n -3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling

Abstract

Background and Purpose— Omega-3 polyunsaturated fatty acids ( n-3 PUFAs) attenuate neonatal hypoxic/ischemic (H/I) brain damage, but the underlying mechanisms are not fully understood. This study tested the hypothesis that n-3 PUFAs enhance Akt-dependent prosurvival signaling by promoting the biosynthesis of phosphatidylserine in neuronal cell membranes. Methods— Dietary n-3 PUFA supplementation was initiated on the second day of pregnancy in dams. H/I was induced in 7-day-old rat pups by ipsilateral common carotid artery occlusion followed by hypoxia (8% oxygen for 2.5 hours). Neurological outcomes, brain tissue loss, cell death, and the activation of signaling events were assessed after H/I. The effects of n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) on oxygen-glucose deprivation–induced cell death and the underlying mechanism of protection were also examined in primary cortical neuron cultures. Results— n-3 PUFAs reduced brain tissue loss at 7 days after H/I and improved neurological outcomes, whereas inhibition of PI3K/Akt signaling by LY294002 partially abrogated this neuroprotective effect. Docosahexaenoic acid/eicosapentaenoic acid also prevented ischemic neuronal death through the Akt prosurvival pathway in vitro. Furthermore, docosahexaenoic acid/eicosapentaenoic acid increased the production of phosphatidylserine, the major membrane-bound phospholipids, after ischemia both in vitro and in vivo. A reduction in membrane phosphatidylserine by shRNA-mediated knockdown of phosphatidylserine synthetase-1 attenuated Akt activation and neuronal survival after docosahexaenoic acid/eicosapentaenoic acid treatment in the oxygen-glucose deprivation model. Conclusions— n-3 PUFAs robustly protect against H/I-induced brain damage in neonates by activating Akt prosurvival pathway in compromised neurons. In addition, n-3 PUFAs promote the formation of membrane phosphatidylserine, thereby promoting Akt activity and improving cellular survival.

Docosahexaenoic Acid Rescues Synaptogenesis Impairment and Long-Term Memory Deficits Caused by Postnatal Multiple Sevoflurane Exposures

“…DHA deficits may hamper neurite growth for neural development [14] and decrease soma size of hippocampus neuron and number of synaptic vesicles after learning task [15, 16]. We showed that DHA supplementation could reverse sevoflurane-induced synaptic injuries and improve the memory performance in the adulthood, which were consistent with other studies showing neuroprotective effects of DHA [17, 18]. …”

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

“…How exactly n-3 PUFAs modulate microglial responses remains largely unknown, although recent studies suggest a role of DHA-containing lipid bodies and their functional interplay with mitochondria [54, 55]. We have previously found that n-3 PUFAs enhance Akt signaling after hypoxia/ischemic brain injury [56]. While Akt is known to exert anti-inflammatory effects on microglia and macrophages [14], it remains to be determined whether n-3 PUFAs induce M2 polarization after stroke.…”

Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase‐3β‐mediated activation of autophagy

“…The samples were dehydrated and embedded in araldite and then sectioned (80 nm), counterstained with uranylacetate and lead citrate and autophagosomes were detected with a TEM. Images were acquired digitally from a randomly selected pool of 10 to 15 fields under each condition (Eskelinen, Reggiori, Baba, Kovacs, & Seglen, 2011). 2.9 | Primary cultured rat cortical neurons culture Primary rat cortical neurons were prepared from newborn SD rats as described previously (Zhang et al, 2015). In brief, the primary cortical neurons were seeded at 1 × 10 5 Áml −1 on 96-well plates or 24-well plates with poly L-lysine-coated and resuspended in DMEM/F12 which contains 10% FBS and 2% B27 supplement and then maintained in a humidified incubator (37 C, 5% CO 2 ) for 10 days.…”