tacrolimus and Cognition-Disorders

Topics: Adult; Cognition Disorders; Cyclosporine; Female; Humans; Liver Transplantation; Male; Mental Disorders; Morbidity; Tacrolimus

The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.

Topics: Animals; Cognition Disorders; Dendrites; Down-Regulation; Hippocampus; Immunosuppressive Agents; Klotho Proteins; Male; Maze Learning; Mice; Mice, Inbred BALB C; Nerve Tissue Proteins; Open Field Test; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Random Allocation; Signal Transduction; Spatial Learning; Spatial Memory; Synapses; Tacrolimus

The aim of the present work was to explore the outcome of combination of Calcineurin (CaN) inhibitor and Protein Kinase A (PKA) activator, in mouse models of experimental dementia.. Cognitive deficits were induced in mice by injecting Streptozotocin (STZ) intracerebroventricularly (i.c.v.); on the other hand aged animals were procured as a natural model of dementia. To assess cognitive function of mice Morris water maze (MWM) test was utilized; various biochemical studies and histopathological studies were also carried out.. STZ injection and aging resulted in significant development of cognitive deficits; along-with enhancement of Myeloperoxidase (MPO) levels, Thiobarbituric Acid Reactive Species (TBARS), Acetylcholinestrase (AChE) activity, and reduced Glutathione (GSH) levels. Histopathological studies demonstrated pathological changes such as amyloid deposition and severe neutrophilic infiltration in brains of these mice. Donepezil /combination of Tacrolimus and Forskolin treatment markedly improve cognitive function, biochemical parameters, and histopathological alterations in STZ treated and aged mice.. The outcome reveals that combination of CaN inhibitor and PKA activator has significantly alleviated memory dysfunction, biochemical alteration and histopathological changes quiet comparable to Donepezil. It has been inferred that combination of CaN and PKA can be served as an important target in dementia.

Topics: Acetylcholinesterase; Aging; Alzheimer Disease; Animals; Brain; Calcineurin; Calcineurin Inhibitors; Cholinesterase Inhibitors; Cognition Disorders; Colforsin; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Female; Glutathione; Male; Maze Learning; Mice; Peroxidase; Streptozocin; Tacrolimus; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

Upregulation in calcineurin (CaN) signaling has been implicated in various neurodegenerative disorders. In the present study, we have investigated the effect of FK506--a CaN inhibitor--on streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type in rats. STZ was administered intracerebroventricularly to induce a cognitive deficit and oxidative stress. Nonimmunosuppressive doses (0.5 and 1 mg/kg postoperatively) of FK506 (tacrolimus) were administered for 21 day in STZ-treated rats. Cognitive functions were assessed using the Morris water maze and passive avoidance tasks. Malondialdehyde and nitrite glutathione levels, as well as acetylcholinesterase activity, were determined to evaluate oxidative stress and cholinergic functions. Lactate dehydrogenase levels were estimated and histological analysis of the dentate gyrus and the CA1 region of the hippocampus was carried out to identify degenerative changes. STZ produced significant deterioration of cognitive functions, oxidative stress, and degenerative changes in the cortical and hippocampal brain regions. FK506 dose-dependently attenuated STZ-induced cognitive deficits, oxidative stress, and degenerative changes in the cortex and hippocampus. These results suggest a potential role of CaN signaling in degenerative processes, and that inhibition of CaN may be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Avoidance Learning; Calcineurin Inhibitors; Cognition; Cognition Disorders; Dementia; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Malondialdehyde; Maze Learning; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Tacrolimus

The authors investigated the utility of both traditional and everyday cognitive measures in predicting medication adherence and employment status among kidney transplant recipients. In addition, the role of noncognitive predictors was examined.. Cognitive measures of processing speed, memory, everyday problem solving, executive functioning, and questionnaires assessing mood, medication adherence, and employment status were individually administered to 108 kidney transplant recipients. Because the eligibility criteria differed for the two analyses, there were 103 participants in the medication adherence analyses and 94 participants in the employment analyses. Stepwise hierarchical regression and sequential binomial logistic regression analyses were conducted for continuous and dichotomous outcome measures, respectively.. Findings indicate that both poorer performance on the everyday problem-solving test and a higher number of depressive symptoms were predictive of poorer self-reported medication adherence (R(2) = .19, p < .01). Furthermore, being on antidepressant medication, having a higher number of depressive symptoms, and poorer performance on traditional neuropsychological measures were predictive of fewer hours worked (Nagelkerke's R(2) = .29, ps <.05).. This study highlights the differential associations between neurocognitive and psychosocial status, and medication adherence and employment status following kidney transplantation. The findings suggest that the relative importance of traditional and everyday measures is dependent upon the outcome examined.

Topics: Activities of Daily Living; Adult; Cognition Disorders; Cyclosporine; Employment; Executive Function; Female; Humans; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Medication Adherence; Memory; Middle Aged; Neuropsychological Tests; Predictive Value of Tests; Problem Solving; Regression Analysis; Retrospective Studies; Self Concept; Surveys and Questionnaires; Tacrolimus; Verbal Learning

Cyclosporine and FK506, a well-known immunosuppressant drugs that are presently being used for prevention of allograft rejection. Recently, several studies suggest their therapeutic potential in the treatment of neurodegenerative diseases. Therefore, present study was conducted to explore their therapeutic potential against 3-nitropropionic acid induced cognitive dysfunctions and biochemical alterations in striatum, cortex and hippocampal regions of brain. Further, attempt has also been made to investigate their possible interaction with nitric oxide modulators.3-Nitropropionic acid (10 mg/kg) for 14 days treatment significantly impaired cognitive task as evidenced by Morris water as well as plus maze performance tasks. 3-Nitropropionic acid treatment significantly disturbed glutathione redox ratio and different levels of glutathione (as indicated by alterations in total glutathione, reduced glutathione, oxidized glutathione, glutathione-S-transferase levels). Acetylcholinesterase enzyme activity was also significantly disturbed by 3-NP treatment. Further, FK-506 (0.5, 1 and 2 mg/kg, p.o.) and cyclosporine (2.5, 5 and 10 mg/kg, p.o.) treatment significantly improved cognitive functions both in Morris water maze and plus maze tasks. Beside these drug treatment significantly attenuated oxidative stress as evidenced by restoring different glutathione levels and acetylcholinesterase activity as compared to control (3-NP treated) animals. Further sub effective doses of cyclosporine (5 mg/kg) and FK-506 (1 mg/kg) effect was potentated by l-NAME and reversed by l-arginine pretreatment. The effects were significant as compared to their effect per se.Study highlights the therapeutic potential of these drugs in the treatment of Huntington's disease. Study further suggest that nitric oxide modulation in involved in the neuroprotective effect of these drugs against 3-NP neurotoxicity.

Topics: Acetylcholinesterase; Analysis of Variance; Animals; Arginine; Behavior, Animal; Brain; Cognition Disorders; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Glutathione; Glutathione Transferase; Male; Maze Learning; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitro Compounds; Oxidative Stress; Propionates; Rats; Rats, Wistar; Tacrolimus; Time Factors