Recent Topics on The Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities

Abstract

Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood–brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed.

Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review

“…An experimental study showed that prednisolone acetate 40 mg/kg can induce depression-like behaviour in rhesus macaques [81]. Exogenous corticosterone can cause induction of glutamate at synapses, which contributes to mood disorders [82,83]. Cognitive decline is found to be related to current or long-term steroid use (even low dose) in RA patients as a vascular side effect [72] but another study reported no significant relation between MMSE and chronic glucocorticoid use [74].…”

Epileptic Seizures After Allogeneic Hematopoietic Stem Cell Transplantation

“…Calcineurin inhibitors (CNIs) are a class of widely used drugs to prevent graft vs. host disease (GVHD) and its sequelae after HSCT. Cyclosporin A (CsA) and tacrolimus (TAC) are mainly Vasculitis or immune-mediated encephalitis caused by cGVHD Unknown included, they exert immunosuppressive actions by binding to immunophilins to inhibit the calcineurin-mediated calciumdependent signaling pathways that mediate the formation of interleukin-2 and T-lymphocyte activation (27). Although many patients benefit from them, neurotoxicities caused by these agents have remained serious, a seizure is one of the severe manifestations which cannot be ignored.…”

“…Previous reports have indicated that both CsA and TAC enhance the permeability of the blood-brain barrier (BBB) by damaging tight junctions directly, inducing apoptosis of brain capillary endothelial cells (30), and decreasing P-glycoprotein's efflux pump function (27,31). In addition, CsA exposure can increase nitric oxide (NO) production in brain endothelial and astroglial cells, further mediating endothelial injury and impairment of BBB function (32,33).…”

Mitigation of Alzheimer’s Disease Neuropathologies by Human Neural Stem Cell-derived Extracellular Vesicles

“…These EV not only cross the bloodbrain barrier, but also negate concerns regarding the possibility of teratoma formation and immune rejection that confound related stem cell-based approaches [15,17,22]. Immune rejection is a particularly signi cant problem in the case of AD, since the long-term use of immunesuppresants can result in toxicity, particularly in the aged, and may also exacerbate AD-related pathologies [35,58].…”