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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 vascular lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody to laminin, which identifies the basal lamina in blood vessels in control tissue (A). Laminin immunoreactivity is markedly upregulated in the damaged area of a pilocarpine-treated rat of the saline-treated group (B) sacrificed 4 days after SE. Pretreatment with the GH secretagogue ghrelin (C) did not affect the increase of laminin immunoreactivity. Notably, pretreatment with JMV-1843 (D) prevented the changes observed in the other treatment groups, which are quantified in E. ## = P<0.01 vs the control non-epileptic group,* = P<0.05 vs the saline pilocarpine-treated group, Fisher's LSD test. Scale bar, 300 µm.
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pone-0072716-g003: Photomicrographs illustrating the vascular lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody to laminin, which identifies the basal lamina in blood vessels in control tissue (A). Laminin immunoreactivity is markedly upregulated in the damaged area of a pilocarpine-treated rat of the saline-treated group (B) sacrificed 4 days after SE. Pretreatment with the GH secretagogue ghrelin (C) did not affect the increase of laminin immunoreactivity. Notably, pretreatment with JMV-1843 (D) prevented the changes observed in the other treatment groups, which are quantified in E. ## = P<0.01 vs the control non-epileptic group,* = P<0.05 vs the saline pilocarpine-treated group, Fisher's LSD test. Scale bar, 300 µm.

Mentions: We previously demonstrated that the loss of GFAP immunostaining in the CA3 region of pilocarpine-treated rats is highly associated with an increase in laminin immunoreactivity in the basal lamina of blood vessels [31]. We thus evaluated whether treatment with GHS-R1a agonists would also affect the laminin immunoreactivity in the hippocampus (Figure 3). In the saline group of pilocarpine-treated rats (Figure 3B), laminin levels were 12-fold higher than those measured in normal control rats (P<0.01; Figure 3A,E). Although laminin levels were also increased in rats treated with ghrelin (P<0.01 vs non-epileptic controls; Figure 3C), this change was completely prevented by JMV-1843 (Figure 3D). In fact, laminin levels in JMV-1843-treated rats were not significantly different from those found in control non-epileptic rats (Figure 3A) and lower than in saline-treated pilocarpine rats (P<0.05; Figure 3B,E).


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 vascular lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody to laminin, which identifies the basal lamina in blood vessels in control tissue (A). Laminin immunoreactivity is markedly upregulated in the damaged area of a pilocarpine-treated rat of the saline-treated group (B) sacrificed 4 days after SE. Pretreatment with the GH secretagogue ghrelin (C) did not affect the increase of laminin immunoreactivity. Notably, pretreatment with JMV-1843 (D) prevented the changes observed in the other treatment groups, which are quantified in E. ## = P<0.01 vs the control non-epileptic group,* = P<0.05 vs the saline pilocarpine-treated group, Fisher's LSD test. Scale bar, 300 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755992&req=5

pone-0072716-g003: Photomicrographs illustrating the vascular lesion appearing in the CA3 stratum lacunosum-moleculare after status epilepticus (SE), in pilocarpine-treated rats.The lesion was investigated using an antibody to laminin, which identifies the basal lamina in blood vessels in control tissue (A). Laminin immunoreactivity is markedly upregulated in the damaged area of a pilocarpine-treated rat of the saline-treated group (B) sacrificed 4 days after SE. Pretreatment with the GH secretagogue ghrelin (C) did not affect the increase of laminin immunoreactivity. Notably, pretreatment with JMV-1843 (D) prevented the changes observed in the other treatment groups, which are quantified in E. ## = P<0.01 vs the control non-epileptic group,* = P<0.05 vs the saline pilocarpine-treated group, Fisher's LSD test. Scale bar, 300 µm.
Mentions: We previously demonstrated that the loss of GFAP immunostaining in the CA3 region of pilocarpine-treated rats is highly associated with an increase in laminin immunoreactivity in the basal lamina of blood vessels [31]. We thus evaluated whether treatment with GHS-R1a agonists would also affect the laminin immunoreactivity in the hippocampus (Figure 3). In the saline group of pilocarpine-treated rats (Figure 3B), laminin levels were 12-fold higher than those measured in normal control rats (P<0.01; Figure 3A,E). Although laminin levels were also increased in rats treated with ghrelin (P<0.01 vs non-epileptic controls; Figure 3C), this change was completely prevented by JMV-1843 (Figure 3D). In fact, laminin levels in JMV-1843-treated rats were not significantly different from those found in control non-epileptic rats (Figure 3A) and lower than in saline-treated pilocarpine rats (P<0.05; Figure 3B,E).

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