Psychiatric Indications, page-13

Thanks for the references @hottod - this recent review by Guan is also quite good (Neuren even gets a mention!), section 3 in particular is a good summary of the mode of action of cGP.

https://www.mdpi.com/1420-3049/28/3/1021

I think the subtlety here is that cGP can indeed up and down regulate IGF-1 activity as part of normal homeostasis, but it is dependent on the molar ratio of cGP/IGF-1 –

“The different effects of cGP on endothelial cell survival/growth are dependent on its concentration relative to that of IGF-1, in which a higher cGP/IGF-1 molar ratio leads to a stimulatory effect, whereas a lower cGP/IGF-1 ratio results in an inhibitory effect.”

This is mediated by competitive binding of cGP and IGF-1 to the IGF binding protein IGFBP-3 as shown in the summary diagram from one of Jon’s slides


Given that a low cGP ratio is required to obtain an inhibitory effect, Guan concludes

“In general, the clinical relevance of cGP is in those conditions associated with IGF-1 deficiency…”

So my interpretation remains that NNZ-2591 is unlikely to be useful in CNS indications where the aim is to reduce IGF-1 activity but, tbh, endocrinology is not really my area so happy to stand corrected!

Finally, I note that although IGF-1 levels are elevated in both MDD and schizophrenia, this is not necessarily seen as a negative but rather a response to the diseases. It is questionable, however, whether NNZ-2591 would provide any significant additional benefit as the disease pathophysiology is quite different to neurodevelopmental disorders.