[The role of docosahexaenoic acid in neuronal function]. / Rola kwasu dokozaheksaenowego w czynnosci komórek nerwowych.

Docosahexaenoic acid (DHA, C22: 6n-3) is the most abundant polyunsaturated fatty acid in neuronal phospholipids, particularly in the cortex. The main source of DHA for neural cells is food, and hepatic and astroglia DHA synthesis from essential a-linolenic acid (C18: 3n-3). Accretion of DHA in the brain is most intensive during fetal life and the first two years of life. An adequate level of DHA in cell membranes is important for many functions of neural cells and this is presumably the reason for DHA saving in the adult mammalian brain during dietary a-linolenic acid deficiency. DHA-containing phospholipids in membranes are flexible and membranes possessing a high content of them are quite thin, more permeable to ions and small molecules, have looser lipid packing, and finally are more "dynamic" than membranes composed of other fatty acid containing phospholipids. Furthermore, these membranes create an appropriate environment for integral proteins highly condensed in neurons, such as receptors, ion channels, enzymes, and peripheral proteins. The quantity of phosphatidylserine in the inner membrane lipid layer depends on the availability of DHA to neurons. Phosphatidylserine promotes neuronal survival by translocation/activation of kinase Akt and Raf-1/MEK. DHA present in membrane phospholipids facilitates v-SNARE/t-SNARE complex formation, which is necessary for fusion of synaptic vesicles and plasma membranes necessary for transmitter exocytosis, and neurite outgrowth-dependent plasticity. DHA plays an important neuroprotective role. DHA has been shown to inhibit PGE2 synthesis and COX-1 expression in astrocytes, and DHA derivatives, especially neuroprotectins D, can suppress inflammatory responses, preventing neuronal damage or apoptosis. The results of high DHA content in neuronal membranes and formation of DHA derivates, as well as the function of DHA-dependent phosphatidylserine, may explain the promising results supporting beneficial DHA supplementation in neurodegenerative diseases and improvement of brain function.

Use of monoclonal anti-EGFR antibody in the radioimmunotherapy of malignant gliomas in the context of EGFR expression in grade III and IV tumors.

We investigated the putative benefits of simultaneous teleradiotherapy and anti-epidermal growth factor receptor (EGFR) 125I monoclonal antibody (MAb) 425 radioimmunotherapy, when applied after neurosurgery in high-grade gliomas, over teleradiotherapy alone. In comparison to previous studies which have reported good results with this type of radioimmunotherapy, we advanced the adjuvant radioimmunotherapy step, that is, gave it during, not after, teleradiotherapy. The randomized prospective study examined two groups: simultaneous postoperative teleradiotherapy and radioimmunotherapy (TRT + RIT; eight patients) versus teleradiotherapy alone (TRT; 10 patients). Patients who after primary operation of grade III (6 cases) or IV glioma (12 cases), showed no or less than 2 mL of remnant tumor on post-operative magnetic resonance (MR) study and were not treated postoperatively by chemotherapy were enrolled and randomized. Anti-EGFR 125IMAb 425 RIT was started during week 4 of radiotherapy, not later than 8 weeks after neurosurgery, and was repeated three times at 1-week intervals. Total activity given was 5026 + 739 MBq/patient. The tolerance of TRT was good. No immediate side effects of concomitant anti-EGRF 125I RIT were observed. Observation showed a median total survival (as evaluated from the primary neurosurgical treatment) of 14 months (range 3.5-28 months). There was no improvement in disease-free or total survival in the group of patients treated by TRT + RIT after neurosurgery. In addition, an immunohistochemical analysis of EGFR expression in gliomas was performed in a group of 100 cases and was distinctly positive in 50% grade IV gliomas and 68% grade III gliomas. We conclude that simultaneous radiotherapy and radioimmunotherapy with anti-EGFR 125I-MAb 425 is not beneficial over radiotherapy alone in adjuvant treatment of high-grade gliomas after neurosurgery. We also recommend individual confirmation of EGFR expression in further anti-EGFR radioimmunotherapy trials.

Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics.

Under pathological conditions, microglial cells undergo activation, which is manifested by the expression of histocompatibility locus antigens class II (HLA II) on their surface as well as by proliferation and varied morphological forms. In schizophrenia, characterised by an essential role played by immunological mechanisms, quantitative analysis of activated microglia -- with well-developed ramification (RM), degenerative traits and damaged processes (from their shortening to their complete lack) (DM) -- may contribute to better understanding of schizophrenia etiopathogenesis. Quantitative analysis was performed on slices derived from the frontal and temporal lobes of 9 brains of schizophrenics and 6 control brains. The nonparametric Mann-Whitney U test was used to assess quantitative differences in the distribution of microglia in these regions of the brain. Statistical analyses were performed with STATISTICA 6.5 Programme. In both structures of the brain, the number of activated microglial cells was higher in schizophrenic brains than in control brains. Except for the first layer of the cerebral cortex with the same amounts of RM and DM, the number of DM cells in the remaining regions was several-fold higher than that of RM cells. It is most likely that disturbances in calcium metabolism and energetic balance as well as antibodies produced in the course of schizophrenia are the agents able to trigger a cascade transforming RM into DM. Quantitative differences in RM and DM, observed between the studied structures and cortical regions, could depend not only on functioning of inter-neuronal and inter-structural links. Our study suggests a pivotal role of microglial cells in repair processes and/or etiopathogenesis of schizophrenia and indicates that they undergo substantial damage in the course of chronic schizophrenia.

Effects of pentosan polysulfate sodium on the estrogen-induced pituitary prolactinoma in Fischer 344 rats.

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. This type of tumor is a rich source of basic fibroblast growth factor (bFGF), which possesses strong mitogenic and angiogenic properties. Pentosan polysulfate sodium (PPS) has been shown to exert antitumor activity by antagonizing the binding of bFGF to cell surface receptors. We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats. Chronic treatment with PPS did not cause any changes in the pituitary weight and serum prolactin concentration in comparison with untreated animals. The density of microvessels identified by CD-31 was also not affected by the tested drug. On the other hand, pentosan has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. Moreover, the TUNEL method has revealed an increased number of apoptotic bodies within the anterior pituitary after treatment with PPS. Despite the antiproliferative and proapoptotic activity of pentosan, the drug failed to inhibit tumor growth. This fact might be due to the lack of antiangiogenic activity of PPS in this experimental design.

Simultaneous radiotherapy and radioimmunotherapy of malignant gliomas with anti-EGFR antibody labelled with iodine 125. Preliminary results.

BACKGROUND: In this paper we present the preliminary results of a prospective trial of the efficacy of simultaneous radiotherapy and anti-EGFR (125)I radioimmunotherapy of malignant gliomas with 2 years' total survival as the end-point, raising the question whether anti-EGFR (125)I radioimmunotherapy influences the disease-free survival in these patients. MATERIAL AND METHODS: Patients with anaplastic astrocytoma or primary glioblastoma were previously treated by a macroscopically radical neurosurgical approach and randomized either to radiotherapy + radioimmunotherapy arm or treated by radiotherapy alone. Seven patients were included in the group with radioimmunotherapy, among them five with GBM and two with AA, and five patients in the control arm. Patients were irradiated to 60 Gy using three-dimensional conformal noncoplanar techniques. Anti-EGFR (125)I monoclonal antibody 425 radioimmunotherapy (50 mCi/course) was started during 4th week of radiotherapy and was repeated three times in one week intervals. RESULTS: Time of follow-up ranges between 2 and 10 months in the anti-EGFR (125)I radioimmunotherapy arm and 4 and 9 months in the control arm. Recurrence was diagnosed in all patients in the EGFR (125)I group with a lethal outcome in two of them and in 4 patients in the control group. Median time to recurrence was 2 and 5 months respectively. CONCLUSIONS: Taking into account early recurrences observed, we propose to continue the studies on the efficacy of adjuvant anti-EGFR (125)I radioimmunotherapy in a selected group of patients in whom the greatest benefit may be expected on the basis of molecular studies, among them EGFR expression investigation.