Stargazin Interaction With Serine Racemase Mediates Cerebral Ischemia/Reperfusion Injury in Rats

D-Serine is thought to be involved in N-methyl-D-aspartate (NMDA)-type glutamate receptor-mediated neurotoxicity and plays a pathophysiologic role in stroke. D-Serine is synthesized by serine racemase (SR), which directly converts L-serine into D-serine. The deletion of SR has been reported to protect against cerebral ischemia damage. Additionally, SR catalytic activity is physiologically regulated by its binding to stargazin. However, whether the stargazin-SR interaction affects the level of stroke damage remains elusive. We showed that cerebral ischemia increased the interaction of stargazin and SR and decreased the levels of D-serine. Disrupting the stargazin-SR interaction by knocking down stargazin aggravated cerebral ischemic insults. We found that cerebral ischemia decreased the phosphorylation of stargazin at the Thr-321 residue, which was phosphorylated by cAMP-dependent protein kinase A (PKA). Treatment with the PKA inhibitor H89 blocked stargazin T321 phosphorylation, augmented the stargazin-SR interaction, decreased D-serine levels, and alleviated focal cerebral ischemic damage in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Thus, the stargazin-SR interaction is a promising strategy in the treatment of stroke.

Abstract TP115: Nrf2 Plays an Essential Role in Long-Term Neuroprotection of Ginseng in Permanent Cerebral Ischemia

Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation; therefore, it represents a promising target for stroke intervention. The natural potential Nrf2-inducer ginseng, extracted from the root of Panax ginseng C.A.Meyer, has been widely used in East Asia for thousands of years, exhibiting potent anti-inflammatory and antioxidative properties. However, the long-term effects of Nrf2 and the standardized Korean red ginseng extract (ginseng) on permanent cerebral ischemic damage have not yet been reported. Methods: Wildtype (WT) and Nrf2 –/– adult mice were treated with either vehicle (water) or ginseng for 7 days and subjected to the permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrogliosis and microgliosis, and water regulatory protein aquaporin 4 (AQP4) were examined 28 days after the initiation of stroke. Data acquisition and analyses were performed by an observer blinded to the treatment. Results: When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume by 40.4±10.1% (n=7 per group; p<0.05), increased levels of reactive gliosis and AQP4 protein after pdMCAO. Interestingly, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3±6.9%, n=12; p<0.01), but not in the Nrf2 -/- mice (25.5±5.6%, n=11; p=0.241). Conclusion: Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and neuroprotection of ginseng.

A REVIEW ON β-ESCIN

β - escin is a mixture of triterpene saponins and other components including alpha aescin, progestoescigenin, barringtogenol, cryptoescin and benzyopyrones.Βaescin or β-escin isolated from the horse chestnut seeds (Aesculus hippocastanum L.) β-escin has been traditionally used to treat conditons such as chronic venous insufficiency, inflammation, hemorrhoids, edema, elevated glucose, obesity, and cerebral ischemic damage. The drug shows its property in clinical trail’s patient with HIV-1 used as a traditional medicines.

Nrf2 Plays an Essential Role in Long-Term Brain Damage and Neuroprotection of Korean Red Ginseng in a Permanent Cerebral Ischemia Model

Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation, and therefore represents a promising target for stroke intervention. However, the long-term effects of Nrf2 and the standardized Korean red ginseng (ginseng), a potent Nrf2 natural inducer, on permanent cerebral ischemic damage have not yet been reported. Wildtype (WT) and Nrf2-/- adult mice were pretreated with either vehicle or ginseng, and were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrocytes and microglia, and the water regulatory protein aquaporin 4 (AQP4) were examined at 28 days after stroke. When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume (40.4 ± 10.1%) and exacerbated the progression of reactive gliosis and AQP4 protein levels after pdMCAO. In contrast, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3 ± 6.9%), but not in the Nrf2-/- mice (25.5 ± 5.6%). In conclusion, Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and the neuroprotection of ginseng.