Protective but Not Anticonvulsant Effects of Ghrelin and JMV-1843 in the Pilocarpine Model of Status epilepticus

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 mm2 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.

Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway

“…In the hippocampus, ghrelin was continuously administered for 2 hr prior to pilocarpine initiation, whereas in mice ghrelin was systemically administered 30 min before pilocarpine intravenous infusion. Despite a number of studies that have also described anticonvulsant effects following ghrelin administration (Portelli et al, 2012a), there is still debate on whether ghrelin has an important role in epileptic mechanisms (Biagini et al, 2011;Biagini et al, 2011;Lucchi et al, 2013). The only plausible reason for the differences in our results and that of the group of Biagini is perhaps the timing of the ghrelin injection.…”

“…The only plausible reason for the differences in our results and that of the group of Biagini is perhaps the timing of the ghrelin injection. It could be that administration of ghrelin 30 min prior to pilocarpine administration, as opposed to 10 min as described by Biagini et al (2011) and Lucchi et al (2013), allowed ghrelin more time to reach the central ghrelin receptors to desensitize/internalize the receptors, resulting in an anticonvulsant effect in our case. Although it is known that acylated peptides cross the blood-brain barrier more quickly than their unacylated counterparts (Pardridge, 2012), it still remains a matter of debate whether the anticonvulsant effect following systemic ghrelin administration is in fact due to ghrelin acting on the central ghrelin receptors or due to the fact that ghrelin can be quickly converted to DAG (Delhanty et al, 2015;Satou et al, 2011).…”

Ischemic–hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus

“…These characteristics were all detected in the CA3 stratum lacunosum-moleculare (Fig. 1B), where a bilateral seed-shaped lesion was consistently found in all examined pilocarpine-treated rats that experienced a SE [17,21,26].…”

“…In particular, the CA3 lesion was always observed in adult rats, even when convulsive seizures were arrested 10 min after the onset of SE [21,26]. However, even when this lesion was particularly extended, sometimes reaching the stratum lucidum, it very rarely affected Fig.…”

“…Control immunostaining is shown in a normal, saline-treated rat. Laminin levels were quantified in B, according to previously described methods [17,21,26], including rats studied at weeks (w) after SE induction. Note that the area of specific laminin immunostaining, as measured by excluding the pyramidal cell layer and granular cell layer, respectively, in the CA3a and CA3b sectors and dentate hilus and gyrus, increased with different dynamics during SE (0.5 h, n = 3; 1 h, n = 4; 2 h, n = 4; 3 h, n = 5; 24 h, n = 4; 48 h, n = 2; 72 h, n = 6; 1 week, n = 7; 2 weeks, n = 7; 3 weeks, n = 3).…”