47,723 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
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
Paradoxical reactions elicited by diazepam in children with classic autism.
No full textAdministration of diazepam (10 mg i.m.) to seven children (two girls and five boys) affected by infantile autism elicited paradoxical behavioural responses. Mainly, anxiogenic effect, unsocialized aggressive behaviour and explosive aggression were dramatically increased in comparison with the same symptoms present before and after treatment. The results show for the first time that benzodiazepines may elicit paradoxical behavioural response in autistic children. The possible involvement of an altered function at the level of GABA/benzodiazepine receptor complex is discussed
Protein Tyrosine phosphatase receptor type C (CD45) C77G mutation and susceptibility to multiple sclerosis, autoimmune and infectious diseases
No full textThe protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45 molecule, is a glycoprotein expressed on the cell surface of all hematopoietic cells except erythrocytes. Functionally, PTPRC is an immunomodulatory gene required for the efficient development of the immune system where it is involved in antigen receptor signal transduction. Several single nucleotide polymorphisms of the PTPRC gene have been described. In humans, the most extensively reported PTPRC polymorphism is the C77G point mutation in exon 4, and this nucleotide transversion causes abnormal PTPRC splicing, thus resulting in an altered expression pattern of isoforms with enhanced expression of high-molecular-weight isoforms (CD45RA, CD45RB, and CD45RC) and decreased low-molecular-weight CD45RO molecules. This altered expression pattern of isoforms can have significant effects on immune function, autoimmunity, and viral infections. Previous epidemiological studies have investigated the relationship between the C77G variant and several diseases. An association between this polymorphism and susceptibility to multiple sclerosis (MS) has been reported in some research papers, thereby suggesting a possible etiologic role of PTPRC in the development of this disease. Subsequent studies performed in other populations, including family-based and case-control studies, could not replicate this relationship between MS and the C77G point mutation, thus suggesting that more statistically powered studies are needed to confirm such an association or not. Furthermore, C77G polymorphism has been suggested to contribute to the development of some infective or autoimmune disorders. As individuals with C77G polymorphism may have increased susceptibility to HIV-1 infection, the frequency of this variant has been investigated in hepatitis C, histiocytosis, and autoimmune diseases, with contrasting results. Although PTPRC represents one of the modifier genes of human autoimmunity, further studies are needed to explain the exact role of PTPRC gene C77G variant in the contribution to the alteration of immune responses in infectious and autoimmune diseases
Therapeutic interventions and adjustments in the management of parkinson disease: Role of combined carbidopa/levodopa/entacapone (stalevo®)
No full textParkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3-0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa-induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing “on” time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/levodopa/entacapone (Stalevo®) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDE-PD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results
Dopamine dysregulation syndrome in Parkinson's disease patients on duodenal levodopa infusion
No full textDopaminergic-induced paraphilias associated with impulse control and related disorders in patients with Parkinson disease
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Allopurinol add-on treatment in intractable seizures.
No full textRecent reports in clinical literature have suggested an antiepileptic effect of the xanthine oxidase inhibitor Allopurinol (ALL) when added to traditional drugs. However, other reports have failed to confirm beneficial effects of this drug. In view of these conflicting results, we have carried out a study aimed at evaluate the effects of ALL in different forms of epilepsy. The result that ALL possesses some antiepileptic effects in Lennox-Gastaut syndromes, characterized by numerous and severe fits, while it is scarcely effective in other forms of epilepsy, suggests that ALL might be involved in the purinergic-mediated inhibition similar to that described in experimental "status epilepticus" studies in animal models
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