Experimental Models of Posterior Reversible Encephalopathy Syndrome: A Review From Pathophysiology to Therapeutic Targets.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies.

Sex differences: From preclinical pharmacology to clinical pharmacology.

Sex is a crucial variable to take into account in medical research. In this review, we attempted to present its importance at all stages of research and even during drug's post-marketing surveillance. Most preclinical research studies do not take sex into account while many diseases are known to present sexual dimorphism. However, a shift in thinking occurred since the January 2016 implementation of the US Institutes of Health recommendations to take sex into account in research. Nevertheless, in preclinical studies, the lack of sex-based statistical analyses persists. Moreover, in humans, women are often under-represented in some clinical trials, despite well-identified sexual dimorphism. In addition, some pathologies are subject to social representations of diseases considered "male" or "female" which can also lead to a delay in diagnosis and management for both sexes. Finally, many drug classes may be subject to sex differences in efficacy and safety. For example, women present more adverse events than men, mainly because of different pharmacokinetic parameters. Accounting sex as a variable from the preclinical phase is essential to improve the transposition of observed results and move towards personalized medicine.

French pharmacovigilance survey of casirivimab - imdevimab monoclonal antibodies in coronavirus disease (COVID-19).

INTRODUCTION: Casirivimab and imdevimab (Ronapreve®) are two recombinant human monoclonal antibodies (mAbs) that bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, preventing the virus from entering cells. In March 2021, this drug was granted emergency use authorisation (EUA) in France for early treatment of COVID-19 in patients at increased risk of progression to severe COVID-19. In August/September 2021, the indication was expanded to COVID-19 prevention (pre- or post-exposure prophylaxis) and treatment of hospitalised patients requiring non-invasive oxygen therapy. The aim of the study was to better describe the adverse drug reaction (ADR) profile and detect safety signals of this new drug used in COVID-19 treatment. METHODS: We described ADR profile with casirivimab/imdevimab reported as suspect/interacting drug to the French pharmacovigilance network and the pharmaceutical company between 17/03/2021 and 30/06/2022. Data presented correspond to the 2 periods of the pharmacovigilance survey: the first carried out by the pharmaceutical company for curative and prophylactic uses and the second by Toulouse university regional pharmacovigilance center (RPVC). RESULTS: A total of 384 reports were analysed and 256 were "serious". ADR profile was comparable between the 2 periods and between curative and prophylactic use, corresponding to expected ADRs such as infusion-related reactions and hypersensitivity, inefficiencies or worsened infections and deaths. Two potential pharmacovigilance signals were also studied: acute pulmonary oedemas and sudden deaths. DISCUSSION: No pharmacovigilance signal emerged from this 15 months French pharmacovigilance survey. Moreover data from published studies are also reassuring. This pharmacovigilance survey was the first one for the new version of EUA and with a new ADR reporting process i.e. declaration to the RPVC instead of the pharmaceutical company. Casirivimab/imdevimab is no longer used in France today but we continue to monitor this drug for any future evidence of resurgent activity on a new variant of Sars-CoV-2.

Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane.

Alcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution ("CTL" group, N = 15), a 5-mg/kg dose of diazepam ("DIA" group, N = 16), a 2-g/kg dose of ethanol ("EtOH" group, N = 18), or a 5-mg/kg dose of diazepam + a 2-g/kg dose of ethanol ("DIA + EtOH" group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between-group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long-term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks.

Sex Differences in Cognitive Impairment Induced by Cerebral Microhemorrhage.

It has been suggested that cerebral microhemorrhages (CMHs) could be involved in cognitive decline. However, little is known about the sex-dependency of this effect. Using a multimodal approach combining behavioral tests, in vivo imaging, biochemistry, and molecular biology, we studied the cortical and hippocampal impact of a CMH in male and female mice (C57BL/6J) 6 weeks post-induction using a collagenase-induced model. Our work shows for the first time that a single cortical CMH exerts sex-specific effects on cognition. It notably induced visuospatial memory impairment in males only. This sex difference might be explained by cortical changes secondary to the lesion. In fact, the CMH induced an upregulation of ERα mRNA only in the female cortex. Besides, in male mice, we observed an impairment of pathways associated to neuronal, glial, or vascular functions: decrease in the P-GSK3ß/GSK3ß ratio, in BDNF and VEGF levels, and in microvascular water mobility. The CMH also exerted spatial remote effects in the hippocampus by increasing the number of astrocytes in both sexes, increasing the mean area occupied by each astrocyte in males, and decreasing hippocampal BDNF in females suggesting a cortical-hippocampal network impairment. This work demonstrates that a CMH could directly affect cognition in a sex-specific manner and highlights the need to study both sexes in preclinical models.

[Adverse drug reactions profiles for abiraterone and enzalutamide: A pharmacovigilance descriptive analysis]. / Profils d'effets indésirables sous abiratérone et enzalutamide : analyse descriptive des données de la base nationale de pharmacovigilance.

OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

Beneficial effects of atorvastatin on sex-specific cognitive impairment induced by a cerebral microhaemorrhage in mice.

BACKGROUND AND PURPOSES: Cerebral microhaemorrhages (CMHs) are associated with cognitive decline in humans. In rodents, CMHs induces cognitive impairment in male mice along with sex-specific cortical and hippocampal changes affecting neural, glial and vascular functions. Statins, have been proposed to prevent cognitive decline. We tested here the action of atorvastatin on CMH-induced cognitive impairment in a murine model of CMH. EXPERIMENTAL APPROACH: Using a multimodal approach combining behavioural tests, in vivo imaging, biochemistry and molecular biology, the effects of oral administration of atorvastatin on the sex-specific changes induced by a cortical CMH were studied in male and female mice (C57BL/6J) at 6-week post-induction using a collagenase-induced model. KEY RESULTS: Atorvastatin caused specific effects according to the sex-specific CMH-induced changes. In males, atorvastatin improved the visuospatial memory, induced a local modulation of microglial response and enhanced brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (trkB) and vascular endothelial growth factor (VEGF) expression in the cortex. In the hippocampus, atorvastatin increased glucose metabolism and modulated astrocytes morphology. In females, atorvastatin did not modulate visuospatial memory despite the increased expression of cortical BDNF and the decrease in the number of hippocampal astrocytes. Atorvastatin also induced a decrease in the expression of cortical oestrogen receptors but did not modify body weight nor serum cholesterol levels in both sexes. CONCLUSION AND IMPLICATIONS: Atorvastatin modulated the sex-specific cognitive impairment induced by the CMH with a pathophysiological impact mainly within the cortical area. It could represent a promising candidate for future sex-stratified clinical trials in patients with CMH.

Role of cortical microbleeds in cognitive impairment: In vivo behavioral and imaging characterization of a novel murine model.

Cerebral microbleeds (CMBs) could contribute to cognitive impairment in the general population and in patients with dementia. We designed a study to (i) develop a murine model of CMBs, (ii) assess whether CMBs affect cognition in this model and (iii) assess whether this model is sensitive to pharmacological modulation. Male C57Bl6/J mice were stereotactically administered collagenase to induce cortical lesion analysed by MRI at 24 h. CMB-mice were assessed at six weeks post-lesion for cognitive performances (Barnes maze and Touchscreen automated paired-associated learning (PAL) task) and for cerebral metabolism (in vivo PET/CT with fluorodeoxyglucose (FDG)). CMB-model sensitivity to pharmacological modulation was assessed by administering atorvastatin (5 mg/kg/day) over the follow-up period. CMB mice were compared to naïve littermates. Collagenase at 0.8 µU/µl appeared suitable to induce reproducible and reliable CMBs. At six weeks, a decline in learning, spatial and visuospatial memory was significantly observed in CMB-mice. Brain metabolism was impaired in all cortex, striatum and the ipsilateral dentate gyrus. A significant improvement in cognition performances was depicted under atorvastatin. In this novel murine model of CMBs, we validated that CMBs lowered cognitive performances and affected regional metabolism. We also proved that this CMB-model is sensitive to pharmacological modulation.