Melatonin improves neuroplasticity by upregulating the growth-associated protein 43 (GAP-43) and NMDAR-post-synaptic density-95 (PSD95) proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to transient focal cerebral ischemia even during a long-term recovery period

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http://onlinelibrary.wiley.com/doi/10.1111/jpi.12114/abstract

1. Wei-Sheng Juan^1,†,
2. Sheng-Yang Huang^1,†,
3. Che-Chao Chang¹,
4. Yu-Chang Hung¹,
5. Yu-Wen Lin¹,
6. Tsung-Ying Chen^1,2,
7. Ai-Hua Lee¹,
8. Ai-Chiang Lee¹,
9. Tian-Shung Wu^1,3,
10. E-Jian Lee^1,*

DOI: 10.1111/jpi.12114

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Journal of Pineal Research

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Keywords:

• Stroke;
• glutamate excitotoxicity;
• neuroplasticity;
• neuroprotection;
• melatonin

Abstract

Recent evidence shows that the NMDAR-post-synaptic density-95 (PSD95), growth-associated protein 43 (GAP-43) and matrix metalloproteinase-9 (MMP-9) protein enhance neuroplasticity at the subacute stage of stroke. Here, we evaluated whether melatonin would modulate the PSD95, GAP-43 and MMP-9 proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to experimental stroke. Adult male Sprague-Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Animals were euthanized for Western immunoblot analyses for the PSD-95 and GAP-43 proteins and gelatin zymography for the MMP-9 activity at 7-day post-insult. Another set of animals was sacrificed for histologic and Golgi-Cox-impregnated sections at 28 days post-insult. In cultured neurons exposed to glutamate excitotoxicity, melatonin significantly up-regulated the GAP-43 and PSD-95 expressions and improved dendritic aborizations (P < 0.05, respectively). Relative to controls, melatonin-treated stroke animals caused a significant improvement of GAP-43 and PSD-95 expressions as well as the MMP-9 activity in the ischemic brain (P < 0.05). Consequently, melatonin also significantly promoted the dendritic spine density and reduced infarction in the ischemic brain, and improved neurobehaviors as well at 28 days post-insult (P < 0.05, respectively). Together, melatonin upregulates GAP-43, PSD-95 and MMP-9 proteins, which likely accounts for its actions to improve neuroplasticity in cultured neurons exposed to glutamate excitotoxicity, and to enhance long-term neuroprotection, neuroplasticity and brain remodeling in stroke rats.