Natural Products and Neuroregeneration: Rethinking Discovery Beyond Bioavailability Through Pseudo-Natural Product...

Natural product (NP)-based neuroregeneration research has generated extensive preclinical evidence over the past five decades. Pharmacological activity across core processes of central nervous system (CNS) repair including neurogenesis, axonal regeneration, and neuroplasticity have been documented. Despite consistent observations of neurite outgrowth, neuroprotection, and partial functional recovery in cellular and animal models, translation into durable clinical therapies has remained limited. Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) similarly exhibit strong regenerative effects in experimental systems, but even direct central administration has failed to produce sustained long-distance axonal regeneration or stable circuit reconstruction. This suggests that delivery constraints alone do not explain the failure to achieve clinically-relevant functional repair. It is proposed herein that this limitation reflects intrinsic constraints in how regenerative signalling is organised across multiple biological scales. Integrating evidence from in vitro and in vivo injury models, we can introduce a Target-Mechanism-Network (T-M-N) approach that systematically maps NPs activity onto a hierarchical regulatory architecture. Across diverse NPs classes, ~55 recurrent molecular targets cluster into 10 functional mechanisms, which converge into four higher-order network control regimes governing energetic competence, regenerative signalling capacity, redox-immune balance, and structural plasticity. This analysis reveals that NPs converge on shared regenerative networks but rarely coordinate all required domains within a unified pharmacological programme. They can thus be seen to represent a pre-organised source of evolutionarily selected pharmacophores encoding discrete elements of neuroregenerative network control. On this basis, pseudo-natural product (PNP) design enabled by computational chemistry and phenotypic screening may provide a strategy to recombine these fragments into engineered scaffolds with improved functional selectivity and regenerative coherence. The need to shift drug discovery from optimisation of individual NPs toward architecture-driven design of multi-functional molecules that address the integrated demands of neuroregeneration is discussed.