Sex differences in the blood–brain barrier: Implications for mental health

Dion‐Albert, Laurence; Binder, Luisa Bandeira; Daigle, Beatrice; Hong-Minh, Amandine; Lebel, Manon; Ménard, Caroline

doi:10.1016/j.yfrne.2022.100989

Cited by 48 publications

(48 citation statements)

References 472 publications

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“…As the purpose of such sex differences remains unclear, it is postulated that the mammalian reproductive process exerted a selection pressure that explains those sexual dimorphisms ( Gilks et al, 2014 ; Della Torre and Maggi, 2017 ). As elegantly reviewed elsewhere, this is reflected to several sex differences at the BBB in health and disease, regarding, but not limited to BBB strength, metabolism, response to stressors and involvement of several pathways, classic and non-classic genomic, as well as non-genomic, involving NO signaling, matrix metalloproteinases, the RhoA/Rho-kinase-2 pathway and other estrogens-mediated pathways ( Weber and Clyne, 2021 ; Dion-Albert et al, 2022a ).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Dalla

Pavlidi

Sakelliadou

et al. 2022

Front. Behav. Neurosci.

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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.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

Dalla

Pavlidi

Sakelliadou

et al. 2022

Front. Behav. Neurosci.

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“…Conversely, Cldn3 expression is reduced in the JEJ of female mice (Fig. 2B, right, p=0.008) which are characterized by stress-induced anxiety-and depression-like behaviors 14 . Exposure to 28-d CVS is associated with the development of maladaptive behaviors in both sexes 34 nevertheless, Cldn3 expression was reduced only in males (Fig.…”

Section: Changes In Jejunum Tight Junction Expression Are Dependent O...mentioning

confidence: 95%

“…The SS subgroup display distinct behavioral changes reminiscent of depressive symptoms in humans with increased social avoidance, anxiety, anhedonia, despair, body weight changes, metabolic disturbances, and corticosterone reactivity [21][22][23] . Furthermore, loss of BBB integrity occurs only in the brain of SS, but not RES, mice 12,14 . Another leading stress paradigm is the chronic variable stress (CVS) model, during which mice are exposed to a repetitive sequence of three stressors, namely tube restraint, tail suspension, and foot shocks.…”

Section: Introductionmentioning

confidence: 92%

“…We recently reported that CSDS alters BBB integrity in a sex-specific manner 12,14 , which may contribute to the sex differences observed in MDD prevalence, symptoms, and treatment response. In female mice, exposure to CSDS (Fig.…”

Section: Chronic Social Stress Alters Intestinal Tight Junction Expre...mentioning

confidence: 99%

“…Stress has been linked to the deterioration of the intestinal barrier via alterations of gut-brain signaling 10,11 . We recently showed that it can alter blood-brain barrier (BBB) integrity in a sex-specific manner through loss of the tight junction protein Claudin-5 (Cldn5), leading to the development of anxiety-and depression-like behaviors [12][13][14][15] . To our knowledge, the impact of stress exposure on gut barrier integrity and assessment of sex differences has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Chronic stress exposure alters the gut barrier: sex-specific effects on microbiota and jejunum tight junctions

Doney

Dion‐Albert

Coulombe-Rozon

et al. 2022

Preprint

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Major depressive disorder (MDD) is the leading cause of disability worldwide. However, 30-50% of patients are unresponsive to commonly prescribed antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis, the bidirectional communications between the central nervous system and gastrointestinal tract that are modulated by gut microorganisms, has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity, still, little is known about intestinal barrier function in these conditions particularly for the small intestine where most food and drug absorption takes place. Thus, here we investigate how chronic social or variable stress, two mouse models of depression, impact the jejunum (JEJ) intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Altered microbial populations as well as changes in gene expression of JEJ tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We took advantage of machine learning to characterize in detail morphological tight junction properties identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated if LPS injection recapitulates stress-induced changes in the JEJ and observed profound sex differences. Finally, LPS-binding protein (LBP), a marker of gut barrier leakiness, was associated with stress vulnerability in mice and translational value was confirmed on blood samples from women with MDD. Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and possibly, human depression.

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