Alfadolone acetate

The aim of this study was to investigate the effect of micro ribonucleic acid (miR)-140 on rats with myocardial ischemia-reperfusion injury (MIRI) through regulating the nuclear factor-κB (NF-κB) pathway.

A total of 36 Sprague-Dawley rats were randomly divided into three groups, including sham group (n=12), model group (n=12) and miR-140 mimics group (n=12). In sham group, only thoracotomy was performed without ischemia-reperfusion. In model group, the MIRI model was first established, followed by intervention using normal saline. In miR-140 mimics group, the MIRI model was first established as well, followed by intervention using miR-140 mimics. The content of serum creatine kinase (CK) and lactate dehydrogenase (LDH) was detected, and the morphology of myocardial tissues was observed via hematoxylin-eosin (HE) staining. Meanwhile, the relative protein expression of NF-κB was determined using Western blotting. Quantitative polymerase chain reaction (qPCR) was conducted to evaluate the expression of miR-140. The content of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) was determined via enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay.

The content of serum CK and LDH rose significantly in model group and miR-140 mimics group when compared with sham group (p<0.05). However, it declined significantly in miR-140 mimics group compared with model group (p<0.05). HE staining results showed that there were no obvious abnormalities in the morphology of myocardial tissues in sham group. However, there were injury and inflammatory infiltration in myocardial tissues in model group. Meanwhile, the structure and morphology of myocardial tissues were improved in miR-140 mimics group compared with those in model group. Western blotting revealed that the relative protein expression of NF-κB was evidently higher in model group and miR-140 mimics group than sham group (p<0.05). However, it was remarkably lower in miR-140 mimics group than that in model group (p<0.05). QPCR results demonstrated that the relative expression of miR-140 in model group and miR-140 mimics group was obviously lower than sham group (p<0.05). However, a markedly higher expression of miR-140 was observed in miR-140 mimics group than model group (p<0.05). ELISA results indicated that model group and miR-140 mimics group had remarkably higher content of IL-1β and TNF-α than sham group (p<0.05). However, miR-140 mimics group had remarkably lower content of IL-1β and TNF-α than model group (p<0.05). TUNEL assay indicated that the apoptosis rate increased obviously in model group and miR-140 mimics group compared with sham group (p<0.05). However, it declined significantly in miR-140 mimics group compared with model group (p<0.05).

MiR-140 suppresses inflammation and apoptosis in myocardial tissues of MIRI rats through inhibiting the NF-κB signaling pathway, thereby exerting a cardioprotective effect.

The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid–mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents.

Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose–response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16).

As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls).

Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action.