Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest
Background: Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling.
Methods: Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis.
Results: Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np.
Conclusions: T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.
Brian R Weil
Shannon E Allen
Thomas Barbaccia
Kimberly Wong
Abigail M Beaver
Elizabeth A Slabinski
Jeffrey G Mellott
Peter C Taylor Dickinson
Shaker A Mousa
Resuscitation
. 2023 Feb 16;109735. doi: 10.1016/j.resuscitation.2023.109735. Online ahead of print.
2023
English
INSITU HYBRIDIZATION STUDY OF OBESITY-ASSOCIATED ALTERATION IN GROWTH-HORMONE MESSENGER-RNA LEVELS
differentiation; Endocrinology & Metabolism; expression; fetal-rat; gene-transcription; glucocorticoid hormones; growth hormone; insitu hybridization; insulin; lean zucker rats; messenger-rna; Nutrition & Dietetics; pituitary-tumor cells; ribonucleic-acid; triiodothyronine
In order to investigate whether the impaired GH secretion associated with obesity is due to a pituitary disorder we studied GH mRNA levels by in situ hybridization in genetically obese and lean Zucker rats. The levels of GH mRNA were at least two fold lower in obese rats in comparison to that in lean controls as quantified by both the scanning of autoradiographs of tissue sections and Northern blot analysis. Quantification of somatotrophs revealed no significant difference in their number between lean and obese rat pituitaries. It is therefore likely that the attenuated GH mRNA levels in genetically obese Zucker rats are due to a decrease in GH transcripts per somatotroph rather than a result of a pituitary defect involving a preferential decrease in somatotroph population.
Ahmad I; Steggles A W; Finkelstein J A
International Journal of Obesity
1992
1992-06
Journal Article or Conference Abstract Publication
n/a