Peroxisome proliferator-activated receptor-γ agonist inhibits the mammalian target of rapamycin signaling pathway and has a protective effect in a rat model of status epilepticus

Abstract

Peroxisome proliferator-activated receptor γ (PPAR-γ) has a protective role in several neurological diseases. The present study investigated the effect of the PPAR-γ agonist, pioglitazone, on the mammalian target of rapamycin (mTOR) signaling pathway in a rat model of pentylenetetrazol (PTZ)-induced status epilepticus (SE). The investigation proceeded in two stages. First, the course of activation of the mTOR signaling pathway in PTZ-induced SE was examined to determine the time-point of peak activity, as reflected by phopshorylated (p)-mTOR/mTOR and p-S6/S6 ratios. Subsequently, pioglitazone was administrated intragastrically to investigate its effect on the mTOR signaling pathway, through western blot and immunochemical analyses. The levels of the interleukin (IL)-1β and IL-6 inflammatory cytokines were detected using ELISA, and neuronal loss was observed via Nissl staining. In the first stage of experimentation, the mTOR signaling pathway was activated, and the p-mTOR/mTOR and p-S6/S6 ratios peaked on the third day. Compared with the vehicle treated-SE group, pretreatment with pioglitazone was associated with the loss of fewer neurons, lower levels of IL-1β and IL-6, and inhibition of the activation of the mTOR signaling pathway. Therefore, the mTOR signaling pathway was activated in the PTZ-induced SE rat model, and the PPAR-γ agonist, pioglitazone, had a neuroprotective effect, by inhibiting activation of the mTOR pathway and preventing the increase in the levels of IL-1β and IL-6.

Machine learning shows association between genetic variability in PPARG and cerebral connectivity in preterm infants

“…S10 ). PPARG gene expression is up-regulated in neurons in response to excitotoxicity and ischemia ( 62 , 63 ), and modulates the microglial response to injury ( 64 , 65 ). PPARG agonists improve neuronal and glial survival in a variety of animal models involving ischemia and inflammation ( 62 , 66 – 69 ) and it has been suggested that they provide clinical improvement in children with autism ( 70 ).…”

Phosphorylation of PRAS40 contributes to the activation of the PI3K/AKT/mTOR signaling pathway and the inhibition of autophagy following status epilepticus in rats

“…Under conditions of nutrient sufficiency, the mTOR pathway is activated when mTORC1 inhibits autophagy by phosphorylating the Unc-51 like autophagy activating kinase 1 complex, which is a promoter of autophagy (14). However, under nutrient starvation, opposite events lead to the elevation of autophagy levels and cytoplasmic contents are eliminated to generate energy for essential cellular activities (10). There has been controversy regarding autophagy-associated alterations following SE.…”

“…Abnormal activation of the mTOR pathway in SE has been reported by previous studies. For instance, San et al (10) revealed…”

Chronobiology of limbic seizures: Potential mechanisms and prospects of chronotherapy for mesial temporal lobe epilepsy

“…Inhibition of mTOR pathway is likely one the mechanisms by which KD mediates these effects (McDaniel et al, 2011), which also involves the activation of peroxisomal proliferator-activated receptor γ (PPARγ) (Simeone et al, 2017). PPARγ is also linked to the control of the circadian clock (Chen and Yang, 2014) and hence a target for epilepsy treatment (San et al, 2015). Indeed, KD has been used as an antiepileptic treatment for some patients with drug-resistant epilepsy, but the underlying mechanisms of the KD action are still largely unknown.…”