Ewa Krzystanek

Effects of long-term treatment with the neuroleptics haloperidol, clozapine and olanzapine on immunoexpression of NMDA receptor subunits NR1, NR2A and NR2B in the rat hippocampus.

BACKGROUND Antagonists of the N-methyl-d-aspartate receptor (NMDA-R) are associated with symptoms of schizophrenia, leading to the hypothesis that NMDA-R hypofunction leads to the pathogenesis of disease. We evaluated the long-term effect of neuroleptic administration on the NMDA subunits via immunohistochemical analysis. METHODS Rats received olanzapine, clozapine and haloperidol before evaluation of the expression of the NR1, NR2A and NR2B subunit proteins in the hippocampal areas of the brain, via a densytometric analysis of immunoexpression in the rat hippocampus. RESULTS All of the neuroleptics examined caused a decrease in the expression of the NR1 subunit, and thus, one can assume that both olanzapine, clozapine and haloperidol decreased the number of NMDA receptors in the CA1 and CA2 areas of the brain. CONCLUSIONS A decrease in hippocampal glutamatergic signalling after long-term neuroleptic administration may cautiously explain the incomplete effectiveness of these drugs in the therapy of schizophrenia-related cognitive disturbances.

Synthesis, Structure, and Biological Activities of Some N-(4,5-Dihydro-1H-imidazol-2-yl)-l,3-dihydrobenzimidazole Derivatives

A series of novel N‐(4,5‐dihydroimidazol‐2‐yl)‐1,3‐dihydrobenzimidazole derivatives 2a–d, 3a–d and 4a–p were prepared and their structure was determined by IR and NMR spectroscopic data as well as X‐ray analysis of carbonitrile 2a. The compounds were studied as potential inhibitors of the human blood platelet aggregation induced by adrenaline or ADP. Compounds of type 3 proved efficacious for the reduction of arterial blood pressure upon intravenous administration to normotensive rats.

Effects of olanzapine and paroxetine on phospholipase D activity in the rat brain

BACKGROUND Phospholipase D (PLD) plays a key role in a second messenger system producing phosphatidic acid, mediating, among others, serotonin 5-HT2 receptor activity. The aim of the study was to evaluate a possible effect of atypical antipsychotic drug, olanzapine (OLZ), and selective serotonin reuptake inhibitor (SSRI) antidepressant, paroxetine (PX), on oleate-activated PLD activity in plasma membranes isolated from rat brain cortex. METHODS PLD activity was determined using a fluorometric assay. Ritanserin was used to determine the 5-HT receptor mode of action. RESULTS A single dose of 10 mmol/kg OLZ produced no change in rat brain cortex PLD activity, 20 mmol/kg OLZ caused a nonsignificant decrease, and long-term (21 days) administration of OLZ resulted in a 41.9% decrease in PLD activity. Single doses of PX significantly decreased PLD activity: 10 mmol/kg - by 28.6%; 20 mmol/kg - by 31.5%, and long-term (21 days) administration of PX - by 39.5%. CONCLUSION The study indicates that the 5-HT2 receptor-mediated inhibition of oleate-activated PLD may be a common part of the mechanisms of action of OLZ and PX.

Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: the importance of ketonuria

BACKGROUND Dimethyl fumarate (DMF) is approved for use in patients with relapsing-remitting multiple sclerosis (MS). Its mechanism of action is still not well understood, but besides the immunological pathways in MS, it may also affect the metabolism of normally functioning internal organs, tissues and cells. CASE PRESENTATION We report on the case of 29-year-old woman with satisfactorily-controlled type 1 diabetes (T1D), who was diagnosed as having MS. After administration of DMF she experienced intense, adverse gastro-intestinal reactions together with ketonuria up to 160 mg/dL. The highest ketone concentrations in the urine were observed approximately 2 h after each DMF dose and always with co-existing adverse reactions. Dose reduction did not improve symptoms and treatment had to be stopped. Twelve hours after the last dose of DMF all laboratory results returned to normal ranges and all gastro-intestinal adverse reactions were resolved within the following 24 h. CONCLUSION This is a first report of ketonuria in a MS-patient with T1D treated with DMF. Patients with MS and co-existing metabolic diseases, which are not contraindicated for DMF treatment, represent a unique opportunity to address questions regarding the possible mechanisms of action of DMF on the cellular metabolism. The use of DMF in patients with metabolic diseases needs closer attention.