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Neuroprotective effects of PPARgamma agonists against oxidative insults in HT-22 cells
Paul Aoun1, David G Watson, James W Simpkins
1Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA.
Abstract:
Peroxisome proliferator-activated receptors (PPARs) are involved in regulating many metabolic and inflammatory processes. The present study explores the role of PPAR ligands in protecting neuronal cultures from toxic insults. For that purpose, we used WY14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid] as a PPARalpha agonist, L-165041 and L-783483 as PPARbeta ligands, and 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2), troglitazone, and ciglitazone for PPARgamma. Experiments were performed using HT-22, an immortalized mouse hippocampal cell line, and SK-N-SH, a human neuroblastoma cell line. Cell viability against glutamate, hydrogen peroxide (H(2)O(2)), and serum deprivation insults was determined using a calcein acetoxymethyl (AM) assay. Of the compounds tested, only 15d-PGJ2 and troglitazone showed a dose-dependent neuroprotection from glutamate and H(2)O(2) insults in HT-22 cells. None of the PPAR agonists was protective in SK-N-SH cells. A minimum of 4-6 h preincubation with 15d-PGJ2 was required to achieve significant neuroprotection. On the other hand, troglitazone was protective even when administered simultaneously with glutamate, or for up to 8 h postglutamate insult. To investigate whether the neuroprotective effects are mediated through PPARgamma, we first determined through Western blotting that HT-22 and SK-N-SH cells express PPARgamma. However, the neuroprotective effects of those compounds are unlikely to be mediated through the PPARgamma for two reasons: (1) various concentrations of another PPARgamma agonist (ciglitazone) were not neuroprotective; (2) by itself, PPAR exhibits a low affinity for DNA, and high-affinity binding requires heterodimerization with RXR, the 9-cis-retinoic acid receptor; administering 9-cis-retinoic acid in conjunction with 15d-PGJ2 did not alter the neuroprotective effects of the latter. Our results demonstrate neuroprotective effects of 15d-PGJ2 and troglitazone that are likely independent of PPARgamma.
Insights
Certain peroxisome proliferator-activated receptor (PPAR) ligands, specifically 15d-PGJ2 and troglitazone, demonstrated neuroprotection in neuronal cultures against toxic insults. These protective effects appear independent of PPARgamma activation.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Peroxisome proliferator-activated receptors (PPARs) regulate metabolic and inflammatory processes.
- Understanding neuroprotection mechanisms is crucial for treating neuronal damage.
- PPAR ligands are investigated for their potential therapeutic roles in neurological conditions.
Purpose of the Study:
- To investigate the neuroprotective effects of various PPAR ligands on neuronal cultures.
- To determine if neuroprotection is mediated through PPARgamma activation.
- To compare the efficacy of different PPAR agonists against specific toxic insults.
Main Methods:
- Utilized HT-22 (mouse hippocampal) and SK-N-SH (human neuroblastoma) cell lines.
- Exposed cells to glutamate, hydrogen peroxide (H2O2), and serum deprivation.
- Assessed cell viability using the calcein acetoxymethyl (AM) assay; confirmed PPARgamma expression via Western blotting.
Main Results:
- 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) and troglitazone exhibited dose-dependent neuroprotection against glutamate and H2O2 in HT-22 cells.
- No tested PPAR agonists provided protection in SK-N-SH cells.
- Neuroprotection by 15d-PGJ2 and troglitazone was likely independent of PPARgamma, as evidenced by the lack of protection from ciglitazone and no potentiation by 9-cis-retinoic acid.
Conclusions:
- 15d-PGJ2 and troglitazone demonstrate significant neuroprotective properties in specific neuronal cell models.
- The observed neuroprotection is not mediated through the canonical PPARgamma pathway.
- Further research is warranted to elucidate the precise mechanisms underlying the PPAR-independent neuroprotective effects.
