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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 the glial lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody against the glial fibrillary acidic protein (GFAP), which specifically stains astrocytes. In a pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE, the GFAP immunostaining is completely abolished in the core of the lesion, which is surrounded by strongly immunopositive reactive astrocytes (A-C). The lesion core was manually demarcated and its area measured, as indicated by the blackish area in A. Pretreatment with the GH secretagogue ghrelin (B) and JMV-1843 (C) resulted in less marked lesions, as shown in D. * = P<0.05, ** = P<0.01 vs the saline group, Fisher's LSD test. Scale bar, 300 µm.
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pone-0072716-g002: Photomicrographs illustrating the glial lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody against the glial fibrillary acidic protein (GFAP), which specifically stains astrocytes. In a pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE, the GFAP immunostaining is completely abolished in the core of the lesion, which is surrounded by strongly immunopositive reactive astrocytes (A-C). The lesion core was manually demarcated and its area measured, as indicated by the blackish area in A. Pretreatment with the GH secretagogue ghrelin (B) and JMV-1843 (C) resulted in less marked lesions, as shown in D. * = P<0.05, ** = P<0.01 vs the saline group, Fisher's LSD test. Scale bar, 300 µm.

Mentions: Following SE, a focal lesion, characterized by the complete disappearance of GFAP immunoreactivity and surrounded by intensely-labelled reactive astrocytes, was found in the CA3 stratum lacunosum-moleculare of saline-treated rats (Figure 2A), confirming our previously described findings [30]–[31]. Although this lesion was not prevented by any of the tested GHS-R1a agonists, it was significantly reduced in both ghrelin and JMV-1843 treatment groups (Figure 2B,C). In particular, the mean area of GFAP loss, represented as% compared to saline-treated rats, was 70% in the ghrelin group (P<0.05 vs saline) and 57% in the JMV-1843 group (P<0.01 vs saline) (Figure 2D).


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 the glial lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody against the glial fibrillary acidic protein (GFAP), which specifically stains astrocytes. In a pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE, the GFAP immunostaining is completely abolished in the core of the lesion, which is surrounded by strongly immunopositive reactive astrocytes (A-C). The lesion core was manually demarcated and its area measured, as indicated by the blackish area in A. Pretreatment with the GH secretagogue ghrelin (B) and JMV-1843 (C) resulted in less marked lesions, as shown in D. * = P<0.05, ** = P<0.01 vs the saline group, 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-g002: Photomicrographs illustrating the glial lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody against the glial fibrillary acidic protein (GFAP), which specifically stains astrocytes. In a pilocarpine-treated rat of the saline-treated group, sacrificed 4 days after SE, the GFAP immunostaining is completely abolished in the core of the lesion, which is surrounded by strongly immunopositive reactive astrocytes (A-C). The lesion core was manually demarcated and its area measured, as indicated by the blackish area in A. Pretreatment with the GH secretagogue ghrelin (B) and JMV-1843 (C) resulted in less marked lesions, as shown in D. * = P<0.05, ** = P<0.01 vs the saline group, Fisher's LSD test. Scale bar, 300 µm.
Mentions: Following SE, a focal lesion, characterized by the complete disappearance of GFAP immunoreactivity and surrounded by intensely-labelled reactive astrocytes, was found in the CA3 stratum lacunosum-moleculare of saline-treated rats (Figure 2A), confirming our previously described findings [30]–[31]. Although this lesion was not prevented by any of the tested GHS-R1a agonists, it was significantly reduced in both ghrelin and JMV-1843 treatment groups (Figure 2B,C). In particular, the mean area of GFAP loss, represented as% compared to saline-treated rats, was 70% in the ghrelin group (P<0.05 vs saline) and 57% in the JMV-1843 group (P<0.01 vs saline) (Figure 2D).

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