tacrolimus and Epilepsy

Side effects of certain drugs such as cyclosporin A (CsA) and phenytoin may induce gingival overgrowth which in some instances become unacceptable to the patient because esthetic, functional, and other effects. Use of these drugs is related to important medical situations, such as organ transplantation and control and withdrawal of the drugs is contraindicated. Tacrolimus is an immunosuppressant used to prevent graft rejection in organ transplant patients and has been shown to cause fewer oral side effects than CsA. This report deals with a case of probable synergism between the use of CsA and phenytoin which caused an intense gingival overgrowth in a kidney transplant patient. A treatment protocol including very thorough oral hygiene, scaling and root planing, clorhexidine digluconate rinses (0.12%), and substituting CsA with tacrolimus is described. Response to treatment after 6 months of tacrolimus use was excellent with almost complete reversion of the gingival enlargement. One-year follow-up demonstrated a stable gingival situation. The successful substitution of CsA with tacrolimus provides great expectations for the management of CsA-related gingival enlargement.

Topics: Anticonvulsants; Cyclosporine; Drug Synergism; Drug Therapy, Combination; Epilepsy; Female; Gingival Overgrowth; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Phenytoin; Tacrolimus; Time Factors

Topics: Animals; Calcineurin; Cell Death; Central Nervous System; Cyclosporine; Epilepsy; Hippocampus; Immunosuppressive Agents; Kindling, Neurologic; Long-Term Potentiation; Neuronal Plasticity; Neurons; Nitric Oxide; Receptors, AMPA; Receptors, GABA; Receptors, N-Methyl-D-Aspartate; Synapses; Tacrolimus

It is still an urgent need to find alternative and effective therapies to combat epileptic seizures. Tacrolimus as a potent immunosuppressant and calcineurin inhibitor is emerging as promising drug to suppress seizures. However, there are few reports applying tacrolimus to epilepsy and providing data for its antiseizure properties. In this study, we investigated the antiseizure effects of 5 and 10 mg/kg doses of tacrolimus treatment priorly to pentylenetetrazol (PTZ) induction of seizures in rats. As an experimental design, we establish two independent rat groups where we observe convulsive seizures following 70 mg/kg PTZ and sub-convulsive seizures detected by electroencephalography (EEG) following 35 mg/kg PTZ. Thereafter, we proceed with biochemical analyses of the brain including assessment of malondialdehyde level as an indicator of lipid peroxidation and detection of superoxide dismutase (SOD) enzyme activity and PGF2α. Tacrolimus pre-treatment dose-dependently resulted in lesser seizure severity according to Racine's scale, delayed start-up latency of the first myoclonic jerk and attenuated the spike percentages detected by EEG in seizure-induced rats. However, only the higher dose of tacrolimus was effective to restore lipid peroxidation. An increase in SOD activity was observed in the PTZ group, mediated by seizure activity per se, however, it was greater in the groups that received treatment with 5 and 10 mg/kg of Tacrolimus. PGF2α bursts following PTZ induction of seizures were reversed by tacrolimus pre-treatment in a dose-dependent manner as well. We report that the well-known immunosuppressant tacrolimus is a promising agent to suppress seizures. Comparative studies are necessary to determine the possible utilization of tacrolimus in clinical cases.

Topics: Animals; Anticonvulsants; Brain; Dinoprost; Disease Models, Animal; Epilepsy; Humans; Immunosuppressive Agents; Oxidative Stress; Pentylenetetrazole; Rats; Seizures; Superoxide Dismutase; Tacrolimus; Time-to-Treatment

Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.. A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.. The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.. At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.. Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.. Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.

Topics: Electroencephalography; Epilepsy; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus

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

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

Topics: Adult; Cannabidiol; Drug Interactions; Epilepsy; Female; Humans; Immunosuppressive Agents; Nephritis, Interstitial; Prognosis; Tacrolimus

The widespread use of immunosuppressive agents has significantly increased the rates of successful solid-organ and stem cell transplants, especially with liver and kidney. Cyclosporine and tacrolimus are most commonly used for this purpose. Although these agents have different mechanisms of action, both have various adverse effects, including nausea, vomiting, headache, hypertension, nephrotoxicity, and rarely epileptic seizures. In our first case, a patient presented with epileptic seizures and hemiparesis after a liver transplant, and posterior reversible encephalopathy syndrome related to cyclosporine toxicity was considered. Once cyclosporine levels in the blood decreased, the patient had both clinical and radiologic improvements. In our second case, a patient presented with delirium after a liver transplant. Again, when cyclosporine levels in the blood decreased, the patient showed improvement in clinical findings. Neurologic complications may develop after liver transplant, and these complications are encountered most frequently within the first postoperative month. Neurologic complications are multifactorial; insufficient graft function, intracranial bleeding, cerebral infarcts, infections, and immunosuppressive drug toxicity (tacrolimus and cyclosporine) may be considered among these factors. As shown in our presented cases, most neurologic complications can be successfully treated by correcting the underlying factor.

Topics: Cyclosporine; Epilepsy; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Muscle Weakness; Paresis; Postoperative Complications; Reflex, Babinski; Tacrolimus

Topics: Anticonvulsants; Autoimmune Diseases; Early Medical Intervention; Epilepsy; Humans; Infusions, Intravenous; Tacrolimus

The polygenic origin of generalized absence epilepsy results in dysfunction of ion channels that allows the switch from physiological asynchronous to pathophysiological highly synchronous network activity. Evidence from rat and mouse models of absence epilepsy indicates that altered Ca(2+) channel activity contributes to cellular and network alterations that lead to seizure activity. Under physiological circumstances, high voltage-activated (HVA) Ca(2+) channels are important in determining the thalamic firing profile. Here, we investigated a possible contribution of HVA channels to the epileptic phenotype using a rodent genetic model of absence epilepsy. In this study, HVA Ca(2+) currents were recorded from neurons of three different thalamic nuclei that are involved in both sensory signal transmission and rhythmic-synchronized activity during epileptic spike-and-wave discharges (SWD), namely the dorsal part of the lateral geniculate nucleus (dLGN), the ventrobasal thalamic complex (VB) and the reticular thalamic nucleus (NRT) of epileptic Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) and non-epileptic August Copenhagen Irish (ACI) rats. HVA Ca(2+) current densities in dLGN neurons were significantly increased in epileptic rats compared with non-epileptic controls while other thalamic regions revealed no differences between the strains. Application of specific channel blockers revealed that the increased current was carried by L-type Ca(2+) channels. Electrophysiological evidence of increased L-type current correlated with up-regulated mRNA and protein expression of a particular L-type channel, namely Cav1.3, in dLGN of epileptic rats. No significant changes were found for other HVA Ca(2+) channels. Moreover, pharmacological inactivation of L-type Ca(2+) channels results in altered firing profiles of thalamocortical relay (TC) neurons from non-epileptic rather than from epileptic rats. While HVA Ca(2+) channels influence tonic and burst firing in ACI and WAG/Rij differently, it is discussed that increased Cav1.3 expression may indirectly contribute to increased robustness of burst firing and thereby the epileptic phenotype of absence epilepsy.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Animals; Animals, Newborn; Biophysical Phenomena; Calcium Channel Blockers; Calcium Channels; Disease Models, Animal; Electric Stimulation; Epilepsy; Immunosuppressive Agents; Membrane Potentials; Mutation Rate; Nerve Tissue Proteins; Neurons; Rats; Rats, Wistar; Salmeterol Xinafoate; Tacrolimus; Thalamic Nuclei; Up-Regulation

Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn't seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Epilepsy; Hippocampus; Infusion Pumps; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Tacrolimus; Thiazolidines

Topics: Adult; Anti-Inflammatory Agents; Atrophy; Brain; Chronic Disease; Cyclophosphamide; Encephalitis; Epilepsy; Facial Hemiatrophy; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Young Adult

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.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Disease Models, Animal; Electric Stimulation Therapy; Enzyme Inhibitors; Epilepsy; Kindling, Neurologic; Male; Neural Inhibition; Okadaic Acid; Perforant Pathway; Phosphoprotein Phosphatases; Protein Phosphatase 2; Rats; Rats, Wistar; Tacrolimus

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.

Topics: Animals; Brain; Calcineurin; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Epilepsy; Evoked Potentials; Excitatory Postsynaptic Potentials; Graft Rejection; Hippocampus; Immunosuppressive Agents; In Vitro Techniques; Neurons; Neurotoxicity Syndromes; Rats; Seizures; Sirolimus; Tacrolimus; Transplantation

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.

Topics: Animals; Brain; Brain Injuries; Calbindin 2; Cell Count; Chemistry, Pharmaceutical; Cyclosporine; Epilepsy; Female; Immunosuppressive Agents; Neurons; Neuroprotective Agents; Organ Size; Parvalbumins; Pregnancy; Rats; Rats, Wistar; S100 Calcium Binding Protein G; Staining and Labeling; Tacrolimus

The potential in vivo anticonvulsant effect of calcineurin (protein phosphatase 2B) inhibitor ascomycin against seizures induced by intrahippocampal microdialysis of picrotoxin was examined in the present study. After establishing individual picrotoxin seizure thresholds, ascomycin was continually microperfused into the rat hippocampus through microdialysis probes at concentrations 10, 50 and 100 microM. No behavioral or electroencephalographic effects were observed during microperfusion of ascomycin alone. Low concentrations (10 microM) of ascomycin did not prevent picrotoxin seizures, however, 50 and 100 microM ascomycin showed antiepileptic effect, completely suppressing seizures in 41.7% and 75% of the animals studied respectively. Mean seizure duration and mean number of seizures were significantly reduced (P < 0.01) by microperfusion of 100 microM ascomycin. Calcineurin activity might be involved in the biochemical changes leading to picrotoxin-induced epileptic seizures. The present findings provide additional in vivo evidence of the involvement of phosphorylation/dephosphorylation mechanisms in the development of epileptic seizures, suggesting that calcineurin modulation may be a possible strategy in the search for new anticonvulsant drugs.

Topics: Animals; Anticonvulsants; Calcineurin Inhibitors; Convulsants; Epilepsy; Hippocampus; Immunosuppressive Agents; Male; Perfusion; Phosphorylation; Picrotoxin; Rats; Rats, Sprague-Dawley; Tacrolimus

Previous studies have shown that the immunosuppressant cyclosporin A (CsA), a specific blocker of the mitochondrial permeability transition (MPT) pore, can dramatically ameliorate the selective neuronal necrosis resulting from ischemia-reperfusion, traumatic brain injury, and N-methyl-d-aspartate (NMDA)-evoked neurotoxicity. The purpose of this study was to determine whether two different immunosuppressants, CsA and FK-506, could ameliorate the neuronal damage observed after kainate-induced seizures in strains that are differentially susceptible to excitotoxin-induced cell death.. Excitotoxin-resistant (C57BL/6) or -susceptible (FVB/N) mice were administered kainate alone (30 mg/kg), CsA alone (5, 10, or 20 mg/kg), or one of the immunosuppressants (CsA, 5 mg/kg or 10 mg/kg; FK-506, 0.5 mg/kg) followed by kainate. After drug administration, mice were monitored continuously for the onset and extent of seizure activity. After a survival of 7 days, animals were assessed for hippocampal damage.. Whereas CsA alone induced no epileptogenic effects and both immunosuppressants were without effect on the induction of kainate-induced seizures, administration of CsA to excitotoxin-susceptible mice (FVB/N) virtually eliminated neuronal cell death. In contrast, induction of neuronal cell death was evident when CsA was administered to excitotoxin-resistant mice (C57BL/6). Administration of FK-506, another commonly used immunosuppressant, which lacks an effect on the MPT, had no effect on modification of susceptibility to kainate-induced cell death in either strain.. As our data show differential protection of hippocampal neurons against excitotoxic cell death by pretreatment with CsA, these results suggest that strain-dependent differences in mitochondrial integrity and function may exist.

Topics: Animals; Cell Death; Cyclosporine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Genotype; Hippocampus; Ion Channels; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neurons; Neuroprotective Agents; Phenotype; Premedication; Tacrolimus

A 5-year-old girl with Ph-positive chronic myelogenous leukemia, who underwent umbilical cord blood transplantation, developed two episodes of electrical status epilepticus while receiving tacrolimus (FK506) then cyclosporin A (CsA), as treatment against graft-versus-host disease. MRI including diffusion weighted MR imaging of the brain revealed abnormalities in the hippocampus and posterior white matter following FK506 and CsA treatment, respectively. While posterior white matter injury has been described with both FK506 and CsA, no previous report describes hippocampal injury from either drug. The MRI changes in the hippocampus in our case suggest possible increased susceptibility to hippocampal injury with FK506.

Topics: Child, Preschool; Cord Blood Stem Cell Transplantation; Epilepsy; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Limbic System; Magnetic Resonance Imaging; Tacrolimus

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

Calcineurin (CaN) immunoreactivity and content increased markedly in kindled rat brain, and this increment was due to CaN in the membrane fraction. Investigation of the effects of cyclosporin A and FK506 (immunosuppressants which inhibit CaN activity in T lymphocytes) in the kindling phenomena showed that the kindling stage progression was reversibly blocked by these drugs. These findings suggest that calcineurin may play an essential role in acquiring epileptogenesis in kindling.

Topics: Amygdala; Animals; Calcineurin; Calmodulin-Binding Proteins; Cerebral Cortex; Cyclosporine; Densitometry; Epilepsy; Hippocampus; Immunohistochemistry; Immunosuppressive Agents; Kindling, Neurologic; Male; Phosphoprotein Phosphatases; Rats; Rats, Sprague-Dawley; Tacrolimus