PubMed · 7457241
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J H Garcia, K A Conger, R Morawetz, J H Halsey. 1980. Postischemic brain edema: quantitation and evolution.. https://pubmed.ncbi.nlm.nih.gov/7457241/
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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.
It has been said that the selective permeability across the blood--brain barrier depends on several physicochemical properties of drugs such as hydrophobicity, molecular weight, and hydrogen-bonding potential. In order to investigate quantitatively the relationship between the blood--brain barrier permeability and the hydrophobicity of drugs, we have measured the micelle/water partition properties (Pmic) by the MLC (micellar liquid chromatography) method using a gel filtration version and compared with the blood--brain barrier permeability. The thermodynamic aspects of partition were derived by separating the micelle/water partition coefficient (log Pmic) into the enthalpy term PH and the entropy term PS. It was found that the PH shows a good correlation to the permeability, although log Pmic fails to do so. The result means that PH, which is easily obtained from the in vitro experiment, can be used as an excellent standard in discussing the transport phenomena through the blood--brain barrier.
Cysteamine (CySH), a thiol compound that crosses the blood-brain barrier, inhibited the proliferation of neural neoplastic cells in vitro. The IC50 of cysteamine with respect to inhibition after 72 h of drug exposure, was approximately 70 microM in the glioma cell line, 2607, and approximately 80 microM in the neuroblastoma cell line, DAOY. Interestingly, the inhibition of proliferation of 2607 cells produced by 72 h treatment with CySH could also be induced with exposure periods as short as 8 h. Another thiol bearing compound, penicillamine methyl ester, also arrested the proliferation of 2607 cells with IC50 approximately 160 microM. Cell cycle analysis revealed that CySH acted to lengthen the cell cycle period of 2607 cells by slowing the passage of cells through S phase and caused the cells to finally arrest in G2/M. In the other cell lines tested, CySH arrested cells in all phases of the cell cycle. These observations suggest that CySH and its congeners may have some utility in the treatment of neoplasia in vivo.