tacrolimus and Dementia

Evidence suggests patients prescribed calcineurin inhibitors (CNIs) have a reduced prevalence of dementia, including Alzheimer's disease (AD); however, this result has never been replicated in a large cohort and the involved mechanism(s) and site of action (central versus periphery) remain unclear.. We aim to determine if prescription of CNIs is associated with reduced prevalence of dementia, including AD, in a large, diverse patient population. Furthermore, we aim to gain insight into the mechanism(s) and site of action for CNIs to reduce dementia prevalence.. Electronic health records (EHRs) from patients prescribed tacrolimus, cyclosporine, or sirolimus were analyzed to compare prevalence, odds, and hazard ratios related to dementia diagnoses among cohorts. EHRs from a random, heterogeneous population from the same network were obtained to generate a general population-like control.. All drugs examined reduced dementia prevalence compared to the general population-like control. There were no differences in dementia diagnoses upon comparing tacrolimus and sirolimus; however, patients prescribed tacrolimus had a reduced dementia prevalence relative to cyclosporine.. Converging mechanisms of action between tacrolimus and sirolimus likely explain the similar dementia prevalence between the cohorts. Calcineurin inhibition within the brain has a greater probability of reducing dementia relative to peripherally-restricted calcineurin inhibition. Overall, immunosuppressants provide a promising therapeutic avenue for dementia, with emphasis on the brain-penetrant CNI tacrolimus.

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Dementia; Humans; Kidney Transplantation; Prevalence; Sirolimus; Tacrolimus

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