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Protective but not anticonvulsant effects of ghrelin and JMV-1843 in the pilocarpine model of Status epilepticus.

Lucchi C, Curia G, Vinet J, Gualtieri F, Bresciani E, Locatelli V, Torsello A, Biagini G - PLoS ONE (2013)

Bottom Line: In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression.In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats.These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

ABSTRACT
In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.

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Photomicrographs illustrating neuronal cell loss in the medial entorhinal cortex layer III after status epilepticus (SE), in pilocarpine-treated rats.Neurons were identified by the anti-neuron-specific nuclear protein (NeuN) antibody, as shown in the control staining (A). NeuN-immunopositive cells were markedly decreased in pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE (B). Similar findings were found in rats treated with ghrelin before receiving pilocarpine (C). This phenomenon was significantly counteracted by JMV-1843 administration (D). Neuronal cell counts are shown in E. ## = P<0.01 vs the control non-epileptic group, * = P<0.05 vs both the saline and ghrelin groups, Fisher's LSD test. Scale bar, 300 µm.
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pone-0072716-g006: Photomicrographs illustrating neuronal cell loss in the medial entorhinal cortex layer III after status epilepticus (SE), in pilocarpine-treated rats.Neurons were identified by the anti-neuron-specific nuclear protein (NeuN) antibody, as shown in the control staining (A). NeuN-immunopositive cells were markedly decreased in pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE (B). Similar findings were found in rats treated with ghrelin before receiving pilocarpine (C). This phenomenon was significantly counteracted by JMV-1843 administration (D). Neuronal cell counts are shown in E. ## = P<0.01 vs the control non-epileptic group, * = P<0.05 vs both the saline and ghrelin groups, Fisher's LSD test. Scale bar, 300 µm.

Mentions: We then evaluated neuronal cell densities in the medial entorhinal cortex layer III (Figure 6), another region of the hippocampal formation particularly vulnerable to pilocarpine-induced damage [27], [32]. Neurons in layer III were decreased to approximately 10% of control levels (P<0.01) in the saline group of pilocarpine-treated rats (cf. Figure 6A and 6B). Similar decreased values were found in ghrelin-treated rats (P<0.01 vs control levels; Figure 6C). Again, JMV-1843 had protective effect (Figure 6D), although much smaller than the one observed in the hilus. JMV-1843-treated rats were also characterized by decreased neuronal cell counts, corresponding to approximately 20% of values found in control non-epileptic rats (P<0.01). However, neuronal cell density was significantly (P<0.05) higher (+60−70%) in the JMV-1843 group compared with saline- or ghrelin-treated rats (Figure 6E).


Protective but not anticonvulsant effects of ghrelin and JMV-1843 in the pilocarpine model of Status epilepticus.

Lucchi C, Curia G, Vinet J, Gualtieri F, Bresciani E, Locatelli V, Torsello A, Biagini G - PLoS ONE (2013)

Photomicrographs illustrating neuronal cell loss in the medial entorhinal cortex layer III after status epilepticus (SE), in pilocarpine-treated rats.Neurons were identified by the anti-neuron-specific nuclear protein (NeuN) antibody, as shown in the control staining (A). NeuN-immunopositive cells were markedly decreased in pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE (B). Similar findings were found in rats treated with ghrelin before receiving pilocarpine (C). This phenomenon was significantly counteracted by JMV-1843 administration (D). Neuronal cell counts are shown in E. ## = P<0.01 vs the control non-epileptic group, * = P<0.05 vs both the saline and ghrelin groups, Fisher's LSD test. Scale bar, 300 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3755992&req=5

pone-0072716-g006: Photomicrographs illustrating neuronal cell loss in the medial entorhinal cortex layer III after status epilepticus (SE), in pilocarpine-treated rats.Neurons were identified by the anti-neuron-specific nuclear protein (NeuN) antibody, as shown in the control staining (A). NeuN-immunopositive cells were markedly decreased in pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE (B). Similar findings were found in rats treated with ghrelin before receiving pilocarpine (C). This phenomenon was significantly counteracted by JMV-1843 administration (D). Neuronal cell counts are shown in E. ## = P<0.01 vs the control non-epileptic group, * = P<0.05 vs both the saline and ghrelin groups, Fisher's LSD test. Scale bar, 300 µm.
Mentions: We then evaluated neuronal cell densities in the medial entorhinal cortex layer III (Figure 6), another region of the hippocampal formation particularly vulnerable to pilocarpine-induced damage [27], [32]. Neurons in layer III were decreased to approximately 10% of control levels (P<0.01) in the saline group of pilocarpine-treated rats (cf. Figure 6A and 6B). Similar decreased values were found in ghrelin-treated rats (P<0.01 vs control levels; Figure 6C). Again, JMV-1843 had protective effect (Figure 6D), although much smaller than the one observed in the hilus. JMV-1843-treated rats were also characterized by decreased neuronal cell counts, corresponding to approximately 20% of values found in control non-epileptic rats (P<0.01). However, neuronal cell density was significantly (P<0.05) higher (+60−70%) in the JMV-1843 group compared with saline- or ghrelin-treated rats (Figure 6E).

Bottom Line: In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression.In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats.These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

ABSTRACT
In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.

Show MeSH
Related in: MedlinePlus