A single dose of glycogen phosphorylase inhibitor improves cognitive functions of aged mice and affects the concentrations of metabolites in the brain.

Inhibition of glycogen phosphorylase (Pyg) - a regulatory enzyme of glycogen phosphorolysis - influences memory formation in rodents. We have previously shown that 2-week intraperitoneal administration of a Pyg inhibitor BAY U6751 stimulated the "rejuvenation" of the hippocampal proteome and dendritic spines morphology and improved cognitive skills of old mice. Given the tedious nature of daily intraperitoneal drug administration, in this study we investigated whether a single dose of BAY U6751 could induce enduring behavioral effects.

Glycogen phosphorylase inhibition improves cognitive function of aged mice.

Inhibition of glycogen breakdown blocks memory formation in young animals, but it stimulates the maintenance of the long-term potentiation, a cellular mechanism of memory formation, in hippocampal slices of old animals. Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice.

Validated liquid chromatography-mass spectrometry method for the quantification of glycogenolysis phosphorylase inhibitor in mouse tissues - 5-isopropyl-4-(2-chlorophenyl)-1-ethyl-1,4-dihydro-6-methyl-2,3,5-pyridinetricarboxylic acid ester disodium salt hydrate.

5-Isopropyl-4-(2-chlorophenyl)-1-ethyl-1,4-dihydro-6-methyl-2,3,5-pyridinetricarboxylic acid ester disodium salt hydrate, is a noncompetitive inhibitor of glycogen phosphorylase - a critical enzyme in the process of glycogenolysis. This chemical compound is most widely used in studies focused on the inhibition of liver and muscle glycogenolysis. However, there are also reports linking phosphorylase inhibitor action with cognitive function and glycogen metabolism in the brain.

Quantitative Proteomics Reveals Significant Differences between Mouse Brain Formations in Expression of Proteins Involved in Neuronal Plasticity during Aging.

Aging is associated with a general decline in cognitive functions, which appears to be due to alterations in the amounts of proteins involved in the regulation of synaptic plasticity. Here, we present a quantitative analysis of proteins involved in neurotransmission in three brain regions, namely, the hippocampus, the cerebral cortex and the cerebellum, in mice aged 1 and 22 months, using the total protein approach technique. We demonstrate that although the titer of some proteins involved in neurotransmission and synaptic plasticity is affected by aging in a similar manner in all the studied brain formations, in fact, each of the formations represents its own mode of aging.

Absolute Proteome Analysis of Hippocampus, Cortex and Cerebellum in Aged and Young Mice Reveals Changes in Energy Metabolism.

Aging is associated with a general decline of cognitive functions, and it is widely accepted that this decline results from changes in the expression of proteins involved in regulation of synaptic plasticity. However, several lines of evidence have accumulated that suggest that the impaired function of the aged brain may be related to significant alterations in the energy metabolism. In the current study, we employed the label-free "Total protein approach" (TPA) method to focus on the similarities and differences in energy metabolism proteomes of young (1-month-old) and aged (22-month-old) murine brains.

Expression of Fbp2, a Newly Discovered Constituent of Memory Formation Mechanisms, Is Regulated by Astrocyte-Neuron Crosstalk.

Fbp2 (muscle isozyme of fructose 1,6-bisphosphatase) is a glyconeogenesis-regulating enzyme and a multifunctional protein indispensable for long-term potentiation (LTP) formation in the hippocampus. Here, we present evidence that expression of Fbp2 in murine hippocampal cell cultures is regulated by crosstalk between neurons and astrocytes. Co-culturing of the two cell types results in a decrease in Fbp2 expression in astrocytes, and its simultaneous increase in neurons, as compared to monocultures.

Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging.

Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders. Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer's and Parkinson's disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed.

Aging-associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte-to-neuron lactate shuttle.

Lactate derived from astrocytic glycogen has been shown to support memory formation in hippocampi of young animals, inhibiting it in old animals. Here we show, using quantitative mass spectrometry-based proteomics, immunofluorescence, and qPCR that aging is associated with an increase of glycogen metabolism enzymes concentration and shift in their localization from astrocytes to neurons. These changes are accompanied with reorganization of hippocampal energy metabolism which is manifested by elevated capacity of aging neurons to oxidize glucose in glycolysis and mitochondria, and decreased ability for fatty acids utilization.

The influence of warm ischemia elimination on kidney injury during transplantation - clinical and molecular study.

Kidney surface cooling was used during implantation to assess the effect of warm ischemia elimination on allograft function, histological changes and immune-related gene expression. 23 recipients were randomly assigned to a group operated on with kidney surface cooling during implantation (ice bag technique, IBT group), and the other 23 recipients receiving the contralateral kidney from the same donor were operated on with a standard technique. Three consecutive kidney core biopsies were obtained during the transplantation procedure: after organ recovery, after cold ischemia and after reperfusion.

Involvement of cellular metabolism in age-related LTP modifications in rat hippocampal slices.

Recent studies emphasized crucial role of astrocytic glycogen metabolism in regulation of synaptic transmission and plasticity in young animals. However, the interplay between age-related synaptic plasticity impairments and changes in energetic metabolism remains obscure. To address this issue, we investigated, in hippocampal slices of young (one month) and aged rats (20-22-months), the impact of glycogen degradation inhibition on LTP, mRNA expression for glycogen metabolism enzymes and morphology of dendritic spines.

Long term potentiation affects intracellular metalloproteinases activity in the mossy fiber-CA3 pathway.

Matrix Metalloproteinases (MMPs) are a family of endopeptidases known to process extracellular proteins. In the last decade, studies carried out mainly on the Schaffer collateral-CA1 hippocampal projection have provided solid evidence that MMPs regulate synaptic plasticity and learning. Recently, our group has shown that MMP blockade disrupts LTP maintenance also in the mossy fiber-CA3 (mf-CA3) projection (Wojtowicz and Mozrzymas, 2010), where LTP mechanisms are profoundly different (NMDAR-independent and presynaptic expression site).

The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients.

The aim of the study was to examine whether CTLA-4 (CD152) and CD28 gene polymorphisms affect the outcome of kidney transplantation (KTx). Polymorphisms of the CTLA-4 gene (-318 C>T, +49 A>G, and the microsatellite polymorphism in the 3'UTR of exon 4 (AT)(n)) and a CD28 gene (IVS3 +17T>C) were investigated in 314 allograft recipients with a mean age of 41.9+/-12 years.

Novel peptide recognized by RhoA GTPase.

A phage-displayed random 7-mer disulfide bridge-constrained peptide library was used to map the surface of the RhoA GTPase and to find peptides able to recognize RhoA switch regions. Several peptide sequences were selected after four rounds of enrichment, giving a high signal in ELISA against RhoA-GDP. A detailed analysis of one such selected peptide, called R2 (CWSFPGYAC), is reported.