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Ginsenoside Rg1 Attenuated Oligomeric Beta-amyloid 1-42 Mediated Neurotoxicity by Inhibiting Neuronal Stress

Author: HuangTianWen
Tutor: ChenXiaoChun
School: Fujian Medical
Course: Neurology
Keywords: ginsenoside Rg1 oligomeric Aβ1-42 JNK/p38 SAPK mitochondria oxidative stress cAMP/PKA/CREB signaling pathway
CLC: R749.1
Type: PhD thesis
Year: 2007
Downloads: 313
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Alzheimer’s disease(AD) is a progressive neurodegenerative disorder that is characterized by its typical clinical sympotoms, like memory impairment and change in personality. Accumulating evidence points to a crucial role of the overproduction and accumulation of beta-amyloid peptide as a trigger of the pathological cascade of AD. The mechanisms involved in the Aβ-mediated neurotoxicity are still unclear, but there is evidence suggesting that oxidative stress and mitochondrial dysfunction play an important role in its neurotoxical processes. And the disorder of cAMP/PKA/CREB signaling pathway for the consolidation of LTP is another Aβ-mediated neurotoxicity.Therefore, inhibition the neuronal stress (including inhibition the stress-activated protein kinaseJNK/p38, improving the mitchondrial function) and enhance the cAMP/PKA/CREB signaling pathway have potential for the treatment of AD. Ginsenoside is a Chinese traditional medicine for over 2000 years. It has lots of pharmacological functions, including both nootropic and anti-aging effects. And it has a great potential value for treatment of AD. Rg1 is one of the representative constituents of ginsenoside.Thus the present study included three sections, aimed at investigating the neurotoxicity of oligomeric Aβ1-42 and exploring the molecular mechanisms of Aβ1-42-induced apoptosis,protective effect of ginsenoside Rg1 on neuronal stress and cAMP/PKA/CREB signaling pathway. Primary cultures of cortical neurons were prepared from the embryonic day 15-16 C57BL/6 mouse. The neurons were treated with Rg1 and/or Aβ1-42 at different concentration in different time. The results were showed as follows:In the Part One, the TUNEL positive number and caspase-3 activity was increased significantly in cortical neurons treated with oligomeric Aβ1-42 at 5.0μM concentration for 48 h. However, ginsenoside Rg1 partly decreased the elevation of TUNEL positive number and caspase-3 activity induced by oligomerical Aβ1-42.In the Part Two, ginsenoside Rg1 has protective effect on oligomeric Aβ1-42-induced neuronal stress. (1) The p-p38/p38 SAPK got the highest level in cortical neurons treated with Aβ1-42 at 5.0μM concentration for 5 min. And the p-JNK/JNK SAPK reach the highest level in neuron treated with Aβ1-42 at 5.0μM concentration for 15 min. But ginsenoside Rg1 could decrease the elevation of p-p38/p38 SAPK and p-JNK/JNK SAPK. (2) Ginsenoside Rg1 protected mitochondria from damage induced by oligomeric Aβ1-42 at 5.0μM concentration for 24 h and/or 48 h: Ginsenoside Rg1 decreased the elevation of ROS, H2O2 and NO induced by oligomeric Aβ1-42; Ginsenoside Rg1 attentuated decreasing of neuronal mitochondrial membrane potential, the ATP level, the complexⅣactivity and attentuated the cytochrome c releasing induced by oligomeric Aβ1-42.In the Part Three, ginsenoside Rg1 has protective effect on oligomeric Aβ1-42 inhibiting the cAMP/PKA/CREB signaling pathway. The p-CREB/CREB was decreased obviously by oligomeric Aβ1-42 at 5.0μM concentration for 2 h. Meanwhile, PKA activity was significantly inhibited and the level of PKAⅡαsignificantly increased. However, ginsenoside Rg1 reversed the change of p-CREB/CREB, PKA activity and PKAⅡαinduced by oligomeric Aβ1-42.To summarize, ginsenoside Rg1 inhibited the neuronal stress , protected mitochondria from damage and the apoptotic cell death induced by oligomeric Aβ1-42; Enhancing the cAMP/PKA/CREB signaling pathway may be benefit to the formation of LTP and impove learing and memory’s acquisition.

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