Translation of paclitaxel-induced peripheral neurotoxicity from mice to patients: the importance of model selection.

ABSTRACT: Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

Photothrombotic Mouse Models for the Study of Melatonin as a Therapeutic Tool After Ischemic Stroke.

Melatonin is a potent neuroprotective agent which has shown therapeutic effects in animal models of brain injury such as stroke. Currently, there are few effective treatments for the therapeutics of stroke, the second leading cause of death and a major cause of disability worldwide. As demonstrated by the high number of publications during the last two decades, there is growing interest in understanding how and if melatonin could be a possible drug for stroke in humans, given also its very low and limited toxicity. Here, we describe the detailed protocol for performing the photothrombotic model of stroke which involves the occlusion of small cerebral vessels caused by the photoactivation of the previously injected light-sensitive dye Rose Bengal. Importantly, this model allows for the study of cellular and molecular mechanisms underlying the pathophysiology of stroke and thus can be used for investigating the neuropharmacological role of melatonin and the melatonin system in stroke. In particular, future research is warranted to demonstrate how and if melatonin impacts neurodegeneration, neuroprotection, and neuro-regeneration occurring after the brain injury caused by the occlusion of cerebral vessels.

Early Application of Ipsilateral Cathodal-tDCS in a Mouse Model of Brain Ischemia Results in Functional Improvement and Perilesional Microglia Modulation.

Early stroke therapeutic approaches rely on limited options, further characterized by a narrow therapeutic time window. In this context, the application of transcranial direct current stimulation (tDCS) in the acute phases after brain ischemia is emerging as a promising non-invasive tool. Despite the wide clinical application of tDCS, the cellular mechanisms underlying its positive effects are still poorly understood. Here, we explored the effects of cathodal tDCS (C-tDCS) 6 h after focal forelimb M1 ischemia in Cx3CR1GFP/+ mice. C-tDCS improved motor functionality of the affected forelimb, as assessed by the cylinder and foot-fault tests at 48 h, though not changing the ischemic volume. In parallel, histological analysis showed that motor recovery is associated with decreased microglial cell density in the area surrounding the ischemic core, while astrocytes were not affected. Deeper analysis of microglia morphology within the perilesional area revealed a shift toward a more ramified healthier state, with increased processes' complexity and a less phagocytic anti-inflammatory activity. Taken together, our findings suggest a positive role for early C-tDCS after ischemia, which is able to modulate microglia phenotype and morphology in parallel to motor recovery.

High-frequency repetitive transcranial magnetic stimulation enhances layer II/III morphological dendritic plasticity in mouse primary motor cortex.

High-frequency repeated transcranial magnetic stimulation (HF-rTMS) is a safe non-invasive neuromodulatory technique and there is a body of evidence shows that it can modulate plasticity in different brain areas. One of the most interesting application of HF-rTMS is the modulation of plasticity in primary motor cortex (M1) to promote recovery after brain injuries. However, the underlying mechanism by which HF-rTMS modulates motor cortex plasticity remain to be investigated. In this study, we investigated the effects of HF-rTMS treatment on morphological plasticity of pyramidal neurons in layer II/III (L2/3) of the primary motor cortex in mice. Our results show that the treatment did not increase anxiety in mice in the open field test and the elevated plus-maze test. Treated mice displayed increased total spine density in apical and basal dendrites, with a predominance of thin spines. The treatment also increased dendritic complexity, as assessed by Sholl analysis at both apical and basal dendrites. Collectively, the results show that HF-rTMS induced remarkable changes in dendritic complexity in primary motor cortex L2/3 connections which may strengthen corticocortical connections increasing integration of information across cortical areas. The data support the use of HF-rTMS as a circuit-targeting neuromodulation strategy.

Palladium uptake by Pisum sativum: partitioning and effects on growth and reproduction.

Environmental palladium levels are increasing because of anthropogenic activities. The considerable mobility of the metal, due to solubilisation phenomena, and its known bioavailability may indicate interactions with higher organisms. The aim of the study was to determine the Pd uptake and distribution in the various organs of the higher plant Pisum sativum and the metal-induced effects on its growth and reproduction. P. sativum was grown in vermiculite with a modified Hoagland's solution of nutrients in the presence of Pd at concentrations ranging 0.10-25 mg/L. After 8-10 weeks in a controlled environment room, plants were harvested and dissected to isolate the roots, stems, leaves, pods and peas. The samples were analysed for Pd content using AAS and SEM-EDX. P. sativum absorbed Pd, supplied as K2PdCl4, beginning at seed germination and continuing throughout its life. Minimal doses (0.10-1.0 mg Pd/L) severely inhibited pea reproductive processes while showing a peculiar hormetic effect on root development. Pd concentrations ≥1 mg/L induced developmental delay, with late growth resumption, increased leaf biomass (up to 25%) and a 15-20% reduction of root mass. Unsuccessful repeated blossoming efforts led to misshapen pods and no seed production. Photosynthesis was also disrupted. The absorbed Pd (ca. 0.5 % of the supplied metal) was primarily fixed in the root, specifically in the cortex, reaching concentrations up to 200 µg/g. The metal moved through the stem (up to 1 µg/g) to the leaves (2 µg/g) and pods (0.3 µg/g). The presence of Pd in the pea fruits, together with established evidence of environmental Pd accumulation and bioavailability, suggests possible contamination of food plants and propagation in the food chain and must be the cause for concern.

Synthesis, reactivity, electrochemical behavior, and crystal structure of a family of multivalent metal carbido-carbonyl clusters based on the Rh10(C)2Au(4-6) framework.

Six metal carbido-carbonyl clusters have been isolated and recognized as members of a multivalent family based on the dioctahedral Rh(10)(C)(2) frame, with variable numbers of CO ligands, AuPPh(3) moieties, and anionic charge: [Rh(10)(C)(2)(CO)(x)(AuPPh(3))(y)](n-) (x = 18, 20; y = 4, 5, 6; n = 0, 1, 2). Anions [Rh(10)(C)(2)(CO)(18)(AuPPh(3))(4)](-) ([2](-)) and [Rh(10)(C)(2)(CO)(18)(AuPPh(3))(4)](2-) ([2](2-)) have been obtained by the reduction of [Rh(10)(C)(2)(CO)(18)(AuPPh(3))(4)] (2) under N(2), while [Rh(10)(C)(2)(CO)(18)(AuPPh(3))(5)](-) ([3](-)) was obtained from [Rh(10)(C)(2)(CO)(20)(AuPPh(3))(4)] (1) by reduction under a CO atmosphere. [3](-) can be better obtained by the addition of AuPPh(3)Cl to [2](2-). [Rh(10)(C)(2)(CO)(18)(AuPPh(3))(6)] (4) is obtained from [3](-) and 2 as well by the reduction and subsequent addition of AuPPh(3)Cl. The molecular structures of [2](2-) ([NBu(4)](+) salt), [3](-) ([NMe(4)](+) salt), and 4 have been determined by single-crystal X-ray diffraction. The redox activities of complexes 1, 2 and [3](-) have been investigated by electrochemical and electron paramagnetic resonance (EPR) techniques. The data from EPR spectroscopy have been accounted for by theoretical calculations.

Platinum, palladium, and rhodium deposition to the Prunus laurus cerasus leaf surface as an indicator of the vehicular traffic pollution in the city of Varese area: an easy and reliable method to detect PGEs released from automobile catalytic converters.

BACKGROUND, AIM, AND SCOPE: The widespread use of some platinum group elements as catalysts to minimize emission of pollutants from combustion engines produced a constantly growing increase of the concentration of these elements in the environment; their potential toxicological properties explain the increasing interest in routine easy monitoring. We have found that leaves of Prunus laurus cerasus are efficient collectors of particulate with a dimension <60-80 mum, and a simple and reliable procedure was developed to reveal traces of platinum, palladium, and rhodium released from automotive catalysts. The analysis of the dust deposited on the foliage is a direct indicator of traffic pollution. MATERIALS AND METHODS: Leaves of P. laurus cerasus were washed by sonication in a mixture of water and 2-propanol and the washings, to be discarded, were separated by centrifugation to yield typically 0.05-1.2 g of dust that, after mineralization, was directly submitted for atomic absorption analysis. RESULTS: Comparison of the 2007 and 2004-2005 results showed a dramatic reduction of the platinum levels and revealed that palladium is now the main component of this traffic-related pollution. DISCUSSION: The results are consistent with the increasing diffusion of cars with a diesel engine whose catalysts are made up of Pt and/or Pd alone, and gives a significant insight into the recent evolution in catalyst design that replaces platinum for palladium. CONCLUSIONS: The proposed analytical procedure is simple, with short preparation times, and greatly reduces matrix effects so that atomic absorption spectroscopy can easily detect the three noble metals at the ng/g level in the dust. RECOMMENDATION AND PERSPECTIVES: The results clearly show that Pd concentrations have increased over time, and must be cause for concern.