Exploring Neuroprotection By Fagaramide And The Cannabinoid Arvanil

  • Alaa Al-Hindawi

Student thesis: Doctoral Thesis


Neuroinflammation is among the common pathophysiological process involved in neurodegenerative diseases' onset and progression. Several pharmacologically active compounds have been revealed to possess anti-neuroinflammatory and neuroprotection activities and thus attenuate disease progression. This research was designed to evaluate the neuroprotection activity of two distinct potential compounds, fagaramide and arvanil, on LPS- stimulated BV2 microglia and H2O2- induced SH-SY5Y neurotoxicity. BV2 microglia were treated with arvanil (0.1, 0.25 and 0.5 μM) or fagaramide (5, 10 and 20 μM) and then stimulated with LPS (100 ng/ml). The results revealed that both arvanil and fagaramide could significantly reduce the levels of the pro-inflammatory cytokines (TNF-α and IL-6). In addition, the protein expression of iNOS and COX-2 with their related mediators, NO and PGE2, respectively, were attenuated significantly when LPS-activated BV2 cells and pre-treated with arvanil and fagaramide. For further investigation on the molecular mechanisms behind the anti-neuroinflammatory activities of arvanil and fagaramide, their modulated effects on the inflammatory signalling pathways have been examined. The results demonstrated that both compounds exerted their anti-neuroinflammatory effects independent of NF-B, MAPKs and Akt signalling pathways in LPS-activated BV2 microglia. Furthermore, the activities of arvanil and fagaramide were not mediated by the activation of the Nrf2/HO-1/NQO1 antioxidant axis in BV2 microglia. The anti-neuroinflammatory activity of arvanil in LPS-stimulated microglia was not possibly mediated through binding to CB1, CB2 and TRPV1 receptors. Furthermore, results from the activity of arvanil and fagaramide on H2O2-induced apoptosis suggested that both compounds could not attenuate the neurotoxicity in differentiated SH-SY5Y neuroblastoma cells, which was induced by H2O2. Collectively, arvanil and fagaramide inhibited neuroinflammation independently from the modulation of NF-B, MAPKs and Akt signalling pathways. The anti-neuroinflammatory activities of arvanil and fagaramide were not mediated by the upregulation of the Nrf2 pathway. Arvanil and fagaramide did not protect the SH-SY5Y neuroblastoma cells from the neurotoxicity of H2O2, suggesting that arvanil and fagaramide activities might be achieved by inhibiting neuroinflammation without reversing neurotoxicity.
Date of Award9 Jan 2023
Original languageEnglish
SupervisorOlumayokun Olajide (Main Supervisor) & Karl Hemming (Co-Supervisor)

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