A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is ...important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day PD 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.
In vivo use of biodegradable magnesium (Mg) metal can be plagued by too rapid a degradation rate that removes metal support before physiological function is repaired. To advance the use of Mg ...biomedical implants, the degradation rate may need to be adjusted. We previously demonstrated that pure Mg filaments used in a nerve repair scaffold were compatible with regenerating peripheral nerve tissues, reduced inflammation, and improved axonal numbers across a short-but not long-gap in sciatic nerves in rats. To determine if the repair of longer gaps would be improved by a slower Mg degradation rate, we tested, in vitro and in vivo, the effects of Mg filament polishing followed by anodization using plasma electrolytic oxidation (PEO) with non-toxic electrolytes. Polishing removed oxidation products from the surface of as-received (unpolished) filaments, exposed more Mg on the surface, produced a smoother surface, slowed in vitro Mg degradation over four weeks after immersion in a physiological solution, and improved attachment of cultured epithelial cells. In vivo, treated Mg filaments were used to repair longer (15 mm) injury gaps in adult rat sciatic nerves after placement inside hollow poly (caprolactone) nerve conduits. The addition of single Mg or control titanium filaments was compared to empty conduits (negative control) and isografts (nerves from donor rats, positive control). After six weeks in vivo, live animal imaging with micro computed tomography (micro-CT) showed that Mg metal degradation rates were slowed by polishing vs. as-received Mg, but not by anodization, which introduced greater variability. After 14 weeks in vivo, functional return was seen only with isograft controls. However, within Mg filament groups, the amount of axonal growth across the injury site was improved with slower Mg degradation rates. Thus, anodization slowed degradation in vitro but not in vivo, and degradation rates do affect nerve regeneration.
There is an increasing interest in biodegradable metal implants made from magnesium (Mg), iron (Fe), zinc (Zn) and their alloys because they are well tolerated in vivo and have mechanical properties ...that approach those of non-degradable metals. In particular, Zn and its alloys show the potential to be the next generation of biodegradable materials for medical implants. However, Zn has not been as well-studied as Mg, especially for stent applications. Manufacturing stents by laser cutting has become an industry standard. Nevertheless, the use of this approach with Zn faces some challenges, such as generating thermal stress, dross sticking on the device, surface oxidation, and the need for expensive thin-walled Zn tubing and post-treatment. All of these challenges motivated us to employ photo-chemical etching for fabricating different designs of Zn (99.95% pure) stents. The stents were constructed with different strut patterns, made by photo-chemical etching, and mechanically tested to evaluate radial forces. Stents with rhombus design patterns showed a promising 0.167N/mm radial force, which was comparable to Mg-based stents. In vitro studies were conducted with uncoated Zn stents as control and Parylene C-coated Zn stents to determine corrosion rates. The Parylene C coating reduced the corrosion rate by 50% compared to uncoated stents. In vivo studies were carried out by implanting photo-chemically etched, uncoated Zn stent segments subcutaneously in a C57BL/6 mice model. Histological analyses provided favorable data about the surrounding tissue status, as well as nerve and blood vessel responses near the implant, providing insights into the in vivo degradation of the metal struts. All of these experiments confirmed that Zn has the potential for use in biodegradable stent applications.
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Magnesium (Mg) metal is of great interest in biomedical applications, especially in tissue engineering. Mg exhibits excellent in vivo biocompatibility, biodegradability and, during ...degradation, releases Mg ions (Mg2+) with the potential to improve tissue repair. We used electrospinning technology to incorporate Mg particles into nanofibers. Various ratios of Mg metal microparticles (<44 µm diameter) were incorporated into nanofiber polycaprolactone (PCL) meshes. Physicochemical properties of the meshes were analyzed by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), mechanical tensile testing, X-ray diffractometry and UV–VIS spectrophotometry. Biological properties of meshes were evaluated in vitro and in vivo. Under mammalian cell culture conditions, Mg-containing meshes released hydrogen gas and relative amounts of free Mg2+ that reflected the Mg/PCL ratios. All meshes were non-cytotoxic for 3T3 fibroblasts and PC-12 pheochromocytoma cells. In vivo implantation under the skin of mice for 3, 8 and 28 days showed that Mg-containing meshes were well vascularized, with improved measures of inflammation and healing compared to meshes without Mg. Evidence included an earlier appearance and infiltration of tissue repairing macrophages and, after 28 days, evidence of more mature tissue remodeling. Thus, these new composite nanofiber meshes have promising material properties that mitigated inflammatory tissue responses to PCL alone and improved tissue healing, thus providing a suitable matrix for use in clinically relevant tissue engineering applications.
The biodegradable metal, magnesium, safely biodegrades in the body, releasing beneficial byproducts. To improve tissue delivery, magnesium metal particles were incorporated into electrospun nanofiber meshes composed of a biodegradable, biocompatible polymer, polycaprolactone (PCL). Magnesium addition, at several concentrations, did not alter PCL chemistry, but did alter physical properties. Under cell culture conditions, meshes released magnesium ions and hydrogen gas and were not cytotoxic for two cell types. After implantation in mice, the mesh with magnesium resulted in earlier appearance of M2-like, reparative macrophages and improved tissue healing versus mesh alone. This is in agreement with other studies showing beneficial effects of magnesium metal and provides a new type of scaffold material that will be useful in clinically relevant tissue engineering applications.
We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite ...(2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms.
Peripheral nerve injuries, caused mainly by traumas, affect over 200,000 people yearly in the US. There is a great need to find an alternative to autografts, the current clinical standard treatment, ...for the injuries, especially the ones resulting in long gaps (> 3 cm). In this research, we investigated on applying Magnesium (Mg) metal filaments as physical guidance to direct nerve regenerations in long-gap defects. Our overall hypothesis is that with the combination of porous conduits, Mg filaments, with additional factors like CNTF or Mg2+ are a promising method in treating long-gap peripheral nerve injuries. On the basis of our previous results, we first proposed that a novel polycaprolactone (PCL) mesh electrospun with Mg metal particles will be a promising candidate as a conduit material. Multiple mechanical and biological features of the mesh were characterized, as well as in vivo tissue response after subcutaneous implantation. The data revealed the presence of Mg metal was beneficial in immune-modulation and tissue repair. One mesh type, PM10, has the desirable properties and was then made into conduits. We hypothesized the conduits made from PM10 would support the repair and later tested it in the sciatic injured rats with stranded Mg Resoloy® wire inserted inside the conduits. The behaviors of the animals were monitored for 14 weeks before collecting the nerve tissues for histological assessments. Though histology shown that the regenerated tissue was healthy, no equivalent functional recovery has been observed compared to isografts. MicroCT scanning revealed that the conduits swelled and blocked the inner space for tissue growth. Besides altering to a more suitable conduit material (polysulfone), we proposed adding a growth factor, with or without the presence of Mg2+ salt solution, will improve the repair outcomes. The behavioral data indicated that empty polysulfone conduits with/without CNTF gave the best repairs. Only behavioral results were included due to the time limited and we expect the future histology will reveals more detail about the effects of Mg. In general, this study shed lights on nerve regenerating effects of Mg and tissue response to Mg when using it in peripheral nerve repair.
To detect the concentrations of reactive oxygen species (ROS), transient receptor potential mucin-1 (TRPML1), and autophagy-related (Atg) proteins (LC3-I, LC3-II, and Beclin1) in vitreous humor of ...patients with simple rhegmatogenous retinal detachment (RRD).
RRD patients enrolled as the RRD group, and patients with idiopathic macular hole (IMH) and idiopathic macular epiretinal membrane (IMEM) were enrolled as control group. The levels of ROS, TRPML1, LC3-I, LC3-II, and Beclin1 in vitreous humor of patients in the RRD and control groups were detected by enzyme-linked immunosorbent assay (ELISA).
The RRD group included 28 eyes 28 patients and had a higher concentration of ROS in vitreous humor (631.86±18.05 vs 436.34±108.22 IU/mL,
<0.05). The ROS level in patients with a wide retinal detachment (RD) extent (RD range ≥1/2) was higher than that with a narrow RD extent (RD range<1/2,
<0.05). ROS concentration was negatively correlated with RD time (
=-0.46,
=0.01). The expression levels of LC3-I and Beclin1 significantly decreased in RRD (
<0.05), but there were no correlations with the RD time, RD extent, or macular involvement.
In eyes with RRD, the concentration of ROS in vitreous humor increases and the expression levels of Atg proteins decrease, reflecting possibly that autophagy is inhibited.
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