Implications of sex-related differences in central nervous system disorders for drug research and development

Butlen-Ducuing, Florence; Bałkowiec-Iskra, Ewa; Dalla, Christina; Slattery, David A.; Ferretti, Maria Teresa; Kokras, Nikolaos; Balabanov, Pavel; Vries, Corinne De; Mellino, Simona; Chadha, Antonella Santuccione

doi:10.1038/d41573-021-00115-6

Cited by 18 publications

(13 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, such knowledge is relatively new and now unfolding for many of those systems, especially with the help of evidence gathered from the presence of those transporters in peripheral barriers, such as in the gastrointestinal tract, the liver, and the kidneys. On the other hand, there is strong evidence that many neuropsychiatric disorders present significant sex differences ( Balta et al, 2019 ) and preclinical research is progressing into incorporating sex as an important biological variable ( Butlen-Ducuing et al, 2021 ). Moreover, psychotropic medication present noteworthy pharmacodynamic and interestingly, pharmacokinetic sex differences ( Kokras et al, 2011 ; Seeman, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Dalla

Pavlidi

Sakelliadou

et al. 2022

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

Treatment of neuropsychiatric disorders relies on the effective delivery of therapeutic molecules to the target organ, the brain. The blood–brain barrier (BBB) hinders such delivery and proteins acting as transporters actively regulate the influx and importantly the efflux of both endo- and xeno-biotics (including medicines). Neuropsychiatric disorders are also characterized by important sex differences, and accumulating evidence supports sex differences in the pharmacokinetics and pharmacodynamics of many drugs that act on the brain. In this minireview we gather preclinical and clinical findings on how sex and sex hormones can influence the activity of those BBB transporter systems and affect the brain pharmacokinetics of psychotropic medicines. It emerges that it is not well understood which psychotropics are substrates for each of the many and not well-studied brain transporters. Indeed, most evidence originates from studies performed in peripheral tissues, such as the liver and the kidneys. None withstanding, accumulated evidence supports the existence of several sex differences in expression and activity of transport proteins, and a further modulating role of gonadal hormones. It is proposed that a closer study of sex differences in the active influx and efflux of psychotropics from the brain may provide a better understanding of sex-dependent brain pharmacokinetics and pharmacodynamics of psychotropic medicines.

show abstract

Section: Introductionmentioning

confidence: 99%

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Dalla

Pavlidi

Sakelliadou

et al. 2022

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Such progress at the education, research and advocacy level is poised also to impact drug development and regulatory activities, where increased attention to sex and gender factors is needed to achieve precision medicine. Following the example of the US Food and Drug Administration, the European regulatory agencies are also focusing on these topics with a number of research, educational and advocacy initiatives [16]. The series of Regulatory Roundtables led by the WBP is spearheading this discussion.…”

Section: Resultsmentioning

confidence: 99%

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience

Hentzen

Ferretti

Santuccione

et al. 2022

Euro J of Neurology

Self Cite

View full text Add to dashboard Cite

Background and purpose Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio‐cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience. Methods We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from literature searches, policy documents and reports by the European Commission and national funding agencies, web‐based searches, Web of Science, and searches of project databases of funding agencies. An informative/non‐systematic search was performed for sections on policies and funding, education, and basic research, while a systematic literature and database review was conducted for quantitative analysis of research output and funded projects in terms of sex and gender analysis. Results Our mapping shows that there is a growing interest in and attention given to sex and gender considerations in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities. Conclusion We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

show abstract

“…Multiple attempts have been made to overcome this issue, but even efforts in which experimental conditions were fully standardized between laboratories have not been completely successful. This may not be surprising given that behavioral testing, for example, is sensitive to environmental factors such as housing conditions (background noise, olfactory cues), experimenter interactions, and the sex or strain of the animal under investigation ( Sousa et al, 2006 ; Bohlen et al, 2014 ; Riedel et al, 2018 ; Pawluski et al, 2020 ; Butlen-Ducuing et al, 2021 ). Many multi-laboratory studies have also observed significant differences between mouse strains and interactions of genotype ∗ laboratory despite efforts to rigorously standardize both housing conditions and experimental design ( Wolfer et al, 2004 ; Richter et al, 2011 ).…”

Section: Introduction and Rationalementioning

confidence: 99%

PEERS — An Open Science “Platform for the Exchange of Experimental Research Standards” in Biomedicine

Sil

Bespalov²,

Dalla

et al. 2021

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should have been considered a priori. To address this problem, we developed “PEERS” (Platform for the Exchange of Experimental Research Standards), an open-access online platform that is built to aid scientists in determining which experimental factors and variables are most likely to affect the outcome of a specific test, model or assay and therefore ought to be considered during the design, execution and reporting stages. The PEERS database is categorized into in vivo and in vitro experiments and provides lists of factors derived from scientific literature that have been deemed critical for experimentation. The platform is based on a structured and transparent system for rating the strength of evidence related to each identified factor and its relevance for a specific method/model. In this context, the rating procedure will not solely be limited to the PEERS working group but will also allow for a community-based grading of evidence. We here describe a working prototype using the Open Field paradigm in rodents and present the selection of factors specific to each experimental setup and the rating system. PEERS not only offers users the possibility to search for information to facilitate experimental rigor, but also draws on the engagement of the scientific community to actively expand the information contained within the platform. Collectively, by helping scientists search for specific factors relevant to their experiments, and to share experimental knowledge in a standardized manner, PEERS will serve as a collaborative exchange and analysis tool to enhance data validity and robustness as well as the reproducibility of preclinical research. PEERS offers a vetted, independent tool by which to judge the quality of information available on a certain test or model, identifies knowledge gaps and provides guidance on the key methodological considerations that should be prioritized to ensure that preclinical research is conducted to the highest standards and best practice.

show abstract

Implications of sex-related differences in central nervous system disorders for drug research and development

Cited by 18 publications

References 4 publications

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience

PEERS — An Open Science “Platform for the Exchange of Experimental Research Standards” in Biomedicine

Contact Info

Product

Resources

About