Hybrids of oxoisoaporphine–tetrahydroisoquinoline: novel multi-target inhibitors of inflammation and amyloid-β aggregation in Alzheimer’s disease

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

“…Both microglia and neuronal cultures treated with Aβ1-42 oligomers provide a widely accepted model of inflammation and neurodegeneration occurring in AD pathology [ 73 , 74 , 75 ]. Recently, the use of macrophages, in particular RAW 264.7 cells, to study the toxic effects of the aggregated form of Aβ as well as the therapeutic potential of antioxidants has been considered [ 47 , 76 ]. The interest in this type of study is also driven by the fact that, as previously mentioned, infiltrating macrophages have been shown to protect from Aβ toxicity by clearing this peptide from the brain through its uptake and subsequent degradation [ 20 , 21 ].…”

“…The key role of peripheral monocytes/macrophages in the pathophysiology of AD is also reinforced by a report that a defective ability of these cells to engulf Aβ is observed in AD patients [ 22 ]. Along this line, the ability of carnosine to modulate the activity of immune cells such as macrophages and microglia [ 36 , 49 , 75 , 76 ], including the enhancement of their antioxidant machinery [ 49 ] as well as the increased production of anti-inflammatory molecules such as TGF-β1 [ 36 ], could be highly relevant for drug development in AD.…”

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs – biological activities and SAR studies

“…Chen and co-workers designed a new series of oxoisoaporphine-tetrahydroisoquinoline analogs based on the concept of molecular hybridization as multi-target directed ligands (MTDLs) in AD. 91 Compound 219 exhibited the following properties: (i) strongly suppressed the production of NOinduced by LPS in BV-2 microglia and RAW 264. model. These results suggest that compound 219 may be a promising anti-Alzheimer agent that needs further exploration.…”

“…Chen and co-workers designed a new series of oxoisoaporphine–tetrahydroisoquinoline analogs based on the concept of molecular hybridization as multi-target directed ligands (MTDLs) in AD. 91 Compound 219 exhibited the following properties: (i) strongly suppressed the production of NO-induced by LPS in BV-2 microglia and RAW 264.7 macrophage (ii) compound 219 also suppressed the expression of iNOS in RAW 264.7 macrophage cells (iii) compound 219 was also shown to suppress the LPS-induced production of pro-inflammatory cytokines such as TNF-α and IL-β (iv) compound 219 was able to reduce Aβ 42 levels by 37.6% (v) exhibited potent inhibitory activity against AChE (IC 50 = 0.031 μM) and BChE (IC 50 = 0.51 μM) (vi) caused a significant delay in paralysis (due to Aβ1–42 toxicity) in C. elegans GMC101 in vivo model. These results suggest that compound 219 may be a promising anti-Alzheimer agent that needs further exploration.…”

Role of Withaferin A as a Neuroprotectant against Beta Amyloid Induced Toxicity and associated mechanism

“…Amyloid plaques, built of the Aβ protein, are the hallmark neuropathological features in the full-blown AD brain [134,222,223]. Aβ in addition to causing neuronal toxicity also plays a very crucial role in activating innate immune system and attracting microglial infiltration leading to induction of inflammation [224,225]. Aβ is considered as an inducer of microglial activation and neuroinflammation, and poses as an underlying factor in the In the alternative (or non-canonical) NF-κB pathway, NF-κB2(p100)/RelB complexes are inactive in the cytoplasm and activate IKKα that phosphorylate NF-κB2 p100 leading to its ubiquitination and proteasomal processing to NF-κB2 p52 which then translocates to the nucleus and induces target gene expression [228][229][230].…”