Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone

Abstract

Binge alcohol drinking has emerged as a typical phenomenon in young people. This pattern of drinking, repeatedly leading to extremely high blood and brain alcohol levels and intoxication is associated with severe risks of neurodegeneration and cognitive damage. Mechanisms involved in excitotoxicity and neuroinflammation are pivotal elements in alcohol-induced neurotoxicity. Evidence has demonstrated that PPARγ receptor activation shows anti-inflammatory and neuroprotective properties. Here we examine whether treatment with the PPARγ agonist pioglitazone is beneficial in counteracting neurodegeneration, neuroinflammation and cognitive damage produced by binge alcohol intoxication. Adult Wistar rats were subjected to a 4-day binge intoxication procedure, which is commonly used to model excessive alcohol consumption in humans. Across the 4-day period, pioglitazone (0, 30, 60 mg/kg) was administered orally twice daily at 12-h intervals. Degenerative cells were detected by fluoro-jade B (FJ-B) immunostaining in brain regions where expression of pro-inflammatory cytokines was also determined. The effects of pioglitazone on cognitive function were assessed in an operant reversal learning task and the Morris water maze task. Binge alcohol exposure produced selective neuronal degeneration in the hippocampal dentate gyrus and the adjacent entorhinal cortex. Pioglitazone reduced FJ-B positive cells in both regions and prevented alcohol-induced expression of pro-inflammatory cytokines. Pioglitazone also rescued alcohol-impaired reversal learning in the operant task and spatial learning deficits in the Morris water maze. These findings demonstrate that activation of PPARγ protects against neuronal and cognitive degeneration elicited by binge alcohol exposure. The protective effect of PPARγ agonist appears to be linked to inhibition of pro-inflammatory cytokines.

Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission

“…Neuroanatomical evidence of PPAR␥ expression in AMY, HIPP, and other brain regions involved in the regulation of emotion and motivation have been previously described (Moreno et al, 2004;Inestrosa et al, 2005;Gofflot et al, 2007;de Guglielmo et al, 2015). Cortical and amygdalar PPAR␥ activation has been linked to the attenuation of the negative effects induced by acute and chronic stress exposure (García-Bueno et al, 2005;Domi et al, 2016) and specific hippocampal PPAR␥ activation appears to play a role in attenuating the cognitive deficits caused by alcohol intoxication (Cippitelli et al, 2017).…”

Genetic variations in chromodomain helicase DNA-binding protein 5, gene-environment interactions and risk of sporadic Alzheimer’s disease in Chinese population

“…In our study, drinking status with CHD5 rs11121295 variant presented a promising association with Alzheimer's disease risk compared with non-drinking carrying that genotype, which indicated that this variant might act in response to drinking, and true associations might be detected by alcoholic stimulation. It has been shown that alcohol could modulate the effect of various cytokines, receptors or neuroimmune signaling in brain, such as midkine (MDK) [ 24 ], PPARgamma receptor [ 25 ], and HMGB1, miRNA and TLR receptors [ 26 ]. Therefore, we speculated, alcohol intake might trigger proinflammatory events through their induction of oxidative stress and extensive inflammation.…”

Pioglitazonun NB2a Fare Nöroblastoma Hücre Kültürüdeki Nöroprotektif Etkisi

“…It has three subtypes: PPARα, PPARβ (δ) and PPARγ. Antidiabetic effects of TZDs have been found to be closely related to the ability to bind to and activate the PPARγ [4] . TZDs have effects on the vascular.system.…”

“…Cellular effects occur via the activation of peroxisome proliferator-activated receptors (PPARs) [3] . Activation of PPARγ is known to regulate inflammatory responses.and reduce the expression of many proinflammatory genes (COX-2, iNOS and cytokines), and it is also associated with inflammation in neurodegeneration [4] . Pioglitazone (PGT), a member of this group, is thought to have neuronprotective property through several mechanisms by increasing the gene transcription with the agonistic effect of PPARγ.…”