Identification of fluocinolone acetonide to prevent paclitaxel‐induced peripheral neuropathy

Paclitaxel (PTX) is among the most commonly used cancer drugs that cause chemotherapy‐induced peripheral neuropathy (CIPN), a debilitating and serious dose‐limiting side effect. Currently, no drugs exist to prevent CIPN, and symptomatic therapy is often ineffective. In order to identify therapeutic candidates to prevent axonal degeneration induced by PTX, we carried out a phenotypic drug screening using primary rodent dorsal root ganglion sensory neurons. We identified fluocinolone acetonide as a neuroprotective compound and verified it through secondary screens. Furthermore, we showed its efficacy in a mouse model of PTX‐induced peripheral neuropathy and confirmed with four different cancer cell lines that fluocinolone acetonide does not interfere with PTX's antitumor activity. Our study identifies fluocinolone acetonide as a potential therapy to prevent CIPN caused by PTX.     

Long-lasting cognitive injury in rats with apparent full gross neurological recovery after short-term cardiac arrest

OBJECTIVE: The long-term behavioral effects of mild global ischemia have not been well described. We used short (5 min) asphyxic-cardiac arrest that resulted in no apparent gross neurological deficits to study the long-term effects of mild hypoxic ischemia on the neurobehavioral status of rats. METHODS: Fifteen adult, male Wistar rats were studied. One group was given asphyxic-cardiac arrest (CA) for 5 min (n=10) and the other group had Sham procedure (n=5). Neurobehavioral testing was performed before and 2 weeks after CA. The neurobehavioral evaluations were: neurological deficit score (NDS), Y Maze, open field, pre-pulse inhibition (PPI) of acoustic startle reflex (ASR), wire hanging, and inclined screen. RESULTS: At 24h post-CA, all of the rats regained normal neurological function as measured by NDS, an integral score for consciousness, brainstem reflexes, sensorimotor function and simple behavioral reflex tests. However, 1 week after CA, the rats exhibited significant activity reductions in the open field and in spontaneous alternation in the Y maze. The CA rats also showed a significant decrease in startle reaction amplitude and startle inhibition in the PPI tests. Two weeks after CA, the changes in motor activity and deficits in PPI remained significant, but the spontaneous alternation recovered. The muscle strength test of wire hanging and inclined screen tests did not exhibit significant change. CONCLUSION: We present a rodent model of mild CA that, despite apparent full recovery of global neurological function at 24h post-resuscitation, exhibited long-term cognitive injury lasting for at least 2 weeks after CA. This model may help understand better the injury associated with CA and develop management strategies for mild brain injury.     

Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys

Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.     

Real-time measurement of blood vessel occlusion during microsurgery.

Measurement and feedback of vascular properties during microsurgery is generally not available. We carried out real-time in vivo measurement and analysis of microsurgical occlusion of 1-2-mm diameter arteries and veins in rodents. A pair of forceps mounted with strain gauges was designed for applying and directly measuring the force on tissue. Forces between 0 and 450 mN were applied, with the device having a resolution of 0.5 mN. We performed in vivo experiments on the rat femoral (n = 5) and abdominal (n = 8) blood vessels to measure the elastic restoration force of the tissue in response to radial compression at different levels of force. On average, the minimum occlusion force was 57 mN for the rat artery. During steady application of force, the perturbations in the blood vessel due to heartbeat are visible in the force data. These force oscillations ranged between 1 and 3 mN around the mean steady-state force applied. It was determined that the magnitude of the Fourier spectral peak corresponding to heartbeat frequency can be used as a measure of the patency of the blood vessel, and can provide feedback to microsurgeons to avoid damage to the vessel by application of excess force.     

Downregulation of extracellular matrix-related gene clusters during osteogenic differentiation of human bone marrow- and adipose tissue-derived stromal cells

Bone marrow- and adipose tissue-derived stromal cells (BMSCs and ASCs, respectively) exhibit a similar capacity for osteogenic differentiation in vitro, but it is unclear whether they share a common differentiation process, because they originate from different tissues. The aim of this study was to explore BMSC and ASC osteogenic differentiation by focusing on the expression of extracellular matrix-related genes (ECMGs), which play a crucial role in osteogenesis and bone tissue regeneration in vivo. We characterized the gene expression profiles of BMSCs and ASCs using a custom complementary deoxyribonucleic acid microarray containing 55 ECMGs. Undifferentiated BMSCs and ASCs actively expressed a wide range of ECMGs. Once BMSCs and ASCs were placed in an osteogenic differentiation medium, 24 and 17 ECMGs, respectively, underwent considerable downregulation over the course of the culture period. The remaining genes were maintained at a similar expression level to corresponding uninduced cell cultures. Although the suppression phenomenon was consistent irrespective of stromal cell origin, collagen (COL)2A1, COL6A1, COL9A1, parathyroid hormone receptor, integrin (INT)-beta3, and TenascinX genes were only downregulated in osteogenic BMSCs, whereas COL1A2, COL3A1, COL4A1, COL5A2, COL15A1, osteopontin, osteonectin, and INT-beta1 genes were only downregulated in osteogenic ASCs. During this time period, cell viability was sustained, suggesting that the observed downregulation did not occur by selection and elimination of unfit cells from the whole cell population. These data suggest that osteogenically differentiating BMSCs and ASCs transition away from a diverse gene expression pattern, reflecting their multipotency toward a configuration specifically meeting the requirements of the target lineage. This change may serve to normalize gene expression in mixed populations of stem cells derived from different tissues.     

Melatonin modulates the fetal cardiovascular defense response to acute hypoxia

Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO‐dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.