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)

The neuropeptide galanin exhibits anticonvulsant effects in experimental epilepsy. Two galanin receptor subtypes, GalR1 and GalR2, are present in the brain. We examined the role of GalR1 in seizures by studying the susceptibility of GalR1 knockout (KO) mice to status epilepticus (SE) and accompanying neuronal injury. SE was induced in GalR1 KO and wild type (WT) mice by Li-pilocarpine, 60 min electrical perforant path stimulation (PPS), or systemic kainic acid (KA). Seizures were analyzed using Harmonie software. Cell injury was examined by FluoroJade B- and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling; neurogenesis was studied using bromodeoxyuridine labeling. Compared with WT littermates, GalR1 KO showed more severe seizures, more profound injury to the CA1 pyramidal cell layer, as well as injury to hilar interneurons and dentate granule cells upon Li-pilocarpine administration. PPS led to more severe seizures in KO, as compared with WT mice. No difference in the extent of neuronal degeneration was observed between the mice of two genotypes in CA1 pyramidal cell layer; however, in contrast to WT, GalR1 KO developed mild injury to hilar interneurons on the side of PPS. KA-induced seizures did not differ between GalR1 KO and WT animals, and led to no injury to the hippocampus in either of experimental group. No differences were found between KO and WT mice in both basal and seizure-induced neuronal progenitor proliferation in all seizure types. Li-pilocarpine led to more extensive glia proliferation in GalR1 KO than in WT, and in both mouse types in two other SE models. In conclusion, GalR1 mediate galanin protection from seizures and seizure-induced hippocampal injury in Li-pilocarpine and PPS models of limbic SE, but not under conditions of KA-induced seizures. The results justify the development and use of GalR1 agonists in the treatment of certain forms of epilepsy.
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PMID:Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice. 1535 Jun 53

Epilepsy afflicts approximately 1% of the population and, although the majority of patients gain effective seizure control through existing medications, a significant number prove refractory to treatment. For intractable focal epilepsies, gene therapy techniques provide a realistic treatment alternative, especially in patients who are considered surgical candidates. Neurotransmitter receptors and ion channels offer attractive gene therapy targets, but the pattern of viral vector transduction and gene expression can dramatically influence the final outcome. Recently, studies have shown that viral vector-mediated transduction and expression of neuroactive peptides, such as galanin and neuropeptide Y, can attenuate seizure sensitivity and prevent seizure-induced cell death in vivo. As future studies define the best means to avoid immunological silencing, as well as establish transduction properties in pathological, epileptic tissue, it should be possible to develop an efficacious gene therapy for intractable focal epilepsy.
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PMID:The clinical potential of antiepileptic gene therapy. 1550 Apr 5

The shift in the balance between the inhibition and the excitation in favor of the latter is a major mechanism of the evolvement of epileptic seizures. On the neurotransmitter level two major players contribute to such misbalance: an inhibitory transmitter gamma-aminobutyric acid, and an excitatory amino acid glutamate. Neuropeptides are powerful modulators of classical neurotransmitters, and thus represent an intriguing tool for restoring the balance between the inhibition and the excitation, through either blocking or activating peptide receptors depending on whether a peptide is pro- or anticonvulsant. Galanin, a 29-amino acid residues neuropeptide which inhibits glutamate release in the hippocampus, is a likely member of the anticonvulsant peptide family. During the past decade growing evidence has been suggesting that galanin is in fact a powerful inhibitor of seizure activity. This review summarizes the state of research of galanin in epilepsy, beginning with the first simple experiments which showed that central injection of galanin agonists inhibited seizures, and that seizures themselves affected galanin signaling in the hippocampus; exploring the impact of active manipulation with the expression of galanin and galanin receptors on seizures, using transgenic animals, antisense and peptide-expressing vector approaches; and concluding with the recent advances in pharmacology, which led to the synthesis of non-peptide galanin receptor agonists with anticonvulsant properties. We also address recently established functions of galanin in seizure-associated neuronal degeneration and neuronal plasticity.
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PMID:Galanin and galanin receptors in epilepsy. 1556 69

Elucidation of the biochemical basis of neuronal degeneration following seizures, ischemia or hypoglycemia appears to be one of the most urgent problems of contemporary science. Close attention has been devoted to endogenous anticonvulsant and/or neuroprotective agents which help to maintain a neuronal homeostasis under pathological conditions. The list of putative neuroprotectants is very long and includes substances with diverse chemical structures, such as, e.g., adenosine, amino acids (kinurenic acid, taurine), neuropeptides (opioid peptides, thyreoliberine, neuropeptide Y, galanin, VIP/PACAP) and some neurosteroids (allopregnanolone, dehydroepiandrosterone). In recent years great progress has been made in the studies into not only their biosynthesis, metabolism and regulation of release in the nervous tissue, but also molecular and functional characteristics of their receptors. Apart from fast ionic effects leading to repolarization of the neuronal membrane, these endogenous neuroprotective agents may exert long-term effects on intracellular second messengers and genomic mechanisms which are crucially involved in the regulation of excitotoxic and apoptotic cascades. It is still an open question whether in the foreseeable future the presented direction of research will allow us to regulate endogenous anticonvulsant and neuroprotective mechanisms in a subtle way in order to substitute for or support other forms of treatment.
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PMID:[Endogenous anticonvulsant and neuroprotective agents]. 1572 28

Unlike adults, kainic acid (KA)-induced status epilepticus (SE) in immature rats causes neither cell death nor recurrent spontaneous seizures. To elucidate the mechanisms of these distinct responses, transcriptional changes in neuropeptides were examined following KA-induced SE. We aimed to determine whether neuropeptides with anticonvulsant/neuroprotective properties were preferentially increased in immature rats while those with a proconvulsant/neurotoxic role were elevated to a greater extent in mature rats. We used high-density oligonucleotide gene arrays and directly compared transcriptional regulation of seven select neuropeptides at P15 and P30 over five time points. Total RNAs were isolated from hippocampi of 12 animals and pooled to hybridize to triplicate Affymetrix Genechips. Microarray results were validated by real-time quantitative RT-PCR (qRT-PCR). Independent individual RNA samples were purified for triplicate runs of qRT-PCR. Neuropeptides are significantly regulated by seizures in both immature and mature hippocampus. The magnitude of increase is significantly higher at P30 compared with that at P15, not only for neuropeptides with neurotoxic/proconvulsant properties but also for those with neuroprotective/ anticonvulsant properties. Galanin is induced at 24 h only in P30 rats. CST shows high expression in immature hippocampus and is further increased after KA-induced SE only in P15. The expression trends seen in the microarray data are confirmed by qRT-PCR for all six neuropeptides analyzed. CST might play a neuroprotective role in immature rats, and its overexpression might prevent neuronal loss after seizure in adults. Also, suppression of tachykinin and corticotropin-releasing hormone might be effective in alleviating seizure-induced neuronal damage.
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PMID:Microarray analysis of postictal transcriptional regulation of neuropeptides. 1580 Mar 81

Major aspects of temporal lobe epilepsy (TLE) can be reproduced in mice following a unilateral injection of kainic acid into the dorsal hippocampus. This treatment induces a non-convulsive status epilepticus and acute lesion of CA1, CA3c and hilar neurons, followed by a latent phase with ongoing ipsilateral neuronal degeneration. Spontaneous focal seizures mark the onset of the chronic phase. In striking contrast, the ventral hippocampus and the contralateral side remain structurally unaffected and seizure-free. In this study, functional and neurochemical alterations of the contralateral side were studied to find candidate mechanisms underlying the lack of a mirror focus in this model of TLE. A quantitative analysis of simultaneous, bilateral EEG recordings revealed a significant decrease of theta oscillations ipsilaterally during the latent phase and bilaterally during the chronic phase. Furthermore, the synchronization of bilateral activity, which is very high in control, was strongly reduced already during the latent phase and the decrease was independent of recurrent seizures. Immunohistochemical analysis performed in the contralateral hippocampus of kainate-treated mice revealed reduced calbindin-labeling of CA1 pyramidal cells; down-regulation of CCK-8 and up-regulation of NPY-labeling in mossy fibers; and a redistribution of galanin immunoreactivity. These changes collectively might limit neuronal excitability in CA1 and dentate gyrus, as well as glutamate release from mossy fiber terminals. Although these functional and neurochemical alterations might not be causally related, they likely reflect long-ranging network alterations underlying the independent evolution of the two hippocampal formations during the development of an epileptic focus in this model of TLE.
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PMID:Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. 1589 45

Galanin is a neuropeptide implicated in the regulation of feeding, reproduction, cognition, nociception, and seizure susceptibility. There are three known galanin receptor (GALR) subtypes (GALR1, GALR2, and GALR3), which bind to galanin with different affinities and have their own unique distributions, signaling mechanisms, and putative functions in the brain and peripheral nervous system. To gain further insight into the possible physiological significance of GALR2, we created mutant mice that were deficient in GALR2 and compared their phenotype to that of wild-type (WT) littermate or age-matched controls, with respect to basic motor and sensory function, feeding behavior, reproduction, mood, learning and memory, and seizure susceptibility. Phenotypic analysis revealed that animals bearing a deletion of GALR2 did not differ significantly from their WT controls in any of the measured variables. We conclude that either GALR2 plays no role in these physiological functions or through redundancy or compensation these mutant animals can adapt to the congenital absence of GALR2. It is also conceivable that GALR2 plays only a subtle role in some of these functions and that the impact of its loss could not be detected by the analytical procedures used here.
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PMID:Phenotypic analysis of mice deficient in the type 2 galanin receptor (GALR2). 1589 80

Galanin, acting at the GalR1-3 subtypes of galanin receptors, is involved in the regulation of cognition, mood, feeding, seizure activity and pain. The understanding of galanin's effects in molecular and cellular terms has been hampered by the lack of receptor subtype selective ligands and antibodies. Previous in situ hybridization data showed that GalR1 and GalR2 receptors are abundant in the rat brain, while the distribution of GalR3 is contradictory and most studies demonstrated a low expression levels in the rat brain. The distribution of galanin receptor subtypes at protein level is unknown. In the present study, we report the regional distribution of the galanin receptors: GalR1 and non-GalR1 receptors, using a recently synthesized high affinity GalR2/3 selective ligand, galanin (2-11), and galanin (1-29), as competitors, in saturating (125)I-galanin membrane binding assay. We show that paraventricular nucleus (PVN) express predominantly GalR1, whereas areas like the dorsal raphe nucleus (DRN), hippocampus and amygdala express both the GalR1 and non-GalR1 receptors. We speculate that the GalR2/3 binding sites detected by galanin (2-11) binding in our study probably represent mostly GalR2 receptors. In addition, we show regionally specific and subtype specific regulation of galanin receptors. Status epilepticus (SE), known to deplete galanin from axonal projections of locus coeruleus and septum/diagonal band neurons in the hippocampus and to induce galanin expression in a subset of hippocampal cells, down regulates GalR2 receptor mRNA and proteins by 30% without altering the GalR1 receptors.
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PMID:Distribution and differential regulation of galanin receptor subtypes in rat brain: effects of seizure activity. 1594 3

Galnon is a low-molecular weight galanin receptor ligand, with affinity towards the three galanin receptors in the micromolar range. Galnon is of interest as a drug candidate due to its stability and ability to pass the blood-brain barrier. Like galanin, galnon has also been shown to affect various physiological functions; however, occasionally galanin and galnon act in opposing ways. Since its introduction in 2002, galnon has been characterized to inhibit seizures, decrease feeding behaviour, diminish physical signs of opiate withdrawal and to alleviate heat-hyperalgesic response to partial sciatic nerve injury. In this review, we will summarize what is known about galnon to date.
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PMID:Galnon--a low-molecular weight ligand of the galanin receptors. 1594 6

The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction in the hippocampal formation. Galnon is a non-peptide, systemically active galanin receptor agonist which has been tested in feeding, seizure and forced swim task in in vivo rodent experimental models. Similarly to galanin (1-29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects in rats. We have investigated the effect of galnon on the synaptic transmission and plasticity in hippocampal dentate gyrus (DG) of C57Bl/6 mice and compared the galnon effects to the effect of galanin (1-29) and galmic, a non-peptide galanin receptor agonist. Similarly to galanin (1-29) and galmic, superfusion of galnon did not alter the input-output responses in DG. Administration of galnon (1 microM) significantly attenuated the LTP induction by 85.5 +/- 1% by 51 min after high frequency trains stimulation. This result was very similar to the effect of galanin (1-29) and galmic, which caused an 80 +/- 1.5% and 94 +/- 2% reduction in the level of field potentiation, respectively. The PPF responses, however, were not altered due to galnon superfusion which is in contrast to the effect of galanin (1-29) or galmic. In summary, these data indicate that the systemically active, non-peptide galanin receptor agonist, galnon can exert similar effects to galanin (1-29) in attenuation of DG LTP in mice.
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PMID:Effect of galnon on induction of long-term potentiation in dentate gyrus of C57BL/6 mice. 1594 18


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