Neuropeptidase

Neuropeptidases are the proteases that inactivate peptide transmitters once they have been released. The group includes neprilysin, angiotensin-converting enzyme, insulin-degrading enzyme, prolyl endopeptidase and membrane aminopeptidases on neuronal and glial surfaces. Unlike classical transmitters, neuropeptides are not recovered by reuptake transporters; degradation is the only off switch, which is why signalling stops within seconds to minutes of release and why local enzyme density shapes the effective range of a peptide signal.

Neprilysin is the clearest worked example. It degrades enkephalins, substance P, natriuretic peptides and amyloid-beta, and it is the target of sacubitril, the neprilysin inhibitor combined with valsartan in an approved heart failure therapy. That combination came with explicit scrutiny of whether systemic neprilysin inhibition might raise brain amyloid, which is exactly the kind of question the enzyme's substrate breadth forces. D-amino acid substitution, terminal capping and cyclisation are the standard structural answers to peptidase attack.

For anyone reading a peptide's data, the practical consequence is that plasma stability and central stability are separate properties. A molecule engineered to resist dipeptidyl peptidase-4 in blood may still be cleaved rapidly once it reaches cerebrospinal fluid or brain interstitium, where a different enzyme complement operates. Delivery route does not rescue this: material entering by the olfactory route meets peptidases in the nasal mucosa first.

The recurring misreading is a serum stability figure presented as a duration of central action. Serum assays use one species and one enzyme mix, and say nothing about the brain. Rodent values are quoted more often than human ones, and rodent peptidase profiles differ.