Correction: Micheli et al. Treatment of Non-Alcoholic Steatosis: Preclinical Study of a New Nutraceutical Multitarget Formulation. Nutrients 2020, 12, 1819.

In the original publication [...].

Anti-inflammatory and anti-hyperalgesic effects induced by an aqueous aged black garlic extract in rodent models of ulcerative colitis and colitis-associated visceral pain.

Inflammatory bowel disease (IBD) is a morbid condition characterized by relapsing-remitting inflammation of the colon, accompanied by persistent gut dysmotility and abdominal pain. Different reports demonstrated biological activities of aged black garlic (ABG), including anti-inflammatory and antioxidant effects. We aimed to investigate beneficial effects exerted by ABGE on colon inflammation by using ex vivo and in vivo experimental models. We investigated the anti-inflammatory effects of an ABG water extract (ABGE) on rat colon specimens exposed to E. coli lipopolysaccharide (LPS), a known ex vivo experimental model of ulcerative colitis. We determined gene expression of various biomarkers involved in inflammation, including interleukin (IL)-1ß, IL-6, nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α. Moreover, we studied the acute effects of ABGE on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) injection in rats. ABGE suppressed LPS-induced gene expression of IL-1ß, IL-6, NF-kB, and TNF-α. In addition, the acute administration of ABGE (0.03-1 g kg-1) dose-dependently relieved post-inflammatory visceral pain, with the higher dose (1 g kg-1) able to significantly reduce both the behavioral nociceptive response and the entity of abdominal contraction (assessed by electromyography) in response to colorectal distension after the acute administration in DNBS-treated rats. Present findings showed that ABGE could represent a potential strategy for treatment of colitis-associated inflammatory process and visceral pain. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin.

The pharmacological blockade of P2X4 receptor as a viable approach to manage visceral pain in a rat model of colitis.

Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1ß levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1ß axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1ß axis inhibition.

Photon-Counting Computed Tomography in Atherosclerotic Plaque Characterization.

Atherosclerotic plaque buildup in the coronary and carotid arteries is pivotal in the onset of acute myocardial infarctions or cerebrovascular events, leading to heightened levels of illness and death. Atherosclerosis is a complex and multistep disease, beginning with the deposition of low-density lipoproteins in the arterial intima and culminating in plaque rupture. Modern technology favors non-invasive imaging techniques to assess atherosclerotic plaque and offer insights beyond mere artery stenosis. Among these, computed tomography stands out for its widespread clinical adoption and is prized for its speed and accessibility. Nonetheless, some limitations persist. The introduction of photon-counting computed tomography (PCCT), with its multi-energy capabilities, enhanced spatial resolution, and superior soft tissue contrast with minimal electronic noise, brings significant advantages to carotid and coronary artery imaging, enabling a more comprehensive examination of atherosclerotic plaque composition. This narrative review aims to provide a comprehensive overview of the main concepts related to PCCT. Additionally, we aim to explore the existing literature on the clinical application of PCCT in assessing atherosclerotic plaque. Finally, we will examine the advantages and limitations of this recently introduced technology.

Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation.

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT2A, 5-HT6, and 5-HT7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se, supporting the concept that 5-HT2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT2A and 5-HT6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT7 receptor. Considering previous studies showing that 5-HT6 receptor inhibition, but not activation, and 5-HT7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT2A receptor activation.

A Novel Ophthalmic Solution Containing Glicopro® Complex for the Treatment of Patients with Dry Eye Disease: Results from a Pilot Study.

(1) Background: Dry eye disease (DED) is a multifactorial ocular surface disease characterized by an imbalance in ocular surface homeostasis, and tear substitutes constitute the first line of treatment. The present study aimed to evaluate the changes in the signs and symptoms of patients with DED treated with a novel tear substitute containing the GlicoPro® complex. (2) Methods: Patients with DED not successfully responding to other tear substitutes were enrolled and treated with a novel ophthalmic solution (two drops four times daily). Patients were examined before starting the study treatment (T0) and after 30 (T1) and 60 (T2) days of treatment by means of Keratograph for the evaluation of the following: (i) tear meniscus height (TMH); (ii) noninvasive Keratograph break-up time (NIKBUT); (iii) bulbar redness; and (iv) infrared meibography. The SANDE questionnaire was administered to assess ocular discomfort symptoms. Analysis of the tear content of proenkephalin and Met/Leu-enkephalin was also performed. (3) Results: At T2, a significant improvement in NIKBUT first, average, and class, TMH, and SANDE score was found. The tear content of proenkephalins was significantly higher at T1, whereas processed active Met/Leu-enkephalins increased at both T1 and T2. (4) Conclusions: Our novel tear substitute based on GlicoPro® resulted in a significant improvement in ocular discomfort symptoms, tear volume, and stability in the patients treated. The increase in active peptides processed in tears may represent the pathophysiological substrate underlying this finding.

Structural Brain MR Imaging Alterations in Patients with Systemic Lupus Erythematosus with and without Neuropsychiatric Events.

BACKGROUND AND PURPOSE: Systemic lupus erythematosus is a complex autoimmune disease known for its diverse clinical manifestations, including neuropsychiatric systemic lupus erythematosus, which impacts a patient's quality of life. Our aim was to explore the relationships among brain MR imaging morphometric findings, neuropsychiatric events, and laboratory values in patients with systemic lupus erythematosus, shedding light on potential volumetric biomarkers and diagnostic indicators for neuropsychiatric systemic lupus erythematosus. MATERIALS AND METHODS: Twenty-seven patients with systemic lupus erythematosus (14 with neuropsychiatric systemic lupus erythematosus, 13 with systemic lupus erythematosus), 24 women and 3 men (average age, 43 years, ranging from 21 to 62 years) were included in this cross-sectional study, along with 10 neuropsychiatric patients as controls. An MR imaging morphometric analysis, with the VolBrain online platform, to quantitatively assess brain structural features and their differences between patients with neuropsychiatric systemic lupus erythematosus and systemic lupus erythematosus, was performed. Correlations and differences between MR imaging morphometric findings and laboratory values, including disease activity scores, such as the Systemic Lupus Erythematosus Disease Activity Index and the Systemic Lupus International Collaborating Clinics Damage Index, were explored. An ordinary least squares regression analysis further explored the Systemic Lupus Erythematosus Disease Activity Index and Systemic Lupus International Collaborating Clinics Damage Index relationship with MR imaging features. RESULTS: For neuropsychiatric systemic lupus erythematosus and non-neuropsychiatric systemic lupus erythematosus, the brain regions with the largest difference in volumetric measurements were the insular central operculum volume (P value = .003) and the occipital cortex thickness (P = .003), which were lower in neuropsychiatric systemic lupus erythematosus. The partial correlation analysis showed that the most correlated morphometric features with neuropsychiatric systemic lupus erythematosus were subcallosal area thickness asymmetry (P < .001) and temporal pole thickness asymmetry (P = .011). The ordinary least squares regression analysis yielded an R 2 of 0.725 for the Systemic Lupus Erythematosus Disease Activity Index score, with calcarine cortex volume as a significant predictor, and an R 2 of 0.715 for the Systemic Lupus International Collaborating Clinics Damage Index score, with medial postcentral gyrus volume as a significant predictor. CONCLUSIONS: The MR imaging volumetric analysis, along with the correlation study and the ordinary least squares regression analysis, revealed significant differences in brain regions and their characteristics between patients with neuropsychiatric systemic lupus erythematosus and those with systemic lupus erythematosus, as well as between patients with different Systemic Lupus Erythematosus Disease Activity Index and Systemic Lupus International Collaborating Clinics Damage Index scores.

Ultramicronized N-palmitoylethanolamine associated with analgesics: Effects against persistent pain.

Current epidemiological data estimate that one in five people suffers from chronic pain with considerable impairment of health-related quality of life. The pharmacological treatment is based on first- and second-line analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs, paracetamol, antidepressants, anti-seizure drugs and opioids, that are characterized by important side effects. N-palmitoylethanolamine (PEA) is a body's own fatty-acid ethanolamide belonging to the family of autacoid local injury antagonist amides. The anti-inflammatory and pain-relieving properties of PEA have been recognized for decades and prompted to depict its role in the endogenous mechanisms of pain control. Together with its relative abundance in food sources, this opened the way to the use of PEA as a pain-relieving nutritional intervention. Naïve PEA is a large particle size lipid molecule with low solubility and bioavailability. Reducing particle size is a useful method to increase surface area, thereby improving dissolution rate and bioavailability accordingly. Micron-size formulations of PEA (e.g., ultramicronized and co-(ultra)micronized) have shown higher oral efficacy compared to naïve PEA. In particular, ultramicronized PEA has been shown to efficiently cross the intestinal wall and, more importantly, the blood-brain and blood-spinal cord barrier. Several preclinical and clinical studies have shown the efficacy, safety and tolerability of ultramicronized PEA. This narrative review summarizes the available pharmacokinetic/pharmacodynamic data on ultramicronized PEA and focuses to its contribution to pain control, in particular as 'add-on' nutritional intervention. Data showing the ability of ultramicronized PEA to limit opioid side effects, including the development of tolerance, have also been reviewed.

Artificial Intelligence in the Differential Diagnosis of Cardiomyopathy Phenotypes.

Artificial intelligence (AI) is rapidly being applied to the medical field, especially in the cardiovascular domain. AI approaches have demonstrated their applicability in the detection, diagnosis, and management of several cardiovascular diseases, enhancing disease stratification and typing. Cardiomyopathies are a leading cause of heart failure and life-threatening ventricular arrhythmias. Identifying the etiologies is fundamental for the management and diagnostic pathway of these heart muscle diseases, requiring the integration of various data, including personal and family history, clinical examination, electrocardiography, and laboratory investigations, as well as multimodality imaging, making the clinical diagnosis challenging. In this scenario, AI has demonstrated its capability to capture subtle connections from a multitude of multiparametric datasets, enabling the discovery of hidden relationships in data and handling more complex tasks than traditional methods. This review aims to present a comprehensive overview of the main concepts related to AI and its subset. Additionally, we review the existing literature on AI-based models in the differential diagnosis of cardiomyopathy phenotypes, and we finally examine the advantages and limitations of these AI approaches.

Correlation of Cognitive Reappraisal and the Microstructural Properties of the Forceps Minor: A Deductive Exploratory Diffusion Tensor Imaging Study.

Cognitive reappraisal (CR) is a mechanism for emotion regulation, and the prefrontal cortex (PFC) plays a central role in the regulation of emotions. We tested the hypothesis of an association between CR function and microstructural properties of forceps minor (a commissural bundle within the PFC) in healthy subjects (HS). We analyzed a population of 65 young HS of a public dataset. The diffusion tensor imaging (DTI) sequence of every subject was analyzed to extract the derived shape (diameter and volume) and DTI metrics in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the forceps minor. The CR subscale of the German version of the Emotion Regulation Questionnaire (ERQ) was used for CR assessment. The Shapiro-Wilk test was applied to test the assumption of normality in all these parameters, adopting a statistical threshold at p < 0.05. Whenever appropriate a non-parametric two-tailed partial correlation analysis was applied to test for correlations between the CR ERQ score and the derived shape and DTI metrics, including age and sex as confounders, adopting a statistical threshold at p < 0.05. The non-parametric two-tailed partial correlation analysis revealed a mildly significant correlation with FA (ρ = 0.303; p = 0.016), a weakly significant negative correlation with MD (ρ = - 0.269; p = 0.033), and a mildly significant negative correlation with RD (ρ = - 0.305; p = 0.015). These findings suggest a correlation between DTI microstructural properties of forceps minor and CR.

Effect of late gadolinium enhancement on left atrial impairment in myocarditis patients.

OBJECTIVE: The aims of our study were to investigate the effect of the extent and location of late gadolinium enhancement (LGE) on the left atrium (LA) function in patients with acute myocarditis (AM) using cardiovascular magnetic resonance (CMR). METHOD: This retrospective study performed CMR scans in 113 consecutive patients (89 males, 24 females; mean age 45.8 ± 17.3 years) with AM that met the updated Lake Louise criteria. Reservoir, conduit, and booster LA functions were analyzed by CMR feature tracking using dedicated software. Besides LA strain measurements, myocardial scar location and extent were assigned and quantified by LGE imaging. RESULTS: AM patients with septal LGE had impaired reservoir, conduit, and conduit strain rate function in comparison with AM patients with non-septal LGE (p = 0.001, for all). In fully adjusted multivariable linear regression, reservoir and conduit were significantly associated with left ventricle (LV) LGE location (ß coefficient = 8.205, p = 0.007; ß coefficient = 5.185, p = 0.026; respectively). In addition, LA parameters decreased according to the increase in the extent of LV fibrosis (LGE ≤ 10%; LGE 11-19%; LGE ≥ 20%). After adjustment in multivariable linear regression, the association with LV LGE extent was no longer statistically significant. CONCLUSION: In patients with acute myocarditis, LA function abnormalities are significantly associated with LV LGE location, but not with LGE extent. Septal LGE is paralleled by a deterioration of LA reservoir and conduit function. CLINICAL RELEVANCE STATEMENT: Left atrium dysfunction is associated with the presence of late gadolinium enhancement in the left ventricle septum and can be useful in the clinical prognostication of patients with acute myocarditis, allowing individually tailored treatment. KEY POINTS: • Myocardial fibrosis is related to atrial impairment. • The location of myocardial fibrosis is the main determinant of atrial dysfunction in myocarditis patients. • The quantification of atrial mechanisms may provide more in-depth insight into myocarditis pathophysiology.

Ultramicronized N-palmitoylethanolamine Contributes to Morphine Efficacy Against Neuropathic Pain: Implication of Mast Cells and Glia.

BACKGROUND: In the current management of neuropathic pain, in addition to antidepressants and anticonvulsants, the use of opioids is wide, despite their related and well-known issues. OBJECTIVE: N-palmitoylethanolamine (PEA), a natural fatty-acid ethanolamide whose anti-inflammatory, neuroprotective, immune-modulating and anti-hyperalgesic activities are known, represents a promising candidate to modulate and/or potentiate the action of opioids. METHODS: This study was designed to evaluate if the preemptive and morphine concomitant administration of ultramicronized PEA, according to fixed or increasing doses of both compounds, delays the onset of morphine tolerance and improves its analgesic efficacy in the chronic constriction injury (CCI) model of neuropathic pain in rats. RESULTS: Behavioral experiments showed that the preemptive and co-administration of ultramicronized PEA significantly decreased the effective dose of morphine and delayed the onset of morphine tolerance. The activation of spinal microglia and astrocytes, commonly occurring both on opioid treatment and neuropathic pain, was investigated through GFAP and Iba-1 immunofluorescence. Both biomarkers were found to be increased in CCI untreated or morphine treated animals in a PEA-sensitive manner. The increased density of endoneural mast cells within the sciatic nerve of morphine-treated and untreated CCI rats was significantly reduced by ultramicronized PEA. The decrease of mast cell degranulation, evaluated in terms of reduced plasma levels of histamine and N-methyl-histamine metabolite, was mainly observed at intermediate-high doses of ultramicronized PEA, with or without morphine. CONCLUSION: Overall, these results show that the administration of ultramicronized PEA in CCI rats according to the study design fully fulfilled the hypotheses of this study.

Searching for Novel Sources of Hydrogen Sulfide Donors: Chemical Profiling of Polycarpa aurata Extract and Evaluation of the Anti-Inflammatory Effects.

Hydrogen sulfide (H2S) is a signaling molecule endogenously produced within mammals' cells that plays an important role in inflammation, exerting anti-inflammatory effects. In this view, the research has shown a growing interest in identifying natural H2S donors. Herein, for the first time, the potential of marine extract as a source of H2S-releasing agents has been explored. Different fractions obtained by the Indonesian ascidian Polycarpa aurata were evaluated for their ability to release H2S in solution. The main components of the most active fraction were then characterized by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and NMR spectroscopy. The ability of this fraction to release H2S was evaluated in a cell-free assay and J774 macrophages by a fluorimetric method, and its anti-inflammatory activity was evaluated in vitro and in vivo by using carrageenan-induced mouse paw edema. The anti-inflammatory effects were assessed by inhibiting the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and interleukin-6 (IL-6), coupled with a reduction in nitric oxide (NO) and IL-6 levels. Thus, this study defines the first example of a marine source able to inhibit inflammatory responses in vivo through the release of H2S.

Erucin Exerts Cardioprotective Effects on Ischemia/Reperfusion Injury through the Modulation of mitoKATP Channels.

Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of releasing hydrogen sulfide (H2S), an endogenous pleiotropic gasotransmitter responsible for anti-ischemic cardioprotective effects also through the involvement of mitoK channels. Erucin (ERU) is a natural isothiocyanate resulting from the enzymatic hydrolysis of glucosinolates (GSLs) present in Eruca sativa Mill. seeds, an edible plant of the Brassicaceae family. In this experimental work, the specific involvement of mitoKATP channels in the cardioprotective effect induced by ERU was evaluated in detail. An in vivo preclinical model of acute myocardial infarction was reproduced in rats to evaluate the cardioprotective effect of ERU. Diazoxide was used as a reference compound for the modulation of potassium fluxes and 5-hydroxydecanoic acid (5HD) as a selective blocker of KATP channels. Specific investigations on isolated cardiac mitochondria were carried out to evaluate the involvement of mitoKATP channels. The results obtained showed ERU cardioprotective effects against ischemia/reperfusion (I/R) damage through the involvement of mitoKATP channels and the consequent depolarizing effect, which in turn reduced calcium entry and preserved mitochondrial integrity.

Correction: Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis.

[This corrects the article DOI: 10.1371/journal.pone.0170825.].

Base-to-apex Gradient Pattern Assessed by Cardiovascular Magnetic Resonance in Takotsubo Cardiomyopathy.

OBJECTIVES: The purpose of this study was to investigate the base-to-apex gradient strain pattern as a noncontrast cardiovascular magnetic resonance (CMR) parameter in patients with Takotsubo cardiomyopathy (TTC) and determine whether this pattern may help discriminate TTC from patients with anterior myocardial infarction (AMI). MATERIALS AND METHODS: A total of 80 patients were included in the analysis: 30 patients with apical ballooning TTC and 50 patients with AMI. Global and regional ventricular function, including longitudinal (LS), circumferential (CS), and radial strain (RS), were assessed using CMR. The base-to-apex LS, RS, and CS gradients, defined as the peak gradient difference between averaged basal and apical strain, were calculated. RESULTS: The base-to-apex RS gradient was impaired in TTC patients compared with the AMI group (14.04 ± 15.50 vs. -0.43 ± 11.59, P=0.001). Conversely, there were no significant differences in the base-to-apex LS and CS gradients between the AMI group and TTC patients (0.14 ± 2.71 vs. -1.5 ± 3.69, P=0.054: -0.99 ± 6.49 vs. ±1.4 ± 5.43, P=0.47, respectively). Beyond the presence and extension of LGE, base-to-apex RS gradient was the only independent discriminator between TTC and AMI (OR 1.28; 95% CI 1.08, 1.52, P=0.006) in multivariate logistic regression analysis. CONCLUSION: The findings of this study suggest that the pattern of regional myocardial strain impairment could serve as an additional noncontrast CMR tool to refine the diagnosis of TTC. A pronounced base-to-apex RS gradient may be a specific left ventricle strain pattern of TTC.

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System.

The management of abdominal pain in patients affected by inflammatory bowel diseases (IBDs) still represents a problem because of the lack of effective treatments. Acetyl L-carnitine (ALCAR) has proved useful in the treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) injection. Two different protocols were applied. In the preventive protocol, ALCAR was administered daily starting 14 days to 24 h before the delivery of DNBS. In the interventive protocol, ALCAR was daily administered starting the same day of DNBS injection, and the treatment was continued for 14 days. In both cases, ALCAR significantly reduced the establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one. The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis, as analyzed by immunofluorescence. On the other hand, the preventive protocol effectively protected enteric neurons from the inflammatory insult. These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from IBDs.

Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity: In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project.

Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.