National reflection on organs-on-chip for drug development: New regulatory challenges.

Organs-on-chip (OoC) are innovative and promising in vitro models, particularly in the process of developing new drugs, to improve predictivity of preclinical studies in humans. However, a lack of regulatory consensus on acceptance criteria and standards around these technologies currently hinders their adoption and implementation by end-users. A reflection has been conducted at the National Agency for Medicines and Health products safety (ANSM) in order to address this issue, which has gained momentum at the international level in recent years.

Contrast-to-Dose Relationship of Gadopiclenol, an MRI Macrocyclic Gadolinium-based Contrast Agent, Compared with Gadoterate, Gadobenate, and Gadobutrol in a Rat Brain Tumor Model.

Background Detection of cerebral lesions at MRI may benefit from a chemically stable and more sensitively detected gadolinium-based contrast agent (GBCA). Gadopiclenol, a macrocyclic GBCA with at least twofold higher relaxivity, is currently undergoing clinical trials in humans. Purpose To determine the relationship between MRI contrast enhancement and the injected dose of gadopiclenol in a glioma rat model compared with those of conventional GBCA at label dose.

Gadolinium-based contrast agents targeted to amyloid aggregates for the early diagnosis of Alzheimer's disease by MRI.

While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates.

Detection of vascular cell adhesion molecule-1 expression with USPIO-enhanced molecular MRI in a mouse model of cerebral ischemia.

Vascular damage plays a critical role after stroke, leading notably to edema, hemorrhages and stroke recurrence. Tools to characterize the vascular lesion are thus a real medical need. In this context, the specific nanoparticular contrast agent P03011, an USPIO (ultrasmall superparamagnetic iron oxide) conjugated to a peptide that targets VCAM-1 (vascular cell adhesion molecule-1), was developed to detect this major component of the vascular inflammatory response.

Ultra-sensitive molecular MRI of cerebrovascular cell activation enables early detection of chronic central nervous system disorders.

Since endothelial cells can be targeted by large contrast-carrying particles, molecular imaging of cerebrovascular cell activation is highly promising to evaluate the underlying inflammation of the central nervous system (CNS). In this study, we aimed to demonstrate that molecular magnetic resonance imaging (MRI) of cerebrovascular cell activation can reveal CNS disorders in the absence of visible lesions and symptoms. To this aim, we optimized contrast carrying particles targeting vascular cell adhesion molecule-1 and MRI protocols through both in vitro and in vivo experiments.

Plasma concentrations of arginine and related amino acids following traumatic brain injury: Proline as a promising biomarker of brain damage severity.

The aim of this study was to find a plasma biomarker, in relation with nitric oxide (NO), as a sign of brain damage severity following traumatic brain injury (TBI). We first investigated the post-traumatic evolution of the plasma concentrations of NO via the level of NO end-products metabolites (nitrite plus nitrate, NO(x)), that of l-arginine (Arg) and amino acids involved in its metabolism as well as the time course of neurological score in a rat model of lateral fluid percussion brain injury. First, the level of NO(x) was increased in plasma at 24 and 48 h post-TBI with a marked increase at 72 h.

Selective inhibition of inducible nitric oxide synthase reduces neurological deficit but not cerebral edema following traumatic brain injury.

The role of inducible nitric oxide synthase (iNOS) in cerebral edema and neurological deficit following traumatic brain injury (TBI) is not yet clear-cut. Therefore, the aim of this study was to investigate the effect of three different iNOS inhibitors on cerebral edema and functional outcome after TBI. First, the time courses of blood--brain barrier (BBB) breakdown, cerebral edema, and neurological deficit were studied in a rat model of fluid percussion-induced TBI.

Lack of iNOS induction in a severe model of transient focal cerebral ischemia in rats.

Calcium-independent nitric oxide synthase (NOS) activity has been reported in ischemic brains and usually attributed to the inducible isoform, iNOS. Because calcium-independent mechanisms have recently been shown to regulate the constitutive calcium-dependent NOS, we proposed to confirm the presence of iNOS activity in our model of transient focal cerebral ischemia in rats. Our initial results showed that, in our model, ischemia induced an important increase in brain calcium concentration.

Characterization of a rat model to study acute neuroinflammation on histopathological, biochemical and functional outcomes.

Neuroinflammation is one of the events occurring after acute brain injuries. The aim of the present report was to characterize a rat model to study acute neuroinflammation on the histopathological, biochemical and functional outcomes. Lipopolysaccharide (LPS), known as a strong immunostimulant, was directly injected into the hippocampus.

1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats.

There are conflicting data regarding the role of nitric oxide (NO) produced by inducible NO synthase (iNOS) in the pathophysiology of traumatic brain injury (TBI). In this report, we evaluated the effect of a potent selective (iNOS) inhibitor, 1400W, on histopathological outcome following TBI in a rat model of lateral fluid percussion brain injury. First, to design an appropriate treatment protocol, the parallel time courses of iNOS and neuronal NOS (nNOS) gene expression, protein synthesis, and activity were investigated.

Cortical calcium increase following traumatic brain injury represents a pitfall in the evaluation of Ca2+-independent NOS activity.

In this report, our findings highlighted the presence of a high level of calcium in the cortex following traumatic brain injury (TBI) in a rat model of fluid percussion-induced brain injury. This calcium increase represents a pitfall in the assessment of Ca2+-independent nitric oxide synthase (NOS) activity supposed to play a role in the secondary brain lesion following TBI. The so-called Ca2+-independent NOS activity measured in the injured cortex 72 h after TBI had the pharmacological profile of a Ca2+-dependent NOS and was therefore inhibited with a supplement of calcium chelator.