Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Abstract

Long‐term neuroleptic medication of schizophrenic patients induces extrapyramidal motor side effects, of which tardive dyskinesia (TD) is the most severe. The etiology of TD is still obscure. Recently, it was suggested that abnormal iron metabolism may play a crucial role in neuroleptic‐induced dopamine D2 receptor super‐sensitivity. The apparent relationship between neuroleptics and iron is further supported by the increase of iron in the basal ganglia of patients with TD. We now report on the ability of neuroleptics to alter the blood‐brain barrier in the rat and to potentiate the normally limited iron transport into the brain. Thus, chronic treatment of rats with chlorpromazine and haloperidol facilitated 59Fe3+ uptake into brain cells. In contrast, clozapine, an atypical antipsychotic neuroleptic with little extrapyramidal motor side effects, caused iron sedimentation in brain blood vessels with no sign of detectable iron in the cells. Moreover, chronic treatment with chlorpromazine and haloperidol caused a 43% and 24% reduction, respectively, in liver nonheme iron, whereas clozapine induced an 81% increase. The apparent different potentials of chlorpromazine, haloperidol, and clozapine to increase iron transport into the brain from its peripheral stores may be linked to the severity of extrapyramidal motor side effects they induce and to the pathophysiology of TD.

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

“…APs, at concentrations similar to those measured in the serum of highly dosed patients, are already established to induce gross permeability changes in the BBB; for example its permeability to FeCl3, mannitol and inulin are all enhanced by acute administration of 5µM CPZ (Pardridge et al, 1973;Ben-Shachar et al, 1994), a phenomenon indicative of a BBB breach at a drug concentration similar to that occasionally measured in human serum (3µM, 1000ng/ml; Van Putten et al, 1991), and.…”

Extracellular matrix proteins matrix metallopeptidase 9 (MMP9) and soluble intercellular adhesion molecule 1 (sICAM‐1) and correlations with clinical staging in euthymic bipolar disorder

“…Moreover, as one of the major sources of sICAM‐1 is activated macrophages, the level of sICAM‐1 in the blood serves as a proxy for an activated immune system . Elevated sICAM‐1 as well as MMP9 levels are also a marker of inflammatory blood–brain barrier (BBB) disturbances .…”

Ferritin Levels and Their Association With Regional Brain Volumes in Tourette's Syndrome

“…Because the blood-brain barrier blocks cells in the brain from exposure to nonheme iron in the plasma, how well peripheral iron indices correlate with central iron content is unclear. Moreover, the association of central with peripheral iron levels appears to be influenced by multiple factors, including age, iron deficiency, and antipsychotic use (14,15). Whereas some investigators have reported that the quantity of nonheme iron in the human brain is largely independent of body iron stores (6), iron deficiency in rats has been shown to decrease nonheme iron in the brain by more than 40% (16), and a positive correlation (r=0.6) was found between serum and CSF ferritin in individuals with restless legs syndrome (17).…”