A Systematic Review of Mechanisms, Pharmacokinetics, and Structure-Activity Relationships of Small Molecule Terpenoids in Alzheimer's and Parkinson's Disease

Abstract

The neuroprotective potential of small molecule terpenoids in Alzheimer's disease (AD) and Parkinson's disease (PD), addressing the critical gap between abundant preclinical evidence and limited clinical translation. Our central hypothesis posits that terpenoids act as multi-target agents, simultaneously modulating oxidative stress, neuroinflammation, apoptosis, and protein aggregation. Thematic synthesis identified shared versus disease-specific pathway signatures. Our results demonstrate that monoterpenoids, particularly hydrocarbon-rich molecules such as alpha-pinene and limonene, exhibit the highest BBB permeability, driven by low molecular weight, low polar surface area, and high logP. Diterpenoids and triterpenoids show more variable CNS penetration; for example, ginkgolide B achieves in vivo BBB entry, while ursolic acid and celastrol display broad neuroprotective effects despite limited passive diffusion. Multi-omics analysis of Danggui Buxue Tang in APP/PS1 mice revealed suppression of TNF/NF-kappaB and MAPK signaling. In PD models, andrographolide suppresses NLRP3 inflammasome activation via parkin-mediated mitophagy and promotes HSF1/NRF2-mediated autophagy to clear alpha-synuclein. Gut-brain axis evidence from schisandrin studies in AD rats showed that oral dosing altered gut microbiota and modulated 44, 96, and 40 biomarkers in plasma, brain, and feces, respectively. The SAR matrix indicates that tetramethylpyrazine hybrids with increased lipophilicity markedly improve neuroprotective efficacy and BBB permeability. The most promising optimization strategy combines lipophilicity tuning with minimal steric and polar burden while retaining key pharmacophores. Our findings highlight that monoterpene hydrocarbons offer the most favorable BBB permeability, whereas triterpenoids provide the broadest multi-target activity, though clinical translation remains limited by pharmacokinetic liabilities.