Brain Connections in Alzheimer's Rebuilt with New Peptide

-> Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Pro-Cognitive/Anti-Dementia Agents

Which says Dihexa is derived from Angiotensin IV.

From (2004) Angiotensin IV receptor:
Three hypotheses for the memory-potentiating effects of the AT(4) receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed:
(i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides;
(ii) they may modulate glucose uptake by modulating trafficking of GLUT4;
(iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.

(2006) AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-D-aspartate dependent form of long-term potentiation
___"…suggesting that AT4 receptor activation increases intracellular calcium levels via altering voltage dependent calcium channels and triggers an N-methyl-D-aspartate-independent form of long-term potentiation."

(2011) Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle1-Angiotensin IV Analogs

(2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents
^ this paper puts dihexa through its paces, along with a couple of other similar molecules.
Discussion Although not the focus of this study, an obvious question relates to the identity of the molecular target responsible for the procognitive and synaptogenic activity of dihexa and other AngIV-related compounds. Hints to the answer to this question can be found in four recent articles (Yamamoto et al., 2010; 2012; Kawas et al., 2011; Wright et al., 2012), which clearly demonstrate that both the peripheral and central nervous system actions of AT4 receptor antagonists depend on their ability to inhibit the hepatocyte growth factor (HGF)/c-Met (HGF receptor) system by binding to and blocking HGF activation. Conversely, we (C. C. Benoist, Kawas LH, and Harding, JW, unpublished data) have recently demonstrated that both Nle1-AngIV and dihexa bind HGF, leading to its activation, and that the procognitive and/or synaptogenic actions of these compounds are blocked by both HGF and c-Met antagonists. With this knowledge in hand, a library of N-acyl-Tyr-Ile-(6) amino-hexanoic amide analogs was screened for their capacity to potentiate the biologic activity of HGF. This screen identified the hexanoic N-terminal substituent as the most active compound.

So, AT4 antagonists inhibit HGF/c-Met (HGF receptor) system by binding to HGF and blocking HGF activation.
dihexa (and Nle1-AngIV but who cares) are AT4 agonists so they both bind & activate HGF/c-Met
but HGF/c-Met antagonists can still block Dihexa

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