The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

Abstract

Glioma cells release glutamate through expression of system xc−, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.

Peroxisome proliferator‐activated receptor gamma participates in the acquisition of brain ischemic tolerance induced by ischemic preconditioning via glial glutamate transporter 1 in vivo and in vitro

“…The present study showed an additional mechanism of GLT‐1 up‐regulation induced by IPC, which was mediated by PPARγ. In agreement with this notion, PPARγ‐mediated EAAT2 modulation has also been observed in human glioblastoma cells (Ching et al ). In addition, a recent study reported that the combination of the GLT‐1 activator ceftriaxone and the PPARγ agonist pioglitazone significantly potentiates protective effects more than either of the two drugs alone in a rat model of neuropathic pain (Pottabathini et al ).…”

Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation

“…Other on-going strategies include regulation of enzymes that are responsible for producing glutamate [ 52 ] or transporters involved with glutamate release [ 53 ]; however, currently, no clinically available brain-penetrating compounds exist. To date, a limited number of studies have investigated PPARγ as a target for GLT-1 regulation [ 33 , 54 ]. In light of these recent reports demonstrating that PPARγ activation increases astrocytic GLT-1 expression in the context of ischemia and glioma cells, we showed that targeting PPARγ for GLT-1 modulation is also applicable in the context of HIV-1-associated brain inflammation.…”

Metabotropic glutamate receptor 5 may be involved in macrophage plasticity

“…This gradient stimulates the xc-system and leads to enhanced cystine uptake and GSH synthesis. Activation of EAAT reduced extracellular glutamate levels that may be significant for the prevention of neurological complications, as well as for cancer progression [ 11 ]. Macrophages in physiological conditions do not express any of EAAT subtypes, however, in inflammatory conditions LPS and TNF-a increase EAAT expression [ 12 ].…”