PPAR agonists can influence pathological processes through mechanisms that are independent of their classical PPAR receptors. For example, when given at extremely low doses (0.5 and 1 mg/kg), far below those needed to activate PPARγ receptors, pioglitazone still attenuates inflammatory signaling by reducing TNF-α, iNOS, and IL-1β (Thal et al., 2011). Indeed, co-administration of a PPARγ antagonist does not prevent the anti-inflammatory effects of low-dose pioglitazone, confirming a PPARγ receptor-independent mechanism (Thal et al., 2011). Similarly, although pioglitazone reduces tissue loss and cognitive impairment after TBI by PPARγ activation, this drug reduces microglial activation via a PPARγ-independent mechanism (Sauerbeck et al., 2011). A different PPARγ agonist, rosiglitazone, has similar anti-inflammatory effects after TBI, yet its effects depend on PPARγ activation (Yi et al., 2008). The ability to reduce inflammation and the different receptor dependency of pioglitazone and rosiglitazone is likely explained by immune cells expressing both PPARγ and PPARδ receptors and each receptor having different thresholds for activation by rosiglitazone (Sakamoto et al., 2000; Gordon and Martinez, 2010). Additionally, the PPARγ-independent actions of these agonists likely result from their ability
