Involvement of PPARγ in the Anticonvulsant Activity of EP-80317, a Ghrelin Receptor Antagonist

Abstract

Ghrelin, des-acyl ghrelin and other related peptides possess anticonvulsant activities. Although ghrelin and cognate peptides were shown to physiologically regulate only the ghrelin receptor, some of them were pharmacologically proved to activate the peroxisome proliferator-activated receptor gamma (PPARγ) through stimulation of the scavenger receptor CD36 in macrophages. In our study, we challenged the hypothesis that PPARγ could be involved in the anticonvulsant effects of EP-80317, a ghrelin receptor antagonist. For this purpose, we used the PPARγ antagonist GW9662 to evaluate the modulation of EP-80317 anticonvulsant properties in two different models. Firstly, the anticonvulsant effects of EP-80317 were studied in rats treated with pilocarpine to induce status epilepticus (SE). Secondly, the anticonvulsant activity of EP-80317 was ascertained in the repeated 6-Hz corneal stimulation model in mice. Behavioral and video electrocorticographic (ECoG) analyses were performed in both models. We also characterized levels of immunoreactivity for PPARγ in the hippocampus of 6-Hz corneally stimulated mice. EP-80317 predictably antagonized seizures in both models. Pretreatment with GW9662 counteracted almost all EP-80317 effects both in mice and rats. Only the effects of EP-80317 on power spectra of ECoGs recorded during repeated 6-Hz corneal stimulation were practically unaffected by GW9662 administration. Moreover, GW9662 alone produced a decrease in the latency of tonic-clonic seizures and accelerated the onset of SE in rats. Finally, in the hippocampus of mice treated with EP-80317 we found increased levels of PPARγ immunoreactivity. Overall, these results support the hypothesis that PPARγ is able to modulate seizures and mediates the anticonvulsant effects of EP-80317.

Electrographic Changes Accompanying Recurrent Seizures under Ketogenic Diet Treatment

“…By visual inspection, the first seizure induced by 6-Hz stimulation was shorter in KD-treated mice compared to control mice (114.7 ± 15.1 vs. 211.2 ± 31.7 s; p < 0.001, Holm–Šídák test; Figure 1 a). However, no differences in duration were found between the two groups in the following session because seizures shortened significantly in controls (113.9 ± 16.4 s in session 2, p < 0.001 vs. session 1 of control group), as expected [ 25 , 26 , 27 ]. Consistently, the change in seizure duration was caused by the shortening of the non-motor component of the seizure, corresponding to stunned behavior, whereas the motor component did not change in both groups ( Figure 1 b,c).…”

“…However, when performing similar experiments, other investigators observed partial effects [ 23 ] or no results [ 24 ]. As we recently proposed a model of repeated 6-Hz corneal stimulation in which seizures were found to progressively increase in severity, so to prefigure an epileptogenic process [ 25 , 26 , 27 ], we aimed at evaluating the KD effects in this model. Specifically, we decided to carefully monitor the KD effects on the progression in seizure severity caused by repeating the seizure induction, as well as to assess the KD effects on electrographic discharges recorded from mice exposed to the four different sessions of 6-Hz corneal stimulation.…”

Impact of elastin-derived VGVAPG peptide on bidirectional interaction between peroxisome proliferator-activated receptor gamma (Pparγ) and beta-galactosidase (β-Gal) expression in mouse cortical astrocytes in vitro

“…It has been shown that this receptor is also important in astrocyte metabolism, astrocyte-mediated inflammation associated with degenerative pathologies such as Alzheimer's and Parkinson's diseases, multiple sclerosis and in type 2 diabetic mellitus (T2DM) (Iglesias et al 2017). Moreover, PPARγ plays an important role in seizure modulation (Lucchi et al 2017). To date, the thiazolidinediones (TZDs) such as rosiglitazone or pioglitazone are well-known agonists of PPARγ.…”

The Ketogenic Diet and its Clinical Applications in Type I and II Diabetes

“…They concluded that a co-administration may lead to the reduction of KD ratio without loss of seizure protection [44]. More recently, the hypothesis of the involvement of PPARγ in controlling seizure was supported also by another group, where a model of drug-resistant seizures was employed [45]. Back in 1978, a study on the effects of diet-induced ketosis on the signs of hypoglycemia on mice was published.…”