Oligodendrocytes are vulnerable to glutamate excitotoxicity (McAdoo et al., 1999; Pitt et al., 2000; Xu et al., 2005a). High levels of extracellular glutamate are believed to contribute to several neurological diseases and after CNS injury (McAdoo et al., 1999; Pitt et al., 2000; Bogaert et al., 2010; Hinzman et al., 2010, 2012; Thomas et al., 2012; Mehta et al., 2013). Indeed, glutamate antagonists are neuroprotective in many pre-clinical models of neurologic disease (Wrathall et al., 1997; Rosenberg et al., 1999; Faden et al., 2001). Like traditional glutamate antagonists, PPAR activation may also attenuate excitotoxicity. For instance, the PPARγ agonist rosiglitazone increases expression of the glutamate transporter GLT1/EEAT2 mRNA and protein in cultured astrocytes (Romera et al., 2007). An increase in functional GLT1 would promote glutamate uptake by astrocytes thereby reducing extracellular levels. However, when tested in vivo in a model of focal cerebral ischemia, rosiglitazone did not affect GLT1/EAAT2 expression (Verma et al., 2011). Thus, the effects may be context-dependent or require a more rigorous analysis of dosing schedule or pharmacokinetics.
