which CaN mediates GABA receptor-mediated KCC2 in seizures is not fully understood. In the present study, we investigated the altered expression of KCC2 and the effects of the CaN inhibitor FK506 on KCC2 expression in the mouse hippocampus following kainic acid (KA) treatment. FK506 was injected twice 24 h and 30 min before KA treatment and then mice were treated with KA and killed 2 days later. FK506 had anticonvulsant effect on KA-induced seizure activities. CaN cleavage was evident in the hippocampus 24 h after KA treatment. FK506 pretreatment blocked the truncation of CaN in the KA-treated hippocampus. Cresyl violet and TUNEL staining showed that FK506 prevented KA-induced hippocampal cell death. In particular, Western blot analysis showed that KCC2 expression was time dependent, with a peak at 6 h and a return to decreased levels at 48 h, whereas FK506 pretreatment inhibited the KA-induced decrease in KCC2 expression in the hippocampus. Immunofluorescence showed that FK506 pretreatment protected the loss of inhibitory GABAergic KCC2-expressing neurons following KA treatment. Taken together, these results provide evidence that altered KCC2 expression may be associated with Ca(2+)-mediated seizure activity and indicate that neuron-specific KCC2 may be involved in neuroprotection after seizures.

Topics: Animals; Blotting, Western; Calcineurin Inhibitors; Cell Death; Down-Regulation; Excitatory Amino Acid Agonists; Fluorescent Antibody Technique; Hippocampus; Immunohistochemistry; Immunosuppressive Agents; In Situ Nick-End Labeling; K Cl- Cotransporters; Kainic Acid; Male; Mice; Mice, Inbred ICR; Neurons; Status Epilepticus; Symporters; Tacrolimus

Oxidative stress, which is defined as the over-production of free radicals, can dramatically alter neuronal function and has been linked to status epilepticus (SE). The pathological process and underlying mechanisms involved in the oxidative stress during SE are still not fully clear. In the current study, SE was induced in rats by lithium-pilocarpine administration. Our data show that hippocampal neuron death occurs at 6h and is sustained for 7 days after SE. The production of nitric oxide (NO) started to increase at 30 min and was evident at 6h and 7 days after SE, which coincided with increased expression of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and malondialdehyde (MDA) after SE, whereas, activated caspase-3 prominently appeared at 7 days after SE. Further, FK506, an immunosuppressant, partially rescued the neuron death and attenuated the expression of NO, nNOS, iNOS, MDA and activated caspase-3. Taken together, our study indicates that oxidative stress mediated hippocampal neuron death occurs prior to caspase-3 activation and that FK506 plays an important role in protecting hippocampal neurons during status epilepticus.

Topics: Animals; Blotting, Western; Caspase 3; Cell Death; Hippocampus; Immunohistochemistry; Immunosuppressive Agents; Lithium; Male; Malondialdehyde; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Oxidative Stress; Pilocarpine; Rats; Rats, Wistar; Status Epilepticus; Tacrolimus

Calcineurin (CaN) is a neuronally enriched, calcium-dependent phosphatase, which plays an important role in a number of neuronal processes including development of learning and memory, and modulation of receptor's function and neuronal excitability as well as induction of apoptosis. It has been established in kindling model that the status epilepticus (SE)-induced increase in CaN activity is involved in the development of seizures through down-regulation of gamma-aminobutyric acid A receptor (GABA(A)R) activation. However, the mechanism by which CaN mediates GABA(A) receptor dephosphorylation in SE is not fully understood. Here, using a model of kainic acid (KA)-induced SE and CaN inhibitor FK506, we observed the behaviors induced by KA and levels of CaN activity and CaN expression in hippocampus by immunobloting. The results showed that the SE-induced CaN activity was time-dependent, with a peak at 2h and a return to basal level at 24h, whereas a significant increase in CaN expression was seen at 24h after SE. It is proposed that the rapid elevation in CaN activity after KA-induced SE is not likely due to an increase in CaN expression but rather an increase in CaN activation state or kinetics. In addition, we also demonstrated that pre-treatment with FK506 remarkably suppressed the SE-induced CaN activity and its expression, and reversed the SE-induced dephosphorylation of GABA(A)R 2/3 subunits. Taken together, our data suggest that down-regulation in inhibition of GABA(A)R 2/3 by CaN activity contributes to an elevation in neuronal excitability of hippocampus, which may be involved in development of chronic processes of seizures.

Topics: Animals; Behavior, Animal; Calcineurin; Disease Models, Animal; Gene Expression Regulation; Immunosuppressive Agents; Kainic Acid; Male; Phosphorylation; Rats; Rats, Wistar; Receptors, GABA-A; Sirolimus; Status Epilepticus; Tacrolimus; Time Factors

Levetiracetam is an antiepileptic drug that was shown to be effective in various seizure types. Experience with this agent for treating status epilepticus is just emerging. To the best of our knowledge, there is no report in the literature regarding its use in children with nonconvulsive status epilepticus. We here report a liver-transplanted child with nonconvulsive status epilepticus who responded well to oral levetiracetam treatment.

Topics: Anticonvulsants; Child; Female; Humans; Immunosuppressive Agents; Levetiracetam; Liver Transplantation; Piracetam; Status Epilepticus; Tacrolimus; Treatment Outcome

The present study was designed to examine whether neuroprotective agents, FK506 or cyclosporin A (CsA), applied to rats undergoing pilocarpine-induced seizures can minimize further development of the status epilepticus. In order to solve this problem, pilocarpine was injected in 60-day-old Wistar rats to evoke status epilepticus. When epileptic seizures reached a defined, moderate level of intensity, the rats received a single FK506 or CsA injections. During a 6-h period following pilocarpine injection, the animals were observed continuously and motor symptoms were recorded and rated. In epileptic rats injected with FK-506 or CsA, signs of significant amelioration of the course of epilepsy accompanied by longer survival periods were observed. Moreover, some differences between effects of the two agents were seen. The obtained results appear to show that, in addition to neuroprotective action, FK506 and CsA can exert also antiepileptic influences.

Topics: Animals; Behavior, Animal; Cyclosporine; Male; Neuroprotective Agents; Pilocarpine; Rats; Rats, Wistar; Seizures; Status Epilepticus; Tacrolimus

Topics: Brain; Coma; Female; Humans; Immunosuppressive Agents; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Middle Aged; Occipital Lobe; Parietal Lobe; Status Epilepticus; Tacrolimus

A 66-year-old man developed a focal status epilepticus and left hemiparesis 4 days after an orthotopic liver transplantation and administration of FK 506. The magnetic resonance image revealed areas of increased signal on diffusion-weighted imaging (DWI) equally distributed to all vascular territories, most of which resolved completely within 2 weeks after discontinuation of FK 506. We conclude that DWI cannot reliably distinguish between reversible and irreversible lesions and that the presence of hyperintense lesions on DWI is not a definitive predictor of poor prognosis in reversible leukoencephalopathy patients.

Topics: Aged; Brain Edema; Diffusion Magnetic Resonance Imaging; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Paresis; Status Epilepticus; Syndrome; Tacrolimus

Topics: Brain Diseases; Epilepsy; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Status Epilepticus; Tacrolimus