Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways

Abstract

The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone over 5 days before and 24 or 48 h after MCAO alleviated neurological impairments, inhibited apoptosis 24 h, and activated the PI3K/Akt pathway along with increased phosphorylation of Akt (ser473) and GSK-3β (ser9) in the peri-infarct cortical areas 48 h after MCAO. In primary cortical neurons, pioglitazone suppressed the glutamate-induced release of lactate dehydrogenase by a PPARγ-dependent mechanism. This protective effect was reversed after co-treatment with PI3K and Akt inhibitors, LY294002 and SH-6, respectively. Pioglitazone enhanced the expression of the antioxidative transcription factor Nrf2 and its target gene protein, heme oxidase-1, in the peri-infarct area. Pioglitazone also increased activation of the antioxidant response element (ARE) in neuronal PC12 cells transfected with the pNQO1-rARE plasmid. We demonstrate in primary cortical neurons from Nrf2 knockout mice that the lack of Nrf2 completely abolished the neuroprotective effects of pioglitazone against oxidative and excitotoxic damage. Our results strongly suggest that the neuroprotective effects of PPARγ in peri-infarct brain tissues comprise the concomitant activation of the PI3K/Akt and Nrf2/ARE pathways. Key messages Pioglitazone inhibits apoptosis in ischemic brain tissue. Pioglitazone acting on PPARγ activates PI3K/Akt pathway in ischemic brain tissue. Pioglitazone activates via Nrf2 the antioxidant defense pathway in injured neurons. Pioglitazone activates the antioxidant response element in neuronal PC12 cells. Pioglitazone fails to protect primary neurons lacking Nrf2 against oxidative damage. Activation of PPARγ supports the survival of viable neurons in peri-infarct regions.

The Protection of EGCG Against 6-OHDA-Induced Oxidative Damage by Regulating PPARγ and Nrf2/HO-1 Signaling

“…This is inconsistent with the results of other studies showing that EGCG acted as a promoter of antioxidant and anti-inflammatory properties by activating Nrf2 and HO-1 exression. 44 , 46 , 47 One reason for this may be that 6-OHDA-induced oxidative stress and inflammatory response could further activate the protein expression of Nrf2, HO-1, and PPARγ, whereas EGCG treatment restored the cells to a level of low oxidative stress and inflammation. Another reason for the discrepancy of our results might be related to the difference of cell types.…”

Cognitive Impairment in Multiple Sclerosis

“…Recent studies have identified a significant role for pathways of programmed cell death that can ultimately control cell survival and cognitive impairment during MS [46,61,128,130,132,134,[200][201][202] (Table 1). Programmed cell death pathways that involve autophagy, apoptosis, pyroptosis, and ferroptosis can influence cell survival during inflammation [34,39,66,73,74,85,87,[203][204][205][206][207][208][209][210][211][212][213], oxidative stress [10,45,77,86,89,93,119,185,[214][215][216][217][218][219], ischemia [219][220][221][222][223], and mitochondrial dysfunction [32,…”

The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

“…Indeed, the Akt pathway and inhibitory Ser 9 phosphorylation of GSK-3β were shown to prevent miPTP opening and mitochondrial swelling in response to excessive ROS production ( Juhaszova et al, 2004 ). GSK-3β further counteracts Akt/NRF-2-mediated anti-oxidative gene transcription (such as HO-1 Zhao et al, 2021c ), elicits the joint inactivation of the key TCA enzyme PDH with TPKI and inhibits mitochondrial complex I-IV and ATP synthesis. The impaired mitochondrial function, in turn, exacerbates ROS generation (see Yang et al, 2017 ; Figure 2 ).…”