PubMed · 15852072
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Lars Slørdal, Olav Spigset. 2005-04-21. [Basic pharmacokinetics--distribution].. https://pubmed.ncbi.nlm.nih.gov/15852072/
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Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.
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Quantitative Structure-Property Relationship models (QSPR) based on in vivo blood-brain permeation data (logBB) of 88 diverse compounds, 324 descriptors and a systematic variable selection method, namely 'Variable Selection and Modeling method based on the prediction (VSMP)', are reported. Of all the models developed using VSMP, the best three-descriptors model is based on Atomic type E-state index (SsssN), AlogP98 and Van der Waal's surface area (r=0.8425, q=0.8239, F=68.49 and SE=0.4165); the best four-descriptors model is based on Kappa shape index of order 1, Atomic type E-state index (SsssN), Atomic level based AI topological descriptor (AIssssC) and AlogP98 (r=0.8638, q=0.8472, F=60.982 and SE=0.3919). The performance of the models on three test sets taken from the literature is illustrated and compared with the results from other reported computational approaches. Test set III constitutes 91 compounds from the literature with known qualitative BBB indication and is used for virtual screening studies. The success rate of the reported models is 82% in the case of BBB+ compounds and a similar success rate is observed with BBB- compounds. Finally, as the models reported herein are based on computed properties, they appear as a valuable tool in virtual screening, where selection and prioritization of candidates is required.