Peripheral administration of lactate produces antidepressant-like effects.

This corrects the article DOI: 10.1038/mp.2016.179.

Peripheral administration of lactate produces antidepressant-like effects.

In addition to its role as metabolic substrate that can sustain neuronal function and viability, emerging evidence supports a role for l-lactate as an intercellular signaling molecule involved in synaptic plasticity. Clinical and basic research studies have shown that major depression and chronic stress are associated with alterations in structural and functional plasticity. These findings led us to investigate the role of l-lactate as a potential novel antidepressant. Here we show that peripheral administration of l-lactate produces antidepressant-like effects in different animal models of depression that respond to acute and chronic antidepressant treatment. The antidepressant-like effects of l-lactate are associated with increases in hippocampal lactate levels and with changes in the expression of target genes involved in serotonin receptor trafficking, astrocyte functions, neurogenesis, nitric oxide synthesis and cAMP signaling. Further elucidation of the mechanisms underlying the antidepressant effects of l-lactate may help to identify novel therapeutic targets for the treatment of depression.

Mouse multivalent IgG(2a, b) antibody--ricin A-chain immunotoxins combined with homologous or heterologous interleukin 2 in the treatment of a murine malignant lymphoproliferation (EL4).

Two immunotoxins containing ricin A-chain, staphylococcal protein A and mouse anti-Thy 1.2 antibodies of IgG(2a,b) subclass, were prepared. The two multivalent immunotoxins of 750 and 370 kDa and molar ratio A-chain: IgG of 1:2, were used for the treatment of mice bearing ascitic EL4 lymphoma. The immunotoxin-treatment, performed intraperitoneally, was combined or not with homologous or heterologous interleukin 2. The antitumor effects expressed by increase of mice survival time (p < 0.001 as compared with nontreated animals) corresponded to a proportion of 88-90% lymphoma cell-kill by immunotoxin and 93-95% by combination treatment (immunotoxin + interleukin 2), as calculated from the relationship between the survival time of nontreated mice and the number of tumor cells inoculated.

Interleukin 2 enhances the efficiency of immunotoxins in the treatment of mice with ascitic tumors.

Two multivalent immunotoxins (ITs) with cytotoxic potential against Thy 1.2-expressing tumor cells were used in association with mouse interleukin 2 (IL2) for treatment of mice bearing ascitic EL4 lymphomas. The combined treatment, ITs + IL2, induced an enhanced antitumor effect revealed by a significant prolongation of the survival time of mice as compared to the simple treatment with ITs or IL2 alone. According to the survival of mice treated by combined therapy, the proportion of killed tumor cells rose up to 94% as resulted from the dose-dependent curve of the survival of nontreated mice versus the number of tumor cells inoculated.

Treatment of murine EL4 leukemia in ascitic form with anti-Thy 1.2 specific immunotoxins.

C57BL/6 mice with EL4 leukemia cells in ascitic form were intraperitoneally treated with ricin A chain-multivalent antibody immunotoxins. The immunotoxins containing rabbit IgG anti-Thy 1.2 antibodies complemented by protein A of Staphylococcus aureus were able to interact specifically with the target cells and to induce an antitumor effect as revealed by an increase in survival time of the mice. No apparent secondary effects consecutive to a cytotoxic action on the normal Thy 1.2 antigen bearing cells were observed with the immunotoxin doses used.

[Ergonomic study of neuropsychic impairment in relation to health status in printing occupations]. / Etude ergonomique concernant les sollicitations neuropsychiques en relation avec l'état de santé dans certaines professions typographiques.

The exertion and risk factors in relation with the state of health, with the psychophysiological reactivity and with the adaptation and fatigue symptomatology were studied by means of complex psychological, psychophysiological, medical) methods in two professional groups that perform an activity implying important mental and sensorial components: monotasterers and correctors, from three polygraphic enterprises and two publishing houses, totalling 167 subjects (74 monotasterers and 93 correctors). The ergonomic work analysis demonstrated that the exertion and risk factors are conditioned both by the contents of work and by the working environment. The occupational exertion is more complex in monotasterers (mental, sensorial and physical) and predominantly sensorial (visual) in correctors. The work hazards are especially brought about by overstraining of the attention and of the visual analyser, with consequences both on the health of workers and on the quality of production. The investigation of the state of health, of the psychophysiological reactivity, as well as of the adaptation and fatigue symptomatology has detected maladjustment and fatigue phenomena, with impairments of the psychosomatic balance, more marked in monotasterers. The suggestions regarding improvement measures were directed both towards aspects of medico-psychological prophylaxis and elements of corrective ergonomics.

Experimental model for testing the efficiency of immunotoxins administered in vivo: evaluation of two ricin A-chain--multivalent antibody immunotoxins.

Two immunotoxins, the ricin A chain-multivalent hybrid antibody (750 kDa) and the complex A chain-staphylococcal protein A-rabbit IgG antibody (370 kDa), were prepared. A simple method was elaborated to test the immunotoxins' efficiency in selectively killing target cells in tumor-bearing mice. The target cell (murine EL4 leukemia) was coated with a xenogenic molecule by a method conserving its ability to proliferate and kill the inoculated animals. When the challenged animals were treated with these immunotoxins, which were specific for the antigenic molecule coating the tumor cells, survival time was lengthened compared with that of untreated animals, corresponding to a proportion of over 90% cells killed. This demonstrates the efficiency of the immunotoxins and the validity of the method elaborated.

In vivo follow-up of the cytotoxic effect of protein A--ricin toxin conjugate, on antibody-coated target cells.

Antibodies of the IgG class, specifically interacted with H-2 antigens of murine leukemia EL4 cells, were used to bind the ricin toxin covalently linked to protein A of Staphylococcus aureus. The toxin thus complexed, introduced in the cytoplasm by endocytosis, was able to kill the leukemic cells inoculated in animals. The interaction of immunotoxin with the leukemic cells was performed in vitro using one, two or three treatments and the cytotoxic effect on the target cells was followed up in vivo. The time interval between immunotoxin treatments was indicated by the membrane turn-over study of EL4 cells coated with specific antibodies in their monomeric form, complexed by protein A or interacted with protein A--ricin toxin conjugate. A proportion of 99.8% cells killed was obtained after three treatments.

Protein A vectorized toxins--II. Preparation and "in vitro" cytotoxic effect of protein A-ricin A chain conjugate on antibody coated human tumour cells.

Protein A of Staphylococcus aureus was covalently bound to reduced ricin A chain toxin by N-succinimidyl 3-(2-pyridyldithio)propionate. The conjugate consisting mainly of one molecule of protein A bound to two molecules of A chains (Mr 107,000) was purified by tandem affinity chromatography on ConA-Sepharose 4B and IgG-Sepharose 4B. The purified protein A-A chain conjugate was able to bind and kill human lymphoma cells coated either with monoclonal mouse IgG2a anti-kappa antibody or with polyclonal rabbit anti-kappa antibody. The cytotoxic activity of protein A-A chain conjugate in conjunction with either mouse or rabbit anti-kappa antibodies was 10 times higher than that of rabbit IgG anti-mouse IgG coupled with A chain on Daudi cells coated with mouse anti-kappa antibody and 100 times higher than that of rabbit anti-kappa antibody coupled with A chain on non-coated Daudi cells. The cytotoxic effect of protein A-A chain conjugate on antibody-coated Daudi cells (9 x 10(-12) M) was comparable with that of ricin toxin on non-coated Daudi cells (2 x 10(-12) M). The results recommend the use of protein A-ricin A chain toxin conjugate as a unique specific toxin for the "in vitro" killing of antibody-coated target cells.

Interaction between rabbit IgG immune complexes and Ricinus agglutinin.

Ricinus communis agglutinin covalently bound to Sepharose 4B (RcA-Sepharose 4B) was able to selectively bind immune complexes consisting of antigen (bovine serum albumin) and rabbit IgG antibody which were rich in antibody (i.e., high molecular weight complexes of approximately 2000 000). No interaction was recorded between RcA-Sepharose 4B and immune complexes consisting of the antigen plus rabbit IgG antibody which were rich in antigen (i.e., complexes with a molecular weight of 300 000-500 000). These results indicate that binding to RcA is due to the increased density of galactose residues in the high molecular weight polymeric antibody component of the soluble immune complexes.