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)

Galanin is an endogenous neuropeptide that modulates seizures in the brain. Because this neuropeptide does not penetrate the blood-brain barrier, we designed truncated galanin analogues in which nonessential amino acid residues were replaced by cationic and/or lipoamino acid residues. The analogues prevented seizures in the 6 Hz mouse model of epilepsy following intraperitoneal administration. The most active analogue, Gal-B2 (NAX 5055), contained the -Lys-Lys-Lys(palmitoyl)-Lys-NH(2) motif and exhibited high affinity for galanin receptors (K(i) = 3.5 nM and 51.5 nM for GalR1 and GalR2, respectively), logD = 1.24, minimal helical conformation and improved metabolic stability. Structure-activity-relationship analysis suggested that cationization combined with position-specific lipidization was critical for improving the systemic activity of the analogues. Because the anticonvulsant activity of galanin is mediated by the receptors located in hippocampus and other limbic brain structures, our data suggest that these analogues penetrate into the brain. Gal-B2 may lead to development of first-in-class antiepileptic drugs.
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PMID:Design, synthesis, and characterization of high-affinity, systemically-active galanin analogues with potent anticonvulsant activities. 1905 61

G-protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors and are the major drug targets for the treatment of various human diseases. The lack of sensitive and selective antibodies capable of recognizing endogenous GPCRs, however, hampers the progress of research on this class of receptors. GalR1 through GalR3, GPCRs for the neuropeptide galanin, are potential drug targets for seizure, Alzheimer's disease, depression and anxiety, as well as pain and metabolic syndrome; therefore, determining the cellular and subcellular localization of galanin receptors is of high interest. Several Antibodies raised against galanin receptors are currently available from commercial or academic sources. We have tested several antibodies to GalR1 and GalR2 on tissues from respective knockout mice. Unexpectedly, the immunoreactivity patterns are the same in wild-type and in knockout mice, suggesting that current GalR1 and GalR2 antibodies, under standard immunodetection conditions, might not be suitable for mapping the receptors. These findings argue for taking precaution when using antibodies to galanin receptors.
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PMID:Analyzing the validity of GalR1 and GalR2 antibodies using knockout mice. 1915 18

Studies in both humans and rodents suggest that exercise can be neuroprotective, but the mechanisms by which this occurs are still poorly understood. Three weeks of voluntary, physical activity in rats upregulates prepro-galanin messenger RNA levels in the locus coeruleus. Galanin is a neuropeptide extensively coexisting with norepinephrine that decreases neuronal hyperexcitability both in vivo and in vitro. Thus, exercise may diminish neural hyperexcitability through a galaninergic mechanism. The current experiments tested whether voluntary activity wheel running would protect against kainic acid-evoked seizures and whether galaninergic signaling is a necessary factor in this protection. In experiment 1, rats were given access to running wheels or remained sedentary for three weeks. After this period, rats received an intraperitoneal (i.p.) injection of 0, 7, 10 or 14 mg/kg kainic acid. Exercise decreased the severity of or eliminated seizure behaviors and hippocampal c-fos expression induced by kainic acid. In experiment 2, exercising or sedentary rats were injected intracerebroventricularly (i.c.v.) with 0.2 or 0.4 microg of kainic acid following either an injection of M-40 (a galanin receptor antagonist) or saline. Exercise decreased kainic acid-induced seizures at the 0.2 microg dose, and M-40 (6 nmol) decreased this effect. In contrast, there were no detectable differences between exercising and sedentary rats in behavior at the 0.4 microg dose. The results suggest that the protective effects of exercise against seizures are at least partially mediated by regulation of neural excitability through a process involving galanin.
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PMID:Chronic activity wheel running reduces the severity of kainic acid-induced seizures in the rat: possible role of galanin. 1924 73

Gene therapy may represent a promising alternative treatment of epileptic patients who are resistant to conventional anti-epileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant adeno-associated viral (AAV) vectors have been most widely used. Preclinical studies using a selection of "therapeutic" genes injected into the rodent brain to correct the compromised balance between inhibitory and excitatory transmission in epilepsy, showed significant reduction of seizures and inhibition of epileptogenesis. In particular, 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. Recent findings showed a long-lasting NPY over-expression in the rat hippocampus by local application of recombinant AAV vectors associated with reduced generalization of seizures, delayed kindling epileptogenesis, and strong reduction of chronic spontaneous seizures. These results establish a proof-of-principle evidence of the efficacy of gene therapy as anticonvulsant treatment. Additional investigations are required to address safety concerns and possible side effects in more detail.
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PMID:Neuropeptide Y overexpression using recombinant adeno-associated viral vectors. 1933 23

Theoretically, gene therapy techniques offer an attractive alternative treatment option for intractable, focal epilepsies. Although logical gene therapy targets include excitatory and inhibitory receptors, variable viral vector tropism interjects an uncertainty as to the direction of change, seizure suppression, or seizure sensitization. To circumvent this therapeutic liability, adeno-associated virus (AAV) vectors have been constructed where the gene product is constitutively secreted from the transduced cell. Using AAV vectors, the fibronectin secretory signal sequence (FIB) was placed in front of the coding sequence for green fluorescent protein or the active portion of the neuroactive peptide galanin (GAL). Subsequent studies showed that these vectors supported expression and constitutive secretion of these gene products from transfected cells in vitro. More importantly, upon transduction in vivo, AAV-FIB-GAL vectors significantly attenuated focal seizure sensitivity, and this seizure attenuation could be controlled in vivo by using a tetracycline-regulated promoter. The expression and constitutive secretion of green fluorescent protein, or the expression of GAL alone, exerted no effect on focal seizure sensitivity. Moreover, unilateral infusion of the AAV-FIB-GAL vectors into the hippocampus prevented kainic acid-induced hilar cell death. With regard to limbic seizures, bilateral infusion of AAV-FIB-GAL vectors into the piriform cortex prevented both behavioral and localized electrographic seizure activity after the peripheral administration of kainic acid. Also, when rats were electrically kindled to class V seizure activity, subsequent infusion of AAV-FIB-GAL proved capable of significantly elevating the seizure initiation threshold. Thus, these studies clearly demonstrate the anti-seizure effectiveness of AAV vector-mediated expression and constitutive secretion of galanin.
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PMID:Adeno-associated virus vector-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity. 1933 24

The endogenous neuropeptide galanin and its associated receptors galanin receptor 1 and galanin receptor 2 are highly localized in brain limbic structures and play an important role in the control of seizures in animal epilepsy models. As such, galanin receptors provide an attractive target for the development of novel anticonvulsant drugs. Our efforts to engineer galanin analogs that can penetrate the blood-brain-barrier and suppress seizures, yielded NAX 5055 (Gal-B2), a systemically-active analog that maintains low nanomolar affinity for galanin receptors and displays a potent anticonvulsant activity. In this report, we show that NAX 5055 is active in three models of epilepsy: 1) the Frings audiogenic seizure-susceptible mouse, 2) the mouse corneal kindling model of partial epilepsy, and 3) the 6 Hz model of pharmacoresistant epilepsy. NAX 5055 was not active in the traditional maximal electroshock and subcutaneous pentylenetetrazol seizure models. Unlike most antiepileptic drugs, NAX 5055 showed high potency in the 6 Hz model of epilepsy across all three different stimulation currents; i.e., 22, 32 and 44 mA, suggesting a potential use in the treatment of pharmacoresistant epilepsy. Furthermore, NAX 5055 was found to be biologically active after intravenous, intraperitoneal, and subcutaneous administration, and efficacy was associated with a linear pharmacokinetic profile. The results of the present investigation suggest that NAX 5055 is a first-in-class neurotherapeutic for the treatment of epilepsy in patients refractory to currently approved antiepileptic drugs.
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PMID:Developing novel antiepileptic drugs: characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models. 1933 33

For certain gene therapy applications, the simultaneous delivery of multiple genes would allow for novel therapies. In the case of adeno-associated virus (AAV) vectors, the limited packaging capacity greatly restricts current methods of carrying multiple transgene cassettes. To address this issue, a recombinant AAV (rAAV) vector was designed such that a furin proteolytic cleavage site (RKRRKR) was placed between the coding sequences of two genes (green fluorescent protein (GFP) and galanin), to allow cleavage of the chimeric protein into two fragments. In addition, these constructs contained the fibronectin secretory signal sequence that causes the gene products to be constitutively secreted from transduced cells. In vitro studies show that after transfection of HEK293 cells, the appropriate cleavage and constitutive secretion occurred regardless of the order of the genes in the transgene cassette. In vivo, infusion of rAAV vectors into the piriform cortex resulted in both GFP expression and significant galanin attenuation of kainic acid-induced seizure activity. Thus, the present results establish the utility of a proteolytic approach for the expression and secretion of multiple gene products from a single AAV vector transgene cassette.
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PMID:Delivering multiple gene products in the brain from a single adeno-associated virus vector. 1972 40

Galanin modulates seizures in the brain through two galanin receptor subtypes, GalR1 and GalR2. To generate systemically active galanin receptor ligands that discriminate between GalR1 and GalR2, the GalR1-preferring analogue Gal-B2 (or NAX 5055) was rationally redesigned to yield GalR2-preferring analogues. Systematic truncations of the N-terminal backbone led to [N-Me,des-Sar]Gal-B2, containing N-methyltryptophan. This analogue exhibited 18-fold preference in binding toward GalR2, maintained agonist activity, and exhibited potent anticonvulsant activity in mice following intraperitoneal administration.
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PMID:Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery. 2012 Nov 16

Galanin is a neuropeptide that regulates the food intake, neurogenesis, memory, and gut secretion. This study was conducted to evaluate the high-fat diet (HFD)-induced regulation of the galanin receptors (GalRs) and the associated signaling molecules in the adipose tissues of mice. Twenty C57BL/6J mice were given either an HFD or a normal diet for 12 wk. The results of the semiquantitative RT-PCR analyses indicated that the HFD upregulated the expression of GalR1, GalR2, GalR3, resistance to audiogenic seizures, peroxisome proliferator-activated receptorgamma2, adipocyte protein 2, and protein kinase Cdelta and downregulated the expression of peroxisome proliferative activated receptor gamma coactivator 1alpha and uncoupling protein 1 in the adipose tissues. The immunoblot results showed that the protein levels of peroxisome proliferator-activated receptorgamma2 and adipocyte protein 2, and the phosphorylation of c-Raf and extracellular signal-regulated kinase 1/2 were increased, while the phosphorylation of cyclic adenosine monophosphate-responsive element-binding protein, which regulates peroxisome proliferative activated receptor gamma coactivator 1alpha and uncoupling protein 1, was decreased in the epididymal adipose tissues of the HFD-fed mice. These results suggest the possible association of the galanin-mediated signaling pathways in the manifestation of the HFD-induced activation of adipogenesis along with the suppression of thermogenesis in the adipose tissues of mice.
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PMID:Diet-induced obesity regulates the galanin-mediated signaling cascade in the adipose tissue of mice. 2018 29

Adeno-associated virus (AAV) vectors support long-term, nontoxic gene expression in the central nervous system, and these AAV properties prove particularly applicable to the treatment of focal epilepsies, especially intractable temporal lobe epilepsy. A number of clinical studies have employed AAV vectors and to date, no known adverse effects have been directly associated with these treatments, particularly AAV serotype 2 (AAV2). Although other AAV serotypes may confer an advantage in the future, extensive studies on the inhibitory neuropeptides, galanin and neuropeptide Y, have generated enough preclinical evidence of efficacy to warrant AAV2-based clinical trials in the near future. Beyond these trials, emerging evidence suggests that AAV-mediated manipulation of adenosine can significantly impact limbic seizure activity. Thus, with appropriate nonhuman primate transduction patterns and favorable overall toxicology studies, AAV-based manipulation of adenosine could follow the AAV-neuropeptide clinical studies. Finally, recent findings using AAV capsid shuffling and directed evolution have identified a hybrid AAV vector that can selectively cross the seizure compromised blood-brain barrier and transduce cells after peripheral, intravenous administration. Thus, in the more distant future, AAV therapeutics for focal epilepsies may be delivered without any neurosurgical interventions.
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PMID:The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy. 2060 51


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