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Calcineurin inhibitor Neurotoxicity

Yuanyi Zuo, Jun Hu, Xuehua Xu, Xiangting Gao, Yun Wang, Shaohua Zhu
Sodium azide (NaN3), an inhibitor of cytochrome oxidase, induces the release of excitotoxins via an energy impairment and this, in turn, results in neurodegeneration. The present study aimed to investigate the toxic effects NaN3 on apoptosis of PC12 cells and its mechanism of action in peroxisome proliferator‑activated receptor γ co‑activator 1‑α (Pgc‑1α)‑associated signaling pathways. To induce apoptosis, PC12 cells were exposed to NaN3 (0, 5, 10, 20, 40 and 80 mM) for 12, 24, 48 and 72 h...
January 14, 2019: Molecular Medicine Reports
Jason R Tatreau, Sarah L Laughon, Tomasz Kozlowski
BACKGROUND Central nervous system complications after transplantation occur in up to 40% of recipients and these complications are associated with increased length of hospital stay and mortality. Catatonia is a neuropsychiatric clinical syndrome which has been described in case reports and in a small case series as occurring in the immediate post-solid organ transplantation (SOT) period, and it has been attributed to calcineurin inhibitor neurotoxicity, psychological vulnerability, and depression. Among transplant recipients, the incidence of catatonia is unknown; it may be under diagnosed in part due to a broad differential diagnosis in the post-transplantation setting, which includes hypoactive delirium, non-convulsive status epilepticus, drug toxicity, conversion disorder, and volitional uncooperativeness...
August 28, 2018: Annals of Transplantation: Quarterly of the Polish Transplantation Society
Rao Fu, Soichiro Tajima, Kimitaka Suetsugu, Hiroyuki Watanabe, Nobuaki Egashira, Satohiro Masuda
Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs...
February 2019: Acta Pharmacologica Sinica
Jirapa Chetsawang, Sutisa Nudmamud-Thanoi, Ruchee Phonchai, Zuroida Abubakar, Piyarat Govitrapong, Banthit Chetsawang
Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca2+ levels activates the cell death process, including calpain activation in neurons, which was diminished by the overexpression of the calpain inhibitor protein, calpastatin...
July 2018: Neurotoxicology
Sebastiano La Maestra, Guido Frosina, Rosanna T Micale, Chiara D'Oria, Silvano Garibaldi, Antonio Daga, Alessandra Pulliero, Alberto Izzotti
Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aimed at reproducing the pathogenic mechanisms of type I interferonopathies, in order to develop an effective pharmacological modulation and toxicological alterations caused by intracranial delivery of encapsulated CpG...
October 2018: Drug Delivery and Translational Research
Summer J Rozzi, Valeria Avdoshina, Jerel A Fields, Italo Mocchetti
Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls. To provide an experimental clue as to which mechanisms are used by Tat to promote changes in mitochondrial morphology, rat cortical neurons were exposed to Tat (100 nM) for various time points...
December 2018: Cell Death Discovery
Ahmed F El-Yazbi, Ali H Eid, Mahmoud M El-Mas
Cyclosporine, the prototype calcineurin inhibitor, transformed immunosuppressant regimens and practices post-organ transplantation. Therapeutic uses of cyclosporine branched out to include management of different autoimmune disorders. However, multiple additional effects posed significant clinical challenges in face of the prolonged nature of cyclosporine use. Significantly, cyclosporine produced nephrotoxic, cardiotoxic and neurotoxic effects in addition to alteration of hemodynamic function. These adverse effects are shared with other drug groups further complicating the therapeutic situation to include potential exacerbation in case of drug interactions...
March 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Derick A Kalt
Tacrolimus (Tac) is an immunosuppressive drug that is used in preventing organ and tissue rejection in patients after transplantation. Tac administration requires frequent and diligent monitoring by physicians to ensure proper dosage and to limit the potential for harmful adverse effects, which can include renal damage, neurotoxicity, and other serious adverse events. Tac is a calcineurin inhibitor, which suppresses the function of T-cells. Its success as an immunosuppressive agent has been well documented in preventing graft-vs-host disease in several types of organ transplants...
November 8, 2017: Laboratory Medicine
Niviann M Blondet, Patrick J Healey, Evelyn Hsu
The field of pediatric solid-organ transplantation has significantly evolved since its beginnings in the early 20th century. As advancements have led to the development of innovative surgical techniques and novel medication regimens, transplantation has now become a routine practice leading to an increase in the rates of organ recipients worldwide. The care of pediatric solid-organ transplant recipients differs from adults in several areas not only due to technically challenging surgeries, but mostly due to the complexity of their immunosuppression management...
August 2017: Seminars in Pediatric Surgery
R Dhar
Major neurologic morbidity, such as seizures and encephalopathy, complicates 20-30% of organ and stem cell transplantation procedures. The majority of these disorders occur in the early posttransplant period, but recipients remain at risk for opportunistic infections and other nervous system disorders for many years. These long-term risks may be increasing as acute survival increases, and a greater number of "sicker" patients are exposed to long-term immunosuppression. Drug neurotoxicity accounts for a significant proportion of complications, with posterior reversible leukoencephalopathy syndrome, primarily associated with calcineurin inhibitors (i...
2017: Handbook of Clinical Neurology
Badri Man Shrestha
Tacrolimus, a calcineurin inhibitor, has been the cornerstone of immunosuppressive regimens in renal transplant over 2 decades. This has significantly improved the outcomes of renal transplant, including reduction of acute rejection episodes, improvement of renal function and graft survival, and reduction of some of the adverse effects associated with cyclosporine. However, use of tacrolimus is associated with a number of undesirable effects, such as nephrotoxicity, posttransplant diabetes mellitus, neurotoxicity, and cosmetic and electrolyte disturbances...
February 2017: Experimental and Clinical Transplantation
M Gastaca, I Bilbao, M Jimenez, J Bustamante, C Dopazo, R Gonzalez, R Charco, J Santoyo, J Ortiz de Urbina
Our aim was to study the safety and efficacy of immunosuppression with everolimus (EVL) within the 1st month after orthotopic liver transplantation (LT) when calcineurin inhibitors are not recommended. For this purpose, 28 recipients who had been treated with EVL within the 1st month after adult LT were eligible to enter in a retrospective multicenter study. Patients were followed up for 12 months after LT. EVL therapy was initiated at a median of 14 days (range, 4-24) after LT. The reason for early EVL was neurotoxicity in 14 cases, renal dysfunction in 12, and acute cellular rejection combined with renal impairment in 2...
September 2016: Transplantation Proceedings
Ashwani K Gupta, Nader Bahri
BACKGROUND: Neurotoxicity is a common side effect of treatment with calcineurin inhibitors. Tremors are frequently reported as the most common manifestation. Variable presentations can include headaches, seizures, visual hallucinations or blindness. Sixth nerve palsy has been reported in previous cases of bone marrow and cardiac transplant patients receiving calcineurin inhibitors. In many of these previously reported cases, the drug was administered intravenously and very high drug levels were found...
August 19, 2016: BMC Nephrology
Dong Gil Lee, Junghyung Park, Hyun-Shik Lee, Sang-Rae Lee, Dong-Seok Lee
Iron is necessary for neuronal functions; however, excessive iron accumulation caused by impairment of iron balance could damage neurons. Neuronal iron accumulation has been observed in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nevertheless, the precise mechanisms underlying iron toxicity in neuron cells are not fully understood. In this study, we investigated the mechanism underlying iron overload-induced mitochondrial fragmentation in HT-22 hippocampal neuron cells that were incubated with ferric ammonium citrate (FAC)...
July 15, 2016: Toxicology
Federico Cicora, Javier Roberti
Organ transplant recipients may have skin diseases as a result of immunosuppression, but psoriasis is reported infrequently. This skin condition may be induced by immunosuppression imbalance. We present 2 cases of recurrent psoriasis in 2 kidney transplant patients with belatacept-based immunosuppressive regimens. Two years after transplant, upon suspicion of calcineurin inhibitor neurotoxicity in the first patient, tacrolimus was replaced with belatacept. The patient's neurological signs resolved but the patient presented with skin lesions compatible with psoriatic plaques, successfully treated with betamethasone dipropionate and hydrocortisone...
June 2016: Progress in Transplantation
Jérôme Dumortier, Sebastien Dharancy, Yvon Calmus, Christophe Duvoux, François Durand, Ephrem Salamé, Faouzi Saliba
The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved for rejection prophylaxis after liver transplantation. The current article pools the experience of French liver transplant surgeons and physicians in use of everolimus and, particularly, practical guidance on dosing, appropriate concomitant immunosuppression and management of adverse events. In terms of indication, introduction of everolimus from week 4 after liver transplantation, with or without concomitant calcineurin inhibitor (CNI) therapy, offers a significant renal benefit without loss of immunosuppressive efficacy...
July 2016: Transplantation Reviews
Adriana Mika, Piotr Stepnowski
More than 100000 solid organ transplantations are performed every year worldwide. Calcineurin (cyclosporine A, tacrolimus), serine/threonine kinase (sirolimus, everolimus) and inosine monophosphate dehydrogenase inhibitor (mycophenolate mofetil), are the most common drugs used as immunosuppressive agents after solid organ transplantation. Immunosuppressive therapy, although necessary after transplantation, is associated with many adverse consequences, including the formation of secondary metabolites of drugs and the induction of their side effects...
August 5, 2016: Journal of Pharmaceutical and Biomedical Analysis
Mala V Rao, Jabbar Campbell, Arti Palaniappan, Asok Kumar, Ralph A Nixon
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss...
April 2016: Journal of Neurochemistry
Maulik Shah
A third of solid organ transplant recipients experience neurologic complications after transplantation. In this article the author reviews common and uncommon complications of the perioperative period including stroke and peripheral neuropathy, neurotoxicity associated with immunosuppressant medications such as calcineurin inhibitors, and opportunistic infections that target the nervous system. A careful clinical history, neurologic examination, and medication review are vital in generating a differential diagnosis that will guide diagnostic testing and decisions regarding treatment and management, and early recognition of many disorders is imperative to prevent irreversible neurologic morbidity and death...
December 2015: Seminars in Neurology
Marit S Van Sandwijk, Ineke J M Ten Berge, Charles B L M Majoie, Matthan W A Caan, Leo M J De Sonneville, Willem A Van Gool, Frederike J Bemelman
Cognitive impairment is very common in chronic kidney disease (CKD) and is strongly associated with increased mortality. This review article will discuss the pathophysiology of cognitive impairment in CKD, as well as the effect of dialysis and transplantation on cognitive function. In CKD, uremic toxins, hyperparathyroidism and Klotho deficiency lead to chronic inflammation, endothelial dysfunction and vascular calcifications. This results in an increased burden of cerebrovascular disease in CKD patients, who consistently have more white matter hyperintensities, microbleeds, microinfarctions and cerebral atrophy on magnetic resonance imaging scans...
April 2016: Transplantation
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