Disruption of zinc and copper interactions with Aβ(1–40) by a non-toxic, isoniazid-derived, hydrazone: a novel biometal homeostasis restoring agent in Alzheimer's disease therapy?

Abstract

Disruptions of biometal-Aβ(1-40) interactions by an isoniazid-derived hydrazone, INHHQ, were demonstrated via in vitro NMR titrations. The compound has adequate theoretical BBB absorption properties, assessed by in silico studies. In vivo acute toxicity assays indicate that INHHQ is innocuous up to 300 mg kg(-1), showing potential as an anti-Alzheimer's drug.

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…In vitro , removal of Cu 2+ from Aβ prevents its accumulation [ 243 , 244 , 245 ], leads to its degradation, stops hydroxyl radical (•OH) production and oxidative damage, and finally reduces cell death [ 245 ]. For the effects as mentioned above, researches have suggested potential metal chelation therapy for AD [ 246 , 247 , 248 , 249 , 250 , 251 , 252 ]. Nevertheless, the challenge is to build selective and specific metal chelators, as metal ions play crucial roles in Alzheimer’s brains.…”

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

“…Hence, it also decreases cell mortality ( Wu et al, 2008 ). Because of these positive effects of copper elimination, some studies have targeted copper chelators as suitable drugs ( Moret et al, 2006 ; Geng et al, 2012 ; Nguyen et al, 2014 ; Savelieff et al, 2014 ; Hauser-Davis et al, 2015 ; Hung et al, 2015 ; Yang et al, 2016 ). However, the most recently published review on copper chelation therapy states that the results in human clinical trials are discouraging ( Drew, 2017 ), even though some authors have refuted this interpretation ( Squitti et al, 2017a ).…”

Activity Evaluation and Toxicological Profile of New Potential Metal Protein Attenuating Compounds in Biological Models of Alzheimer S Disease

“…Figure 30 reports the free peptide bidimensional contour plot profile (in black), and the change in that profile observed when one equivalent of Cu 2+ is added (in blue). As previously reported (Mekmouche et al, 2005;Hauser-Davis et al, 2015), the spectral changes due to the divalent metals' addition into Aβ samples were centered on histidine residues (His6, His13, and His14), indicating their direct involvement as metal coordinating sites. This causes peak broadenings and losses in signals intensities.…”

“…Chelating ligands such as EDTA lead to a complete signal intensity recovery with the addition of only one equivalent (Hauser-Davis et al, 2015). Instead of this, five equivalents of INHHQ were necessary to obtain the highest possible recovery (grey bars), which, for some residues, does not represent the complete recovery of the signal.…”

“…Figure 31A shows the free peptide bidimensional contour plot profile (in black), and the profile changes when one equivalent of Cu 2+ was added (in blue). Figure 31B it is plotted the obtained profile of the system when five equivalents of INHHQ were added to the solution (grey), evidencing the complete overlap of this plot with the free Aβ one (black) (Hauser-Davis et al, 2015). The recovery profile derived from the treatment of HSQC data is reported as the I/I 0 intensity ratio for each Aβ residue by means of bar graphs.…”