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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
S.07.04
[1]
[2]
[3]
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
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No full textNo abstract available
Three weeks of maternal separation induced a long lasting changes in the palsticity of hippocampal neurons of offspring and mothers
No full textNeural plasticity is the capability of neurons to changes the structure, function and organization of neurons in response to new experiences. It specifically refers to strengthening or weakening nerve connections or adding new nerve cells based on environmental stimuli. These processes are responsible for physiological changes, learning and the formation of appropriate responses to external events. Neural plasticity is among the most important aspects of the field of modern neuroscience and its study is leading to a better understanding of brain development.
In this study the expression levels of BDNF and Arc protein, the density of dendritic spines and the neurogenesis, were studied after a long-lasting stress, due to maternal separation
Neuroplasticity was evaluated in controls (mother and offspring not exposed to maternal separation) and after the stress induced by maternal separation (3h at day from the 3rd to the 21st day after birth). The mothers were sacrificed 21 days after the birth and pups in three different age groups: 21, 30 and 60 days. In the hippocampus of non-stressed we found an increase in the expression levels of the protein BDNF and Arc, in the dendritic spines density and in the neurogenesis, a phenomenon still present at weaning (21 days postpartum). In contrast, opposite effect (decrease) was observed on all the neurogenesis parameters in the mothers separated of their pups for 3 h per day for 20 days. Similarly to the mothers, also in hippocampus of the pups separated from their mothers was present a reduction of BDNF, Arc, dendritic spines density and neurogenesis in all three ages studied (21, 30 and 60). These results demonstrate that stress due to separation in the postnatal period results in adverse effects on neuronal plasticity in the hippocampus of both mothers and offspring
Social isolation, as well as treatment with the CB1 receptor antagonist SR 141716, markedly reduced the anticipatory and consummatory pleasure induced by food presentation
No full textThe mesocortical dopaminergic system is involved in the coping response to environmental stimuli. Accordingly, both stressful and pleasurable stimuli can induce an increase in the extracellular concentration of dopamine in the medial prefrontal cortex of rats. In our experiments we investigated the effect of anticipation and consumption of food on extracellular dopamine concentration in freely moving rats by vertical microdialysis. Rats were trained to consume their meal only two hours a day (from 11.00 A.M. to 1 P.M.). After four weeks of training, dopamine extracellular concentration was measured from 9 A.M. to 3 P.M., thus including the 2 hours before food presentation (anticipatory phase), the 2 hours during food consumption (consummatory phase), and the following 2 hours (satiety). In these rats dopamine extracellular concentration showed a marked increase (+180% over basal values) 80 min before food presentation, reached a maximum during food consumption (+350%), and returned to basal values when food was taken away. Social isolation has been widely used as an animal model of depression. In rats socially isolated at weaning for 6 weeks and trained to consume their meal in 2 hours for 4 weeks, the food restriction-induced increase in dopamine output was dramatically reduced, both in the anticipatory (+70%) and consummatory phase (+60%). This effect was almost indistinguishable from that induced by treatment with the anorectic drug SR 141716, a CB1 receptor antagonist. In fact, in rats treated with SR141716 (1mg/kg, i.p.) both acutely (60 min before food presentation) or chronically (twice a day for 21 days), the increase in dopamine output induced by food restriction was completely antagonized in the anticipatory phase and markedly reduced (+80%) in the consummatory phase.
Our data confirm the crucial role of mesocortical dopaminergic neurons in the regulation of emotion and suggest that the alterations in mood state induced both by social isolation and CB1 receptors blockade are able to blunt the response of cortical dopaminergic neurons to pleasurable stimuli
Processo per preparare imidazopiridino derivati e loro uso in particolare come ligandi per i recettori periferici alle benzodiazepine
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