The Effect of Meclofenoxate on the Transcriptome of Aging Brain of Nothobranchius guentheri Annual Killifish.

Annual fish of the genus Nothobranchius are promising models for aging research. Nothobranchius reproduces typical aspects of vertebrate aging, including hallmarks of brain aging. Meclofenoxate (MF) is a well-known compound that can enhance cognitive performance. The drug is prescribed for asthenic conditions, trauma, and vascular diseases of the brain. It is believed that MF is able to delay age-dependent changes in the human brain. However, until now, there has been no study of the MF effect on the brain transcriptome. In the present work, we performed an RNA-Seq study of brain tissues from aged Nothobranchius guentheri, which were almost lifetime administered with MF, as well as young and aged control fish. As expected, in response to MF, we revealed significant overexpression of neuron-specific genes including genes involved in synaptic activity and plasticity, neurotransmitter secretion, and neuron projection. The effect was more pronounced in female fish. In this aspect, MF alleviated age-dependent decreased expression of genes involved in neuronal activity. In both treated and untreated animals, we observed strong aging-associated overexpression of immune and inflammatory response genes. MF treatment did not prevent this effect, and moreover, some of these genes tended to be slightly upregulated under MF treatment. Additionally, we noticed upregulation of some genes associated with aging and cellular senescence, including isoforms of putative vascular cell adhesion molecule 1 (VCAM1), protein O-GlcNAcase (OGA), protein kinase C alpha type (KPCA), prolow-density lipoprotein receptor-related protein 1 (LRP1). Noteworthy, MF treatment was also associated with the elevated transcription of transposons, which are highly abundant in the N. guentheri genome. In conclusion, MF compensates for the age-dependent downregulation of neuronal activity genes, but its effect on aging brain transcriptome still cannot be considered unambiguously positive.

A simple and sensitive HPLC method for quantification of the metabolin of meclofenoxate in human plasma.

A simple and sensitive high-performance liquid chromatographic method was developed for quantification of the metabolin of meclofenoxate, chlorophenoxyacetic acid, in human plasma. Ibuprofen was used as an internal standard. The present method used protein precipitation for extraction of chlorophenoxyacetic acid from human plasma. Separation was carried out on a reversed-phase C(18) column. The column effluent was monitored by UV detection at 254 nm. The mobile phase was a mixture of methanol and water containing 1.0% glacial acetic acid (70:30 v/v) at a flow rate of 1.0 mL/min. The column temperature was 20 degrees C. This method was linear over the range of 0.047-28.20 microg/mL with a regression coefficient greater than 0.99. The mean recovery of chlorophenoxyacetic acid and IS were (79.54 +/- 6.33)% and (78.48 +/- 2.14)%, respectively, and the method was found to be precise, accurate, and specific during the study. The method was successfully applied for pharmacokinetic study of chlorophenoxyacetic acid in human.

[Increase in cell metabolism in normal, diploid human glial cells in stationary cell cultures induced by meclofenoxate]. / Erhöhung von Zellstoffwechselleistungen in normalen, diploiden, menschlichen Glia-Zellen in stationären Zellkulturen induziert durch Meclofenoxat.

Quantitative biochemical studies were undertaken in order to examine the influence of the accumulation of lipofuscin in secondary lysosomes on cell metabolic activities of normal diploid human glia cells in a stationary cell culture system. Glia cells accumulate lipofuscin as a function of the duration of the stationary cultivation in vitro. The accumulation of lipofuscin can be decreased by the long-term treatment with the pharmacon meclofenoxate (centrophenoxine, Helfergin). Concomitant with the reduction of the accumulated lipofuscin, meclofenoxate-treated glia cells show enhanced rates of RNA synthesis, protein synthesis and glucose uptake. Most likely, in meclofenoxate-treated normal diploid human glia cells in vitro, the utilisation of glucose is shifted from glycolysis to the pentose phosphate pathway. The data suggest that the meclofenoxate-induced reduction of lipofuscin accumulation has a positive effect on cell metabolic functions and causes a delay of the cellular aging of the human glia cells in vitro.