Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvirionment of the central nervous system and defend nervous system against multitude of insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes resulting in dementia. We also show that in the transgenic model of Alzheimer's disease, reactive hypertrophic astrocytes surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative alterations.

Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo–pituitary–adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca2+ in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

Summary: Extracellular space (ECS) volume fraction(IX), ECS tortuosity (A), and nonspecific uptake (k'), three parameters affecting the diffusion of substances in ner vous tissue, were studied during ischemia and anoxia in the rat spinal cord gray matter in vivo. Progressive isch emia evoked by exsanguination, as well as anoxia evoked by respiratory or cardiac arrest, produced prominent ex tracellular K + and pH changes closely related to a de crease in blood pressure and amplitude of field potentials. With use of ion-selective microelectrodes, the changes in the diffusion parameters were measured by quantitative analysis of concentration-time profiles of tetramethylam monium (TMA +) applied by iontophoresis concomitantly with ionic shifts. Under normoxic conditions (in rats with blood pressure of 80-110 mm Hg) diffusion parameters in the dorsal hom gray matter at depth 500-900 fLm were as follows: IX = 0.20 ± 0.019, A = 1.62 ± 0.12, k' = 4.6 ± 2.5 x 10-3 s -1 (mean ± SD, n = 39). Extracellular K +, pH, and diffusion properties gradually changed during progressive ischemia. As the blood pressure fell to 50-60 mm Hg and field potential amplitude to 20-60%, K + rose to 6-12 mM, pHe fell by -0.05-0.1 pH unit, and volume fraction of the ECS significantly decreased, to IX = 0.16 ± 0.019 (n = 22). Even though the tortuosity remained vir tually constant, the nonspecific uptake significantly de creased to k' = 3.4 ± 1.8 x 10-3 S-I. As the blood pressure fell to 20-30 mm Hg and field potential ampli tude to 0-6%, K + rose to 60-70 mM, pHe fell by -0.6-0.8 pH unit, and all three diffusion parameters significantly 301changed. The ECS volume fraction decreased to a = 0.05 ± 0.021, tortuosity increased to A = 2.00 ± 0.24, and TMA + uptake decreased to k' = 1.5 ± 1.6 x 10 -3 S -1 (n = 12). No further increase in extracellular K + or changes in the IX were found during and up to 120 min after the death of the animal. However, there was a further signif icant increase in A = 2.20 ± 0.14 and decrease in k' = 0.4 ± 0.3 x 10-3 s -1 (n = 24). The acid shift reached its maximum level at -5-10 min after respiratory arrest and then the pHe gradually increased by -0.2 unit. Full re covery to "normoxic" diffusion parameters was achieved after reinjection of the blood or after an injection of nor adrenaline during severe ischemia, if this resulted in a rise in blood pressure above 80 mm Hg and a decrease in extracellular K + below 12 mM. At -10 and 30 min after this recovery, the ECS volume fraction significantly in creased above "normoxic" values, to IX = 0.25 ± 0.016 (n = 7) and IX = 0.30 ± 0.021 (n = 6), respectively. The A and k' were not significantly different from the values found under normoxic conditions. Our data represent the first detailed in vivo measurements of diffusion parame ters IX, A, and k' during and after progressive ischemia and anoxia. The observed substantial changes in the diffusion parameters could affect the diffusion and aggravate the accumulation of ions, neurotransmitters, metabolic sub stances, and drugs ...

To understand the structural alterations that underlie early and late changes in hippocampal diffusivity after hypoxia/ischemia (H/I), the changes in apparent diffusion coefficient of water (ADC(W)) were studied in 8-week-old rats after H/I using diffusion-weighted magnetic resonance imaging (DW-MRI). In the hippocampal CA1 region, ADC(W) analyses were performed during 6 months of reperfusion and compared with alterations in cell number/cell-type composition, glial morphology, and extracellular space (ECS) diffusion parameters obtained by the real-time iontophoretic method. In the early phases of reperfusion (1 to 3 days) neuronal cell death, glial proliferation, and developing gliosis were accompanied by an ADC(W) decrease and tortuosity increase. Interestingly, ECS volume fraction was decreased only first day after H/I. In the late phases of reperfusion (starting 1 month after H/I), when the CA1 region consisted mainly of microglia, astrocytes, and NG2-glia with markedly altered morphology, ADC(W), ECS volume fraction and tortuosity were increased. Three-dimensional confocal morphometry revealed enlarged astrocytes and shrunken NG2-glia, and in both the contribution of cell soma/processes to total cell volume was markedly increased/decreased. In summary, the ADC(W) increase in the CA1 region underlain by altered cellular composition and glial morphology suggests that considerable changes in extracellular signal transmission might occur in the late phases of reperfusion after H/I.