Gracilin A Derivatives Target Early Events in Alzheimer's Disease: in Vitro Effects on Neuroinflammation and Oxidative Stress.
Rebeca AlvariñoEva AlonsoMikail E AbbasovChristian M ChaheineMichael L ConnerDaniel RomoAmparo AlfonsoLuis M BotanaPublished in: ACS chemical neuroscience (2019)
The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives 1-7 which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes (CAT, GPx, SODs, and Nrf2) was determined in SH-SY5Y cells, and the simplified derivatives 2 and 3 were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.
Keyphrases
- oxidative stress
- induced apoptosis
- lps induced
- structure activity relationship
- lipopolysaccharide induced
- inflammatory response
- rheumatoid arthritis
- anti inflammatory
- ischemia reperfusion injury
- diabetic rats
- cognitive decline
- immune response
- risk assessment
- poor prognosis
- cell proliferation
- cancer therapy
- mild cognitive impairment
- cerebral ischemia
- subarachnoid hemorrhage