Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers.

BACKGROUND: Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an α2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression. METHODS: Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6-12 h, and its effects on metastasis formation, using various cancer types, were studied in naïve animals and in the context of stress and surgery. RESULTS: Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through α2-adrenergic, but not α1-adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors. CONCLUSIONS: The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.

Preventing Corneal Calcification Associated With Xylazine for Longitudinal Optical Coherence Tomography in Young Rodents.

Purpose: Spectral-domain optical coherence tomography (SD-OCT) is widely used in clinical ophthalmology and recently gained popularity in laboratory research involving small rodents. Its noninvasive nature allows repeated measurements, thereby decreasing the number of animals required. However, when used at a conventional dosage, xylazine (an α2-adrenoceptor) can cause irreversible corneal calcification, especially among young rodents. In the present study, we test whether corneal calcification associated with xylazine is mediated by the α2-adrenoceptor. Methods: Our study tested Sprague-Dawley rats, Long-Evans rats, and CD-1 mice (postnatal day [P]14). Retinal images were captured by SD-OCT. Quantitative PCR (qPCR) was used to study gene expression, whereas receptor localization was examined by immunofluorescent staining followed by confocal microscopy. Calcium deposits were detected via von Kossa staining. Results: When used at dosages appropriate for adult animals, ketamine-xylazine anesthetics led to a high rate of respiratory failure, increased apoptotic activity in the corneal epithelium, and irreversible corneal calcification in P14 rat pups. Meanwhile, OCT image quality decreased drastically as a result of corneal calcification among animals recovering from anesthesia. α2-Adrenoceptor subtypes were highly expressed on P14, in line with rodents' age-specific sensitivity to xylazine. Clonidine, a potent α2-adrenoceptor agonist, dose-dependently induced corneal calcification, which could be prevented by an α2-adrenoceptor antagonist. Conclusions: These data suggest that α2-adrenoceptors contribute to corneal calcification in young rodents. Therefore, we developed a suitable OCT imaging protocol for this cohort, including a carefully tailored ketamine-xylazine dosage (60 mg/kg and 2.5 kg/mg, respectively).

Effect of Brimonidine on the B Cells, T Cells, and Cytokines of the Ocular Surface and Aqueous Humor in Rat Eyes.

PURPOSE: One serious ocular side effect associated with the long-term use of topical brimonidine tartrate is anterior uveitis. This study investigated the changes in the levels of several inflammatory cytokines, B cells, and T cells in rat eyes treated with topical brimonidine tartrate. METHODS: Twenty Sprague-Dawley male rats were divided into 2 groups of 10 rats each. In the brimonidine group, rats were treated with brimonidine 3 times per day for 10 months. The rat cytokine multiplex method was used to determine the levels of cytokines [interleukin (IL)-1α, IL-1ß, IL-2, IL-6, tumor necrosis factor alpha (TNF-α)] in the conjunctiva, cornea, aqueous humor, and lens. The cornea and conjunctiva were subjected to immunohistochemical staining using anti-CD20 antibody and anti-CD3 antibody. RESULTS: The concentrations of IL-1ß, IL-2, and IL-6 in the conjunctiva were significantly lower in the brimonidine group (P = 0.033, 0.017, and 0.016, respectively) than in the control group. Compared to the control group, the concentration of IL-2 in the cornea was also significantly lower in the brimonidine group (P = 0.037). However, in the analysis of the cytokines in the aqueous humor, the concentrations of IL-1ß and IL-2 were significantly higher in the brimonidine group than in the control group (P = 0.016 and 0.008, respectively). There was no significant difference in CD20-positive B-cell and CD3-positive T-cell infiltration of the conjunctival biopsy specimens between the brimonidine group and the control group. Corneal specimens of both groups also showed no infiltration of CD20-positive B cells and CD3-positive T cells. CONCLUSIONS: These results suggest that the increase in some inflammatory cytokines in the aqueous humor after the long-term brimonidine treatment may contribute to the pathogenesis of brimonidine-induced uveitis.