pseudoginsenoside-f11 and Ischemic-Attack--Transient

The polarization of microglia/macrophages after cerebral ischemia is critical for post-stroke damage/recovery. Previously, we found that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, has neuroprotective effects on permanent and transient cerebral ischemia in rats. This study aimed to investigate the effects and potential mechanisms of PF11 on microglia/macrophage polarization following transient cerebral ischemia in rats. In vivo data showed that oral administration of PF11 (12 mg/kg) significantly attenuated cognitive deficits and sensorimotor dysfunction, infarct volume and brain edema in transient middle cerebral artery occlusion (tMCAO)-treated rats, as well as reduced the loss of neurons and the over-activation of microglia in penumbra of ipsilateral striatum and cortex. Notably, the proportion of M2 microglia/macrophages in the total activated microglia/macrophages peaked on day 14 after tMCAO in rats, while PF11 promoted its peak advancing to day 3 post-tMCAO, which allowing the damaged brain to enter the repair period more quickly. Furthermore, PF11 increased the expression of anti-inflammatory markers and decreased the expression of pro-inflammatory markers in ipsilateral striatum and cortex. In addition, in vitro data showed that PF11 inhibited the induction of M1 microglia by oxygen glucose deprivation/re-oxygenation (OGD/R)-induced neurons, and promoted the polarization of microglia to M2 phenotype in a Jumonji domain-containing protein 3 (Jmjd3)-dependent manner. Moreover, PF11 promoted the protection of M2 microglia and attenuated the exacerbation of M1 microglia on OGD/R-induced neuronal damage. Taken together, these results indicate that PF11 protects ischemic neurons by promoting M2 microglia/macrophage polarization in a Jmjd3-dependent manner, ultimately facilitating the functional recovery following transient cerebral ischemia.

Topics: Animals; Brain; Cell Hypoxia; Cells, Cultured; Cytokines; Ginsenosides; Glucose; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Jumonji Domain-Containing Histone Demethylases; Macrophages; Male; Microglia; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley

Stroke is the leading cause of long-term motor disability and cognitive impairment beside the acute brain injury. Recently, neurogenesis has become an attractive strategy for the chronic recovery of stroke. Our previous study showed that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, isolated from leaves of Panax pseudoginseng subsp., exerted neuroprotective effects on stroke by alleviating autophagy/lysosomal defects and repressing calcium overload. The present study investigated whether PF11 improved long-term functional recovery and promoted neurogenesis after ischemic stroke induced by transient middle cerebral artery occlusion (tMCAO) in mice. The data showed that PF11 (16, 32 mg/kg, p.o.) administrated once daily one week before tMCAO significantly reduced brain infarction and brain edema on day 3 after tMCAO. Also, PF11 attenuated the mortality, sensorimotor dysfunction, cognitive impairment and hippocampal atrophy of stroke mice. Moreover, the migration of neuroblasts and the generation of newborn neurons in ipsilateral striatum and dentate gyrus (DG) were significantly enhanced by PF11. In line with this, PF11 prevented the decreased survival rate of newborn neurons on day 42 after tMCAO. In addition, PF11 promoted proliferation and differentiation of neural stem cells in vitro. Furthermore, PF11's pro-neurogenic effect was attributed to its activation of the BDNF/TrkB, which was evidenced by that the pharmacological effects of PF11 was abolished by ANA-12, a specific inhibitor of BDNF receptor. Thus, the present study showed that PF11 could improve long-term neurological impairment and promote neurogenesis after stroke possibly through activating BDNF/TrkB pathway, indicating its potential role on treating ischemic stroke, especially chronic recovery.

Topics: Animals; Cell Differentiation; Ginsenosides; Ischemic Attack, Transient; Male; Mice, Inbred C57BL; Mice, Knockout; Motor Disorders; Neural Stem Cells; Neurogenesis; Neurons; Neuroprotective Agents; Recovery of Function

Calcium overload has been reported to trigger neuronal death following stroke. Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside with various neuroprotective activities, has displayed therapeutic efficacy against permanent ischemic stroke. The present study examined the protective potential of PF11 in rats subjected to 2-h transient middle cerebral artery occlusion (tMCAO) and in cultured primary cortical neuron (PCN) exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). Single intravenous administration of PF11 (12 mg/kg) significantly reduced infarct volume, brain edema, neurological deficit and cortex neuron loss at 24 h after reperfusion. Immunoblotting and immunofluorescence demonstrated that PF11 inhibited the over activation of μ-Calpain and the reduction of calcium calmodulin kinase II-α, reduced the degradation of sarcoplasmic/endoplasmic reticulum ATPase-2 and alleviated endoplasmic reticulum stress (ERS) in tMCAO rats. What's more, rats treated with PF11 (12 mg/kg) intravenously immediately after reperfusion, and then intraperitoneally every 24 h for 14 days exhibited lessened cortex neuron loss, reduced mortality and improved performances of rotarod, grip strength and gait patterns at 1, 4, 7, and 14 days after tMCAO. Furthermore, in vitro investigations showed PF11 increased cell viability, reduced neurites decline, restored ATP level and decreased calcium content in cultured PCN under OGD/R. Moreover, PF11 alleviated ERS, reversed the diminished levels of NMDA-2B subunit, postsynaptic density protein 95 and neuronal nitric oxide synthase both in vivo and in vitro. Our study indicates that PF11 produced neuroprotection and improved long-term outcomes while repressing calcium overload in model of transient focal ischemia, suggesting that PF11 might be a considerable candidate for stroke treatment.

Topics: Animals; Brain; Brain Edema; Calcium; Cell Death; Disease Models, Animal; Ginsenosides; Ischemic Attack, Transient; Neurons; Neuroprotective Agents; Rats