From Self-Assembly to Survival: Neuropeptide Precursor Biology in Neuroprotection

Neuropeptides (NPs) are central regulators of neuronal communication, homeostasis, and adaptive responses to stress. Beyond their well-established roles in modulating behaviour, metabolism, and circadian rhythms, NPs exert potent neuroprotective effects in acute neurological disorders, including ischemic stroke, traumatic brain injury, epilepsy, and neuroinflammatory insults. These protective actions encompass suppression of neuroinflammation, attenuation of excitotoxicity, preservation of mitochondrial integrity, and promotion of neuronal survival and plasticity. However, the efficacy and spatial precision of NP signalling critically depend on the biology of their precursors (NPPs), which are increasingly recognised as active regulators rather than inert biosynthetic intermediates. In this review, we synthesise emerging evidence that NPPs self-assemble and condense within dense-core secretory vesicles through tightly regulated, liquid-liquid phase separation (LLPS)-like mechanisms governed by pH, Ca2+, lipid composition, and intrinsic sequence features. This regulated condensation facilitates selective cargo sorting, efficient proteolytic processing, and controlled release of mature NPs. Importantly, we contrast this physiological, reversible self-assembly with the pathological protein aggregation characteristic of neurodegenerative disease, highlighting how dysregulation of NPP condensation and processing may contribute to impaired neuroprotective signalling in acute and chronic neurological disorders. We further review how key neuroprotective NPs, including α-melanocyte-stimulating hormone (α-MSH), galanin, orexins, neuropeptide Y (NPY), neuropeptide S (NPS), nesfatin-1, and adrenocorticotropic hormone (ACTH)-derived peptides, mitigate acute neuronal injury by modulating microglial activation, inflammatory cytokine production, excitatory-inhibitory balance, and apoptotic pathways. Finally, we discuss therapeutic strategies that leverage NPP and NP biology, including stabilisation of precursor processing, modulation of vesicular environments, and development of peptide analogues and peptidomimetics. By reframing NPPs as upstream determinants of neuroprotective peptide availability, this review highlights new conceptual and translational avenues for innovative neuroprotective therapies in acute neurological disorders.