Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Rapamycin: brain excitability studied in vitro. 1728 92

We report a 17-year-old boy who was diagnosed as autoimmune encephalitis with various neurological complications such as hemiplegia, aphasia and seizures. An autoimmune process was considered to be responsible for the repeated episodes of encephalitis because the symptoms were highly responsive to steroids and anti-glutamate receptor antibodies were detected in the CSF. After administration of the immunosuppressant tacrolimus, we could taper the steroid dosage. He has had no relapse for three years to date. We demonstrated the possibility of steroid-sparing treatment with tacrolimus for a patient with steroid-responsive encephalitis. There were few reports describing tacrolimus therapy for encephalitis. Tacrolimus may be effective for selected patients with recurrent encephalitis in which an autoimmune mechanism is considered as the pathogenesis.
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PMID:[Effect of tacrolimus in a case of autoimmune encephalitis]. 1802 65

The literature contains very little documentation on neurologic complications in liver transplant recipients for Wilson's disease. We retrospectively reviewed 17 consecutive cases of pediatric liver transplantation for the hepatic form of Wilson's disease to assess the types of neurologic complications that occurred, the incidence of those problems, and associated factors in this patient group. The patients were 12 boys and 5 girls; indications for liver transplantation were fulminant hepatic failure in 3 patients and chronic hepatic failure in 14 patients. Neurologic complications were observed in 10 of the 17 patients as 16 episodes. The most common neurologic complications were seizure (7 episodes in 6 patients) and sudden-onset headache (5 episodes in 4 patients). Tacrolimus was identified as the only possible cause of headache in 3 episodes. Encephalitis was the cause in 1 and intracranial hemorrhage was the cause in the other headache episode. We also noted 1 episode of tremor, 1 episode of acute dystonic reaction, 1 episode of diffuse encephalopathy, and 1 episode of common peroneal nerve palsy. Immunosuppressive agents were the primary cause of 12 of the 16 episodes of neurologic complications. Uremia with hypertension, compression of the right common peroneal nerve, encephalitis, and intracranial hemorrhages attributable to coagulopathy caused 1 neurologic episode each. Neurologic complications in patients with the hepatic form of Wilson's disease were frequent during the first 30 days after pediatric liver transplantation but did not affect survival. Transplantation teams should be aware of the high incidence of neurologic complications in pediatric patients with the hepatic form of Wilson's disease.
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PMID:Neurologic complications of liver transplantation in pediatric patients with the hepatic form of Wilson's disease. 1807 18

Susceptibility of the injured rat brain to seizures depends on the developmental stage at which the injury had been inflicted. Our previous study shows that tacrolimus (FK506) and cyclosporin A (CsA) applied following the injury can also decrease or increase the seizure susceptibility in an age-dependent way. To find possible neuronal substrates of the effects, we examined influences of the agents on the injured brain and on its neuronal population. Rat brains were mechanically injured on postnatal days 6 (P6) or 30 (P30). Twenty minutes and 24 hours following the injury, FK506 or CsA were injected in clinically used pharmaceutical formulations (Prograf or Sandimmun, respectively). The brains were fixed on postnatal day 60 and processed for histological examinations. To detect if negative effects of the injury could be abolished by the treatments, we examined the brain weight, the size of the injured region, and the nerve cell density, including the density of calretinin- and parvalbumin-immunopositive cells. We have found that long-term effects of treatments with the FK506- and CsA-containing pharmaceutical formulations were never better than those of the vehicle alone (Cremophor and ethanol mixture). Moreover, the treatments could even amplify negative consequences of the injury alone. It could, therefore, be concluded that all the neuroprotective effects observed in the present study resulted exclusively from the influence of the vehicle alone. These effects of the brain injury and of subsequent treatments performed at different developmental stages were considered as possible determinants of further increase or decrease in susceptibility to seizures observed in adulthood.
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PMID:Injections of vehicle, but not cyclosporin A or tacrolimus (FK506), afford neuroprotection following injury in the developing rat brain. 1832 Jul 18

The ability of calcineurin to regulate IRS-1 and IRS-2 levels has not been examined in any given cells, although calcineurin inhibition by therapeutic immunosuppressants produced cytoprotective and cytotoxic effects (e.g., new-onset of diabetes mellitus, seizure). Chronic (>or=3h) treatment of cultured bovine adrenal chromaffin cells with cyclosporin A or FK506 decreased IRS-2 protein level by approximately 50% (IC(50)=200 or 10nM), without changing IRS-2 mRNA level, and insulin receptor, insulin-like growth factor-I (IGF-I) receptor, IRS-1, PI3K/PDK-1/Akt/GSK-3beta and ERK1/ERK2 protein levels. When the cells were washed to remove the test drug, the decreased IRS-2 level restored to the control level. Cyclosporin A or FK506 treatment inhibited calcineurin activity (IC(50)=500 or 40 nM, in vitro assay). Rapamycin, an FK506-binding protein ligand unable to inhibit calcineurin, failed to decrease IRS-2, but reversed FK506-induced decreases of calcineurin activity and IRS-2 level. Pulse-label followed by polyacrylamide gel electrophoresis revealed that cyclosporin A or FK506 accelerated IRS-2 degradation rate (t(1/2)) from >24 to approximately 4.2h, without altering IRS-2 synthesis. IRS-2 reduction by cyclosporin A or FK506 was prevented by lactacystin (proteasome inhibitor), but not by calpeptin (calpain inhibitor) or leupeptin (lysosome inhibitor). Cyclosporin A or FK506 increased serine-phosphorylation and ubiquitination of IRS-2. Cell surface (125)I-IGF-I binding capacity was not changed in cyclosporin A- or FK506-treated cells; however, IGF-I-induced phosphorylations of GSK-3beta and ERK1/ERK2 were attenuated by approximately 50%, which were prevented by rapamycin or lactacystin. Thus, calcineurin inhibition decreased IRS-2 level via proteasomal IRS-2 degradation, attenuating IGF-I-induced GSK-3beta and ERK pathways.
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PMID:Proteasomal degradation of IRS-2, but not IRS-1 by calcineurin inhibition: attenuation of insulin-like growth factor-I-induced GSK-3beta and ERK pathways in adrenal chromaffin cells. 1853 59

The use of low-frequency stimulation (LFS) as a therapy for epilepsy is currently being studied in experimental animals and patients with epilepsy. In the present study, the role of serine/threonine protein phosphatases in the inhibitory effects of LFS on perforant path kindling acquisition was investigated in rats. Animals were kindled by stimulation of perforant path in a stimulation using rapid kindling procedure (six stimulations per day). LFS (1Hz) was applied immediately after termination of each kindling stimulation. FK506 (1microM; i.c.v.), a serine/threonine protein phosphatase PP2B inhibitor and okadaic acid (1microM; i.c.v.), a serine/threonine protein phosphatases PP1/2A inhibitor, were daily microinjected into the left ventricle 10min before starting the stimulation protocol. Application of LFS retarded the kindling acquisition and delayed the expression of different kindled seizure stages significantly. In addition, LFS reduced the increment of daily afterdischarge duration during kindling development. Neither FK506 nor okadaic acid microinjection interfere with the antiepileptogenic effect of LFS on kindling parameters. Obtained results showed that activation of PP1/2A and PP2B, which play a critical role in LFS induced down-regulation of synaptic strength, had no role in mediating the inhibitory effects of LFS on perforant path kindling acquisition.
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PMID:Serine/threonine protein phosphatases have no role in the inhibitory effects of low-frequency stimulation in perforant path kindling acquisition in rats. 1915 Mar 91

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.
Seizure 2009 Sep
PMID:Calcineurin-mediated GABA(A) receptor dephosphorylation in rats after kainic acid-induced status epilepticus. 1949 70

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.
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PMID:Neurologic complications in adult living donor liver transplant patients: an underestimated factor? 1972 99

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.
Seizure 2010 Apr
PMID:Oxidative stress mediates hippocampal neuron death in rats after lithium-pilocarpine-induced status epilepticus. 2014 94

Tacrolimus (TAC) is an immunosuppressant drug discovered in 1984 by Fujisawa Pharmaceutical Co., Ltd. This drug belongs to the group of calcineurin inhibitors, which has been proven highly effective in preventing acute rejection after transplantation of solid organs. However, neurotoxicity and nephrotoxicity are its major adverse effects. Posterior reversible encephalopathy syndrome (PRES) is the most severe and dramatic consequence of calcineurin inhibitor neurotoxicity. It was initially described by Hinchey et al. in 1996 [N Engl J Med 1996;334:494-450]. Patients typically present with altered mental status, headache, focal neurological deficits, visual disturbances, and seizures. Magnetic resonance imaging is the most sensitive imaging test to detect this. With the more deep-going studies done recently, we have learnt more about this entity. It was noted that this syndrome is frequently reversible, rarely limited to the posterior regions of the brain, and often located in gray matter and cortex as well as in white matter. Therefore, in this review, the focus is on the current understanding of clinical recognition, pathogenesis, neuroimaging and management of TAC-associated PRES after solid organ transplantation.
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PMID:Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. 2069 17


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