Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ammonia is a main factor in the pathogenesis of hepatic encephalopathy. We found that acute ammonia toxicity is mediated by activation of NMDA receptors. Chronic moderate hyperammonemia prevents acute ammonia toxicity in rats. Chronic exposure of cultured neurons to 1 mM ammonia leads to impaired response of the NMDA receptor to activation by its agonists (due to decreased protein kinase C-mediated phosphorylation) and prevents glutamate (Glu) neurotoxicity. Compounds that prevent ammonia toxicity in mice (e.g. carnitine) also prevent Glu toxicity in cultured neurons. These compounds did not prevent activation of NMDA receptor or the rise of Ca2+. They interfered with subsequent steps in the toxic process. The protective effect of carnitine is mediated by activation of metabotropic Glu receptors. Agonists of mGluRs, especially of mGluR5, prevent Glu toxicity. Agonists of muscarinic receptors also prevent Glu toxicity and there seems to be an interplay between muscarinic and metabotropic Glu receptors in the protective effect. We have tried to identify intracellular events involved in the process of neuronal death. It is known that the rise of Ca2+ is an essential step. Glu leads to depletion of ATP; some compounds (e.g. carnitine) prevent Glu-induced neuronal death without preventing ATP depletion: additional events are required for neuronal death. Glu induces activation of Na+/K+-ATPase, which could be involved in the toxic process. Inhibitors of protein kinase C, calcineurin or nitric oxide synthase prevent Glu toxicity. Our results indicate that Glu toxicity can be prevented at different steps or by activating receptors coupled to the transduction pathways interfering with the toxic process. Agents acting on these steps could prevent excitotoxicity in vivo in animals.
 ...
PMID:Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. 974 28

Hyperammonemia is considered the main cause for the neurological alterations found in hepatic failure. However, the mechanisms by which high ammonia levels impair cerebral function are not well understood. It has been shown that chronic hyperammonemia impairs signal transduction pathways associated with NMDA receptors and also alters phosphorylation of some neuronal proteins. The aim of the present work was to analyze the effects of chronic exposure to ammonia on phosphorylation of microtubule-associated protein 2 (MAP-2) in intact neurons in culture and to assess whether modulation of MAP-2 phosphorylation by glutamate receptor-associated transduction pathways is altered in neurons chronically exposed to ammonia. It is shown that chronic exposure to ammonia increases basal phosphorylation of MAP-2 by approximately 70%. This effect seems to be due to a decreased tonic activation of NMDA receptors and of calcineurin. Chronic exposure to ammonia also alters the modulation of MAP-2 phosphorylation by NMDA receptors and metabotropic glutamate receptors. In neurons exposed to ammonia, treatment with NMDA for 30 min induced a significant decrease in phosphorylation of MAP-2. Activation of metabotropic glutamate receptors with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid significantly increased phosphorylation of MAP-2 in control neurons, whereas in neurons exposed to ammonia the response was the opposite, with 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of MAP-2. These results indicate that ammonia alters significantly signal transduction pathways associated with different types of glutamate receptors. This would lead therefore to significant alterations in glutamatergic neurotransmission, which would contribute to the neurological alterations found in hyperammonemia and in hepatic encephalopathy.
 ...
PMID:Chronic exposure to ammonia alters pathways modulating phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture. 1058 18

Tacrolimus is a potent immunosuppressant medication with a low therapeutic index. We report a case of mutism with persistent dysarthria in a patient receiving tacrolimus-based immunosuppression following allogeneic liver transplantation. A 59-year-old female patient with end-stage liver disease secondary to primary sclerosing cholangitis underwent successful allogeneic liver transplantation. The patient was started on tacrolimus for prevention of allograft rejection and subsequently developed complete mutism. Following consultation of the medical toxicology service, tacrolimus was discontinued and the patient's mutism gradually improved. However, the patient still has moderate dysarthria more than 2 years after tacrolimus discontinuation. The Naranjo probability scale revealed a probable adverse reaction of mutism and dysarthria associated with tacrolimus therapy. Mutism is an uncommon complication of calcineurin inhibitors. Both cyclosporine and tacrolimus have been associated with mutism, though mutism may be more common in patients treated with tacrolimus. The mechanism of injury has not been delineated, although liver transplant patients and patients with preexisting hepatic encephalopathy or neurologic disease may be at increased risk for this complication. The mainstay of treatment is tacrolimus dose reduction or discontinuation, although benzodiazepine therapy may be beneficial in the treatment of this disorder. Clinicians should be aware of the potential adverse effects associated with calcineurin inhibitor toxicity in transplant patients and should advocate for aggressive and rapid treatment of this serious adverse drug effect.
 ...
PMID:Mutism and persistent dysarthria due to tacrolimus-based immunosuppression following allogeneic liver transplantation. 2053 6

Early calcineurin inhibitor-induced neurotoxicity (ECIIN) is considered when neurological symptoms occur within 4 weeks after liver transplantation (LT). Risk factors and clinical outcome of ECIIN remain largely unknown. We sought to estimate the incidence, risk factors, and outcome of ECIIN after LT. We retrospectively evaluated 158 patients that underwent LT in a 2-year period and received immunosuppression with calcineurin inhibitors (CNI) and prednisone. ECIIN was considered when moderate/severe neurological events (after excluding other etiologies) occurred within 4 weeks after LT and improved after modification of CNI. Demographic and clinical variables were analyzed as risk factors. Twenty-eight (18%) patients developed ECIIN and the remaining 130 patients were analyzed as controls. History of pre-LT hepatic encephalopathy (OR 3.16, 95% CI 1.29-7.75, P = 0.012), post-LT hyponatremia (OR 3.34, 95% CI 1.38-9.85, P = 0.028), and surgical time >7 h (OR 2.62, 95% CI 1.07-6.41, P = 0.035) were independent factors for ECIIN. Acute graft rejection and infections were more frequent in the ECIIN group. In addition, length of stay was longer in ECIIN patients. In conclusion, pre-LT hepatic encephalopathy, surgical time >7 h, and post-LT hyponatremia are risk factors for ECIIN. Clinical complications and a longer hospital stay are associated with ECIIN development.
 ...
PMID:Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. 2164 43

Neurologic complications are relatively common after solid organ transplantation and affect 15%-30% of liver transplant recipients. Etiology is often related to immunosuppressant neurotoxicity and opportunistic infections. Most common complications include seizures and encephalopathy, and occurrence of central pontine myelinolysis is relatively specific for liver transplant recipients. Delayed allograft function may precipitate hepatic encephalopathy and neurotoxicity of calcineurin inhibitors typically manifests with tremor, headaches and encephalopathy. Reduction of neurotoxic immunosuppressants or conversion to an alternative medication usually result in clinical improvement. Standard preventive and diagnostic protocols have helped to reduce the prevalence of opportunistic central nervous system (CNS) infections, but viral and fungal CNS infections still affect 1% of liver transplant recipients, and the morbidity and mortality in the affected patients remain fairly high. Critical illness myopathy may also affect up to 7% of liver transplant recipients. Liver insufficiency is also associated with various neurologic disorders which may improve or resolve after successful liver transplantation. Accurate diagnosis and timely intervention are essential to improve outcomes, while advances in clinical management and extended post-transplant survival are increasingly shifting the focus to chronic post-transplant complications which are often encountered in a community hospital and an outpatient setting.
...
PMID:Neurologic complications after liver transplantation. 2402 79