784 research outputs found
Vagus nerve stimulation increases neurotrophins gene expression and alters cell proliferation in the rat hippocampus
No full textVagus nerve stimulation (VNS) is effective in patients with treatment-resistant epilepsy. More recently, VNS has been ap- proved for treatment-resistant depression; nevertheless, the molec- ular mechanism(s) underlying its therapeutic action remains un- clear. In light of the proven anticonvulsant properties of VNS, its modulation of neurochemical systems implicated in major de- pression and impact on neuronal functional activity and plasticity, we tested the possibility that VNS could promote the synthesis of neurotrophic factors (BDNF, bFGF and NGF) that promote survival, maintenance and proliferation of neuronal cells, in the rat brain. Moreover, we investigate whether VNS could interfere with neurogenesis in the hippocampal dentate gyrus.
RNase protection assay revealed that acute VNS increases the abundance of BDNF and bFGF mRNAs in the hippocampus, and do not significantly alters the abundance of NGF mRNA. Immunohistochemical studies demonstrate that VNS alters cell proliferation and neurogenesis in dentate gyrus, as demonstrated by the double labeling with specific antibodies for the nuclear neuronal protein NeuN and BrdU.
Our results suggest that VNS could trigger neuronal plastic changes and demonstrate that such stimulation induced an increase in the gene expression of BDNF and bFGF in the rat hippocampus. These increases in growth factors were associated with a disrup- tion of cell proliferation and neurogenesis process in the granule cell layer of the dentate gyrus. These new findings contribute to elucidate the molecular mechanisms underlying the action of VNS, a new therapeutic tool for the treatment of epilepsy and depression.
References
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Marrosu, F., Santoni, F., Puligheddu, M., Barberini, L., Maleci, A., Ennas, F., Mascia, M., Zanetti, G., Tuveri, A., Biggio G., 2005. Increase in 20−50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation. Clin Neurophysiol 116, 2026−36. Marrosu, F., Serra, A., Maleci, A., Pulicheddu, M., Biggio, G., Piga., M., 2003. Correlation between GABAA receptor density and va- gus nerve stimulation in individuals with drug-resistant partial epilepsy. Epilepsy Res 55, 59−70.
Palma, E., Torchia, G., Limatola, C., Trettel, A., Arcella, A., Can- tore, G., Di Gennaro, G., Manfredi, M., Esposito, V., Quarato, P.P., Miledi, R., Eusebi, F., 2005. BDNF modulates GABAA receptors microtransplated from thehuman epileptic brain to Xenopus oocites. Proc Natl Acad Sci USA 102, 1667–1672
Vagus nerve stimulation increases neurotrophins gene expression and alters cell proliferation in the rat hippocampus
No full textVagus nerve stimulation (VNS) is effective in patients with treatment-resistant epilepsy. More recently, VNS has been approved for treatment-resistant depression; nevertheless, the molecular mechanism(s) underlying its therapeutic action remains unclear. The observation that VNS up-regulates cortical GABA receptor in partial epilepsy suggests that VNS can affect brain plasticity. Neuronal plasticity is the result of a number of molecular and neurochenical events, and it is commonly accepted that in the adultbrain synaptic rearrangements and neurogenesis can occur. Thus, physiologicalstinmli mediate synaptic activity that in turn can be regulated by both neurotransmitters and neurotrophic factors, suggesting that neurotrophins participate to morphological and functional changes associated to neuronal plasticity.
In light of the anticonvulsant properties of VNS, its modulation of neurochemical systems implicated in major depression and impact on neuronal functional activity and plasticity, we tested the possibility that VNS could promote the synthesis of brain derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF) and neuronal growth factor (NGF) that promote survival, maintenance e proliferation of neuronal cells. Moreover, we tested the possibility that VNS could interfere with neurogenesisin the dentate gyms of rat hippocampus.
Sprague-Dawley CD rats were implanted with a couple of electrodes aimed at the left vagus nerve, or were sham operated for control. The experiments started three days after surgery, and in treated animals, electrodes were connected to a battery that was activated at the "antiepileptic" parameters (2mA, 30 s on, 5rain off at 30 Hz delivery current, for 3 hours). For RNA extraction animals were sacrificed and the hippocampus was removed. RNA was extracted from whole hippocampus, and quantified by measurement of absorbance at 260 nm. An RNase protection assay was performed to measure the abundance of BDNF, bFGF, NGF and cyclophilin mRNAs. For inmlunohistochemistry and neurogenesis experiments, rats were injected with bromodeoxyuridine (BrdU) prior stimulation. Three hours after VNS animals were euthanized and tissues fixed by intracardiac perfusion with 4% paraformaldehyde, brains were then prepared for histology by using standard procedures.
The results of this study show that 3h VNS increases the abundance of BDNF and bFGF mRNAs in the hippocampus by 26 and 23% respectively, and do not significantly alters the abundance of NGF mRNA compared to control animals. Moreover, VNS decreased by 27% the number of BrdU positive cells in the hippocampal dentate gyms. Interestingly, in the granule cells layer of VNSrats several cell positive to BrdU resulted to be neurons as demonstrated by the double labeling with an antibody specific for the nuclear neuronal proteinNeuN.
Our results suggest that VNS could trigger neuronal plasticity and demonstrate that such stimulation induced an increase in the gene expression of BDNF and bFGF in the rat hippocampus. These increases in growth factors were associated with adismption of cell proliferation and neurogenesis process in the granule celllayer of the dentate gyms. These new findings contribute to elucidate the molecular mechanisms underlying the action of VNS, a new therapeutictool for the treatment of epilepsy and depression.
References
[1] Marrosu, E, Santoni, E, Puligheddu, M., Barberini, L., Maleci, A., Ennas, E, Mascia, M., Zanetti, G., Tuveri, A., and Biggio G., 2005. Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation. Clin Neurophysiol 116, 2026-36.
[2] Marrosu, E, Serra, A., Maleci, A., Pulicheddu, M., Biggio, G., and Piga, M., 2003. Correlation between GABAA receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy. Epilepsy Res 55, 59-70.
[3] Palma, E., Torchia, G., Limatola, C., Trettel, A., Arcella, A., Cantore, G., Di Gennaro, G., Man- fredi, M., Esposito, V., Quarato, RR, Miledi, R., and Eusebi, E, 2005. BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocites. Proc Natl Acad Sci USA 102,
1667-72
Stress and neuroactive steroids
No full textThe discover)' that the endogenous steroid derivatives 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, or 3α,5α-TH PROG) and 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahyclrodeoxycorticosterone, or 3α, 5α-TH DOC) elicit marked anxiolytic and anti-stress effects and selectively facilitate y-aminobutyric acid (GABA)-mediated neurotransmission in the central nervous system (see Chapter 3) has provided new perspectives for our understanding of the physiology and neurobiology of stress and anxiety. Evidence indicating that various stressful conditions that downregulate GABAergic transmission and induce anxiety-like states (Biggio et al., 1990) also induce marked increases in the plasma and brain concentrations of these neuroactive steroids (Biggio et al., 1996, 2000) has led to the view that stress, neurosteroids, and the function of GABAA receptors are intimately related. Changes in the brain concentrations of neurosteroids may play an important role in the modulation of emotional state as well as in the homeostatic mechanisms that counteract the neuronal overexcitation elicited by acute stress. Indeed, neurosteroids not only interact directly with GABAA receptors but also regulate the expression of genes that encode subunits of this receptor complex. This chapter summarizes observations from our laboratories and others, suggesting that neurosteroids and GABAergic transmission are important contributors to the changes in emotional state induced by environmental stress. ©2001 Academic Press
Massive vectors and loop observables: the g − 2 case
No full textWe discuss the use of massive vectors for the interpretation of some recent experimental anomalies, with special attention to the muon g−2. We restrict our discussion to the case where the massive vector is embedded into a spontaneously broken gauge symmetry, so that the predictions are not affected by the choice of an arbitrary energy cut-off. Extended gauge symmetries, however, typically impose strong constraints on the mass of the new vector boson and for the muon g − 2 they basically rule out, barring the case of abelian gauge extensions, the explanation of the discrepancy in terms of a single vector extension of the standard model. We finally comment on the use of massive vectors for B-meson decay and di-photon anomalies
Modulation of GABA(A) receptor gene expression by allopregnanolone and ethanol
No full textExpression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. This effect of steroids appears to be mediated through modulation of GABA(A) receptor signalling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signalling appear to differ among neurons in different regions of the brain. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained both in vivo and in vitro that show how fluctuations in the concentration of allopregnanolone regulate both the expression and function of GABA(A) receptors and consequently affect behaviour. Such regulation is operative both during physiological conditions such as pregnancy and lactation as well as in pharmacologically induced states such as pseudopregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Accordingly, long-lasting exposure of GABA(A) receptors to ethanol, as well as its withdrawal, induces marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and ethanol in modulating the functional activity of specific neuronal populations
“Gestione dell’Ansia nella Moderna Pratica Clinica” (Pfizer). Milano, 23-24 novembre 2009, co-relatori, Prof. A.C. Altamura, G. Perini, G. Maina, M. Biondi, P. Fornaro, G. Biggio, B. Dell’Osso, U. Albert.
No full textFocus su pregablin nel trattamento del GAD
Allopregnanolone modulation of HPA axis function in the adult rat
No full textRationale GABAergic neuronal circuits regulate neuroendo- crine stress response, and the most potent positive endogenous modulator of GABAA receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABAA receptors; in addition, it also induces long-lasting changes in the expres- sion of specific GABAA receptor subunits in various brain regions, with consequent changes in receptor function. Objective The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differ- ences in allopregnanolone levels can influence general resilience.
Results The results showed that there is an apparent correla- tion between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity. Conclusion The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders
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Genes for the GABA(A) receptor subunit types and their expression
No full textNo abstract available
Vagus nerve stimulation induces cell proliferation and changes in neuronal morphology in the rat hippocampus
No full textPurpose of study: Vagus nerve stimulation (VNS) is used to treat pharmacotherapy-resistant epilepsy. Observations of mood elevation during VNS therapy for epilepsy suggested that such treatment might also show efficacy for refractory major depression. The molecular mechanism(s) underlying its therapeutic action remains unclear, however. By using a rat model of VNS we previously showed that acute VNS increases the gene expression of growth factors in the rat brain as well as the release of norepinephrine. We have now examined the effects of chronic VNS on hippocampal cell proliferation as well as on the expression of DCX and BDNF in rat brain and whether such effects might be associated with behavioral changes similar to those induced by chronic antidepressant drugs.
Methods: Male Sprague-Dawley rats were used and a VNS therapy stimulator (Cyberonics, Houston, TX) was implanted. Cell proliferation in the hippocampus of rats subjected to acute (3h) or chronic (1 month) VNS was examined by injection of bromodeoxyuridine (BrdU) and immunohistochemistry. Expression of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) was evaluated by immunofluorescence staining. Behavioral effects were studied in the forced swim and elevated plus- maze tests.
Results: Acute VNS induced an increase in the number of BrdU+ cells in the dentate gyrus that was apparent 24 h (2200±159; P < 0.05) and 3 weeks (2448±129; P < 0.01) after treatment compared with that apparent in sham-operated controls (1760±74). It also induced long- lasting increases in the amount of DCX immunoreactivity (+39%; P < 0.05) and in the number of DCX+ neurons (+57%; P<0.01). Neither the number of BrdU+ cells nor the amount of DCX immunoreactivity was increased 3 weeks after the cessation of chronic VNS. Moreover, VNS induced long-lasting increases in the amount of BDNF immunoreactivity and the number of BDNF+ cells (+104% and +40% respectively; P < 0.001). VNS also affected the dendritic complexity of DCX+ neurons in the hippocampus. Nevertheless, in contrast to chronic imipramine, chronic VNS had no effect on the behavior ofratsintheforcedswimorelevatedplus-mazetests.
Conclusions: In the hippocampus VNS induced cell proliferation and persistent changes in morphology ofDCX+ neurons. These effects were accompanied by a robust increase in the expression of BDNF, which may play an important role in consolidating the changes in neuronal connections as suggested by the increased complexity of the dendritic arborization. Thus, some of the effects of chronic VNS appear to be similar to those induced by chronic treatment with antidepressant drugs but do not correlate with corresponding behavioral changes. Although further clinical and experimental studies are necessary to better understand the mechanisms of VNS, our results show that the promotion of neurogenesis and the expression of growth factors are rapidly induced by VNS differently from antidepressant. Whether such early newly generated neurons contribute to existing or de novo networks that might mediate antiepileptic or antidepressant effects remains to be determined
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