Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory and excitatory transmission in epilepsy. Transduction of neuropeptide genes such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. In particular, the long-lasting NPY over-expression obtained in the rat hippocampus using intracerebral application of recombinant adeno-associated viral (AAV) vectors reduced the generalization of seizures from their site of onset, delayed acquisition of fully kindled seizures and afforded neuroprotection. These results establish a proof-of-principle for the applicability of AAV-NPY vectors for the inhibition of seizures in epilepsy. Additional investigations are required to demonstrate a therapeutic role of gene therapy in chronic models of seizures and to address in more detail safety concerns and possible side-effects.
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PMID:Gene therapy in epilepsy: the focus on NPY. 1719 1

Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABA(A) (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABA(A) receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.
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PMID:Advances in the pathophysiology of status epilepticus. 1736 70

Our present view that the mood disorders involve dysfunction of monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. The therapeutic efficacy of drugs such as the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and lately of SNRIs (serotonin and norepinephrine reuptake inhibitors) helped to shape our view that mood regulation involves the monoaminergic systems in some way. It is thus little surprising when the neuropeptide, galanin, is discovered to coexist with norepinephrine (NE) in locus coeruleus (LC) neurons and with serotonin (5-HT) in the dorsal raphe nucleus (DRN) neurons, a link between galanin mediated signaling and mood regulation is sought. Galanin receptors are expressed in brain structures that are involved in the regulation of mood such as frontal cortex, amygdala, hypothalamus, LC, DRN and hippocampus. It is almost an accident of research fate that the potent effects of galanin on cognitive performance and seizure threshold have led galanin research to focus on the hippocampus where the neuropeptide is present in cholinergic and noradrenergic afferents and where the receptor density is much lower than in the monoaminergic nuclei. Hopefully it is not too late to report on the recent inroads into the roles of galanin and of galanin receptor subtypes 2 and 3 (GalR2 and GalR3) in mood regulation in animal models as well as in human patients with major depression. A body of existing data suggests that GalR2 signaling leads to antidepressant-like, anticonvulsant and neurogenesis-promoting effects, a spectrum of activities that are commonly associated with efficacious antidepressants. Similarly, GalR3 antagonists exhibit anxiolytic and antidepressant-like activity, another clinically useful combination for the treatment of mood disorders. Since both GalR2 and GalR3 are G-protein coupled receptors (GPCRs), a favorite target class for drug development, we believe that the pace of developing galaninergic antidepressants will increase significantly from now on.
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PMID:The brain galanin receptors: targets for novel antidepressant drugs. 1751 15

Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABAA (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABAA receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.
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PMID:Advances in the pathophysiology of status epilepticus. 1778 31

Gene therapy-based overexpression of endogenous seizure-suppressing molecules represents a promising treatment strategy for epilepsy. Viral vector-based overexpression of the neuropeptide galanin has been shown to effectively suppress generalized seizures in various animal models of epilepsy. However, it has not been explored whether such treatment can also prevent the epileptogenesis. Using a recombinant adeno-associated viral (rAAV) vector, we induced hippocampal galanin overexpression under the neuron specific enolase promoter in rats. Here we report that in animals with galanin overexpression, the duration of electrographic afterdischarges was shortened and initiation of convulsions was delayed at generalized seizure stages. However, the hippocampal kindling development was unchanged. Short-term plasticity of mossy fiber-cornu ammonis (CA) 3 synapses was unaltered, as assessed by paired-pulse and frequency facilitation of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices, suggesting that despite high transgene galanin expression, overall release probability of glutamate in these synapses was unaffected. These data indicate that hippocampal rAAV-based galanin overexpression is capable of mediating anticonvulsant effects by lowering the seizure susceptibility once generalized seizures are induced, but does not seem to affect kindling development or presynaptic short-term plasticity in mossy fibers.
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PMID:Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity. 1798 2

Low-frequency stimulation (LFS) has antiepileptogenic effects on kindled seizures. In the present study, the role of galanin receptors in the inhibitory effect of LFS on perforant path kindling acquisition was investigated in rats. Animals were kindled by perforant path stimulation in a rapid kindling manner (six stimulations per day). LFS (0.1 ms pulses at 1 Hz, 600 pulses, and 80-150 microA) was applied immediately after termination of each kindling stimulation. M35 (0.5 and 1.0 nM per site), a nonselective galanin receptor antagonist and M871 (1.0 microM per site), a selective galanin receptor type 2 (GalR2) antagonist, were daily microinjected into the dentate gyrus before starting the stimulation protocol. The expression of GalR2 in the dentate gyrus was also investigated using semi-quantitative RT-PCR. Application of LFS significantly retarded the kindling acquisition and delayed the expression of different kindled seizure stages. In addition, LFS significantly reduced the increment of daily afterdischarge duration during kindling development. Intra-dentate gyrus microinjection of both M35 and M871 significantly prevented the inhibitory effects of LFS on kindling parameters. During the focal kindled seizure stages (1-3) M871 had no significant effect. However, during generalized seizure stages (4 and 5), M871 had the same effect as M35. Semi-quantitative RT-PCR also showed that after kindling acquisition, the GalR2 mRNA level decreased in the dentate gyrus but application of LFS prevented this decrease. Obtained results show that activation of galanin receptors by endogenous galanin has a role in mediating the inhibitory effect of LFS on perforant path-kindled seizures. This role is exerted through GalR1 during focal- and through GalR2 during generalized-kindled seizures.
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PMID:The role of galanin receptors in anticonvulsant effects of low-frequency stimulation in perforant path-kindled rats. 1799 48

The neuropeptide galanin comes under the powerful and versatile modulators of classical neurotransmitters and is present in brain tissues, which are intimately involved in epileptogenesis. It acts as appealing targets for studying basic mechanisms of seizure initiation and arrest, and for the development of novel approaches for various neurodegenerative diseases. Galanin is widely distributed in the mammalian brain which controls various processes such as sensation of pain, learning, feeding, sexual behaviour, carcinogenesis, pathophysiology of neuroendocrine tumors and others. The function of galanin can be exploited through its interaction with three G-protein coupled receptors subtypes such as GalR1, GalR2 and GalR3. The N-terminal region of galanin comprises about highly conserved 15 amino acid residues, which act as the crucial region for agonist-receptor binding. We have constructed a theoretical structural model for the N-terminal region of galanin from Homo sapiens by homology modeling. The stereochemistry of the model was checked using PROCHECK. The functionally conserved regions were identified by surface mapping of phylogenetic information generated by online web algorithm ConSurf. The docking studies on the pharmacologically important galanin receptors with the theoretical model of N-terminal region of galanin predicted crucial residues for binding which would be useful in the development of novel leads for neurodegenerative disorders.
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PMID:Three dimensional modeling of N-terminal region of galanin and its interaction with the galanin receptor. 1828 36

Neuroanatomical localization and physiological properties of galanin suggest that the peptide may be involved in the regulation of seizures. Indeed, administration of galanin receptor agonists into brain areas pertinent to the initiation and propagation of epileptic activity attenuated seizure responses under conditions of animal models of epilepsy; pharmacological blocking of galanin receptors exerted proconvulsant effects. Functional deletion of both galanin and galanin type 1 receptor genes produced transgenic mice with either spontaneous seizure phenotype, or with enhanced susceptibility to seizure stimuli. At the same time, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection techniques, hindered the epileptic process. Galanin exerts anticonvulsant effects through both type 1 and type 2 receptors, with distinct downstream signaling cascades. Several synthetic agonists of galanin receptors with optimized bioavailability have been synthesized and inhibited experimental seizures upon systemic administration, thus opening an opportunity for the development of galanin-based antiepileptic drugs.
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PMID:Galanin and epilepsy. 1850 Jun 39

Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In the present review, we summarize the current data which constitute the basis of targeting GalR1, GalR2 and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors.
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PMID:Galanin, galanin receptors and drug targets. 1850 Jun 47

Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile. Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies.
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PMID:Gene therapy in epilepsy. 1871 7


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