PPARγ-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates Ischemic Brain Damage in Ovariectomized Rats

Abstract

High mobility group box 1 (HMGB1) elevation after cerebral ischemia activates inflammatory pathways via receptors such as the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) and leads to brain damage. Eicosapentaenoic acid (EPA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, attenuates postischemic inflammation and brain damage in male animals. However, postischemic HMGB1 signaling and the effects of EPA on ovariectomized (OVX(+)) rats remain unclear. We hypothesized that EPA attenuates brain damage in OVX(+) rats via the inhibition of HMGB1 signaling in a PPARγ-dependent manner. Seven-week-old female Sprague-Dawley rats were divided into 3 groups; nonovariectomized (OVX(-)) rats and EPA-treated and EPA-untreated OVX(+) rats before cerebral ischemia induction. Another set of EPA-treated OVX(+) rats was injected with the PPARγ inhibitor GW9662. OVX(+) decreased the messenger RNA level of PPARγ and increased that of HMGB1, RAGE, TLR9, and tumor necrosis factor alpha (TNFα) in parallel with ischemic brain damage. EPA restored the PPARγ expression, downregulated the HMGB1 signal-related molecules, and attenuated the ischemic brain damage. Neither OVX(+) nor EPA affected the expression of TLR2 or TLR4. Interestingly, GW9662 partially abrogated the EPA-induced neuroprotection and the downregulation of RAGE and TLR9. In contrast, GW9662 did not affect HMGB1 or TNFα. These results suggest that EPA exerts PPARγ-dependent and PPARγ-independent effects on postischemic HMGB1/TLR9 pathway. The cortical infarct volume exacerbated by OVX(+) is associated with the upregulation of the HMGB1/TLR9 pathway. Suppression of this pathway may help to limit ischemic brain damage in postmenopausal women.

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

“…Although the beneficial effects of n-3 PUFAs have been traditionally accredited to all components without discrimination [57], it is possible that the dramatically-elevated EPA played a major role in the current treatment paradigm. To date, the effect of EPA treatment in stroke was much less studied compared to that of DHA, although it was reported previously that EPA attenuated post-ischemic inflammation and brain injury in part due to its function as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist [58]. Future studies are warranted to elucidate the unique effects of different n-3 PUFAs, such as EPA.…”

Sterile Neuroinflammation and Strategies for Therapeutic Intervention

“…The blockade of glutamate/NMDA stimulation by MK-801 prevented the release of HMGB1 inhibiting neuroinflammation through TLR4 [163]. Eicosapentaenoic acid (EPA), a peroxisome proliferator-activated receptor gamma (PPAR γ ) agonist, restored the optimum PPAR γ expression, attenuating the ischemic brain damage by downregulating the release of HMGB1 signal related molecules [164]. …”

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

“…Once in the extracellular space, HMGB-1 exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) [21,22], TLR2 [23][24][25][26], TLR4 [27][28][29][30], and TLR9 [31]. The interaction between HMGB-1 and its receptors has been shown to induce cell adhesion [32], permeability [33,34], chemotaxis [35], inflammation [36][37][38], autophagy [39][40][41], apoptosis [42][43][44], thrombosis [16,45,46], angiogenesis [47,48], fibrosis [49,50], and epithelialmesenchymal transition (EMT) [51,52].…”