Rosiglitazone Alone Or in Combination with Tissue Plasminogen Activator Improves Ischemic Brain Injury in an Embolic Model in Rats

Abstract

In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR γ) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.

Recombinant human MFG-E8 attenuates cerebral ischemic injury: Its role in anti-inflammation and anti-apoptosis

“…PPAR-γ is known to suppress NF-κB mediated cytokine production through a variety of mechanisms collectively termed transrepression (Ricote and Glass 2007). PPAR-γ agonists such as the thiazolidinediones have shown neuroprotection in cerebral ischemia (Wang et al 2009). Our finding of rhMFG-E8 mediated upregulation of PPAR-γ together with suppression of cytokine release is consistent with the work of Zhang et al who showed that the PPAR-γ agonist, pioglitazone, suppresses NF-κB signaling in permanent focal cerebral ischemia, resulting in neuroprotection (Zhang et al 2011).…”

Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia

“…12 However, the effects of PPAR-γ agonists on white matter integrity after stroke have not been investigated. Recent in vitro studies have documented that several PPAR-γ agonists promote OPC differentiation into mature oligodendrocytes.…”

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

“…Two synthetic PPARg ligands, rosiglitazone and pioglitazone, which are thiazolidinediones (TZDs), are approved by the Food and Drug Administration as treatments for type 2 diabetes. Recent studies have shown that both rosiglitazone and pioglitazone are neuroprotective in animal models of acute ischemic injury; [1][2][3] however, the mechanisms underlying these effects at the cellular level are not fully understood.…”