Role of Astroglial Hemichannels and Pannexons in Memory and Neurodegenerative Diseases

Indexación: Web of ScienceUnder physiological conditions, astroglial hemichannels and pannexons allow the release of gliotransmitters from astrocytes. These gliotransmitters are critical in modulating synaptic transmission, plasticity and memory. However, recent evidence suggests that under pathological conditions, they may be central in the development of various neurodegenerative diseases. Here we review current literature on the role of astroglial hemichannels and pannexons in memory, stress and the development of neurodegenerative diseases, and propose that they are not only crucial for normal brain function, including memory, but also a potential target for the treatment of neurodegenerative diseaseshttp://journal.frontiersin.org/article/10.3389/fnint.2016.00026/ful

Sex steroid hormones and brain function:PET imaging as a tool for research

Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone-mediated signalling via the corresponding hormone receptors can influence brain function at the cellular level and thus affect behaviour and higher brain functions. Altered steroid hormone signalling has been associated with psychiatric disorders, such as anxiety and depression. Neurosteroids are also considered to have a neuroprotective effect in neurodegenerative diseases. So far, the role of steroid hormone receptors in physiological and pathological conditions has mainly been investigated post mortem on animal or human brain tissues. To study the dynamic interplay between sex steroids, their receptors, brain function and behaviour in psychiatric and neurological disorders in a longitudinal manner, however, non-invasive techniques are needed. Positron emission tomography (PET) is a non-invasive imaging tool that is used to quantitatively investigate a variety of physiological and biochemical parameters in vivo. PET uses radiotracers aimed at a specific target (eg, receptor, enzyme, transporter) to visualise the processes of interest. In this review, we discuss the current status of the use of PET imaging for studying sex steroid hormones in the brain. So far, PET has mainly been investigated as a tool to measure (changes in) sex hormone receptor expression in the brain, to measure a key enzyme in the steroid synthesis pathway (aromatase) and to evaluate the effects of hormonal treatment by imaging specific downstream processes in the brain. Although validated radiotracers for a number of targets are still warranted, PET can already be a useful technique for steroid hormone research and facilitate the translation of interesting findings in animal studies to clinical trials in patients

Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS

In Vivo Induction of P‑Glycoprotein Function can be Measured with [18F]MC225 and PET

P-Glycoprotein (P-gp) is an efflux pump located at the blood−brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K1) and volume of distribution (VT) were calculated, which reflectthe in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p < 0.001) and in the low-dose group by 7% (K1-low-dose = 0.28 ± 0.02 vs K1-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group (VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) compared to controls. k2 values did not vary after treatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [18F]MC225 and PET