Quantitative EEG test dose procedure in the prediction of response to treatment with antipsychotic drugs

Abstract

The effects of different cerebro-protective agents on selected key enzymes of the energy metabolism of rat primary glial cultures and rat cerebral cortex were studied. As indicators for the capacity of the most important pathways of energy metabolism the following enzyme activities were determined: hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-P-DH), malate dehydrogenase (MDH), glutamate dehydrogenase (GDH), and cytochrome-c-reductase (CCR). After a one week growth period, rat glial cultures were incubated for 3 or 4 weeks with the substances to be tested. Bencyclane (5 × 10−5mol1) increased the activities of HK, G-6-P-DH, and LDH, whereas PFK and CCR were reduced. Pyritinol (10−4mol1) led to a higher G-6-P-DH activity, simultaneously lowering the values for PFK, CCR, PK, LDH, and MDH. Under the influence of an extract of the leaves of Ginkgo bilobae (EGB; 100mg/1) PFK, LDH, and MDH activities were reduced. All these alterations in enzyme activities went along with simultaneous reductions in protein content, therefore not allowing to exclude toxic effects with regard to the doses used. Moreover, direct interference with the analytical procedure was demonstrable for bencyclane and EGB. Piracetam (10−3mol1), flunarizine (10−6mol1), dihydroergocristine (5 × 10−6mol1), and nicergoline (5 × 10−6mol1) failed to induce any alteration in the employed doses. The most striking effects were obtained with meclofenoxate which was tested at 10−3 and 10−4mol1. The higher dose caused an elevation of HK, PFK, CCR, G-6-P-DH, GDH and MDH activities, while slightly reducing PK. With the lower dose of meclofenoxate CCR and G-6-P-DH activities were increased. Short-term incubation of the cultures with 10−3mol1 meclofenoxate for 24 hr led to an increase in LDH, G-6-P-DH, and GDH activities. Chronic incubation with meclofenoxate (10−3mol1) followed by 48 hr deprivation of the drug resulted in elevated HK, PFK, CCR, G-6-P-DH, GDH, and MDH activities. These changes were accompanied by alterations in related metabolite levels. These include elevations in the concentration of creatine phosphate and fructose-1,6-bisphosphate, whereas glucose-6-phosphate levels were reduced. After one week of meclofenoxate deprivation the activities of CCR and G-6-P-DH were still elevated. The metabolites of meclofenoxate dimethylaminoethanol (DMAE; 10−3mol1) and p-chlorophenoxyacetic acid (10−3mol1) were also investigated. The latter led to similar changes in the enzyme activity pattern as meclofenoxate itself with the exception of unchanged values for HK, whereas DMAE induced increases in CCR and GDH activities. Male rats were chronically treated for four weeks with either meclofenoxate (200 mgkg daily) or DMAE (60 mgkg daily). With both groups CCR activities in brain cortex were increased compared to saline treated animals. It was concluded that rat primary glial cultures could be suitable for the in vitro assay of enzyme activity alterations induced by cerebro-protective agents, to some degree allowing to predict in viva changes.