Neuronal Peroxisome Proliferator-Activated Receptor γ Signaling: Regulation by Mood-Stabilizer Valproate

Abstract

Valproate (Depakote) remains an effective medication for the prevention and treatment of seizures in epilepsy and of mood symptoms in bipolar disorder. Both of these disorders are severe and debilitating, and both warrant further medication options as well as a better understanding of the side effects associated with their current treatments. Although a number of molecular and cellular processes have been found to be altered by valproate, the medication's therapeutic mechanism has not been fully elucidated. In this paper, peroxisome proliferator-activated receptor (PPAR) signaling was examined to determine valproate's effects on this transcriptional regulatory system in neuronal tissue. PPAR signaling has been found to affect a number of biochemical processes, including lipid metabolism, cellular differentiation, insulin sensitivity, and cell survival. When primary neuronal cultures were treated with valproate, a significant decrease in PPARgamma signaling was observed. This effect was demonstrated through a change in nuclear quantities of PPARgamma receptor and decreased DNA binding of the receptor. Valproate also caused gene expression changes and a change to the peroxisome biochemistry consistent with a decrease of PPARgamma signaling. These biochemical changes may have functional consequences for either valproate's therapeutic mechanism or for its neurological side effects and merit further investigation.

Molecular and Therapeutic Potential and Toxicity of Valproic Acid

“…This mechanism could be one factor favoring the teratogenic effect of VPA [60]. In contrast, it was reported that in neuronal cells VPA induced a significant decrease in PPAR γ signaling [61]. These results highlight potential tissue-specific effects of VPA, as observed in several publications, and the difficulties in predicting its effects prior to clinical trials.…”

Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin

“…A caveat to the efficacy of valproate is data showing that valproate leads to decreased levels of peroxisome proliferator‐activated receptor gamma (PPARg) [45]. The thiazolidinediones, which induce PPARg, have been shown to have some efficacy in the treatment of both seizures and MS [46].…”

Metabolic Dysfunction Associated with Adiponectin Deficiency Enhances Kainic Acid-Induced Seizure Severity

“…Interestingly, PPARγ agonists, which are known to increase adiponectin expression, protect against seizure-related pathology (Maurois et al, 2008; Sun et al, 2008; Yu et al, 2008; Abdallah, 2010). Furthermore, the anti-epileptic drug valproic acid modulates PPARγ signaling, and alters adipoR1 and adiponectin expression (Qiao et al, 2006; Lan et al, 2008; Rauchenzauner et al, 2008). Adiponectin injected intracerebrally has also been shown to reduce kainic acid (KA)-induced excitotoxicity (Jeon et al, 2009).…”