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.
Highlights
Ghrelin and des-acyl ghrelin are neuroactive peptides prevalently produced in the stomach by X/Alike cells in rats, or P/D1 cells in humans (Rindi et al, 2002; Kojima, 2005; Chen et al, 2009)
We found that the percentages of rats developing status epilepticus (SE) after pilocarpine administration in groups treated with GW9662 or GW9662+EP80317 were not significantly different from that observed in saline-treated rats (Table 1)
In the present investigation we confirmed that EP-80317 displays anticonvulsant effects in the pilocarpine model and in the repeated 6-Hz corneal stimulation model
Summary
Ghrelin and des-acyl ghrelin are neuroactive peptides prevalently produced in the stomach by X/Alike cells in rats, or P/D1 cells in humans (Rindi et al, 2002; Kojima, 2005; Chen et al, 2009) They regulate very important physiological functions, such as growth hormone secretion, food intake and metabolism by interacting with hypothalamic neurons (Nakazato et al, 2001). Ghrelin was shown to modulate energy metabolism in areas other than the hypothalamus, as well as to be involved in the rewarding system of the brain (Egecioglu et al, 2010; Skibicka and Dickson, 2011; Skibicka et al, 2011; Perelló and Zigman, 2012) Overall, these evidences delineate a variety of physiological roles for ghrelin in the central nervous system (CNS)
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