The role of brain barriers in the neurokinetics and pharmacodynamics of lithium

Luo, Huilong; Chevillard, L; Bellivier, Frank; Mégarbane, Bruno; Étain, Bruno; Cisternino, Salvatore; Declèves, Xavier

doi:10.1016/j.phrs.2021.105480

Cited by 9 publications

(5 citation statements)

References 185 publications

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“…41 Significantly decreased hippocampal BBB permeability has been reported in rats exposed to lithium, while lithium treatment increases the expression of hippocampal claudin-5 and brain-derived neurotrophic factor protein. [42][43][44] A decrease in proinflammatory molecule levels and an increase in occludin and claudin-5 levels has been reported in mice treated with valproic acid. 11 Low antipsychotic drug doses have been linked to neuroprotection in the majority of studies, while higher doses have been associated with cytotoxic effects on BBB endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Serum Zonulin and Occludin Levels in Bipolar Disorder

Zengil¹,

Laloğlu²

2023

Psychiatry Investig

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Objective The etiology of bipolar disorder (BD) is still not fully understood. Little is currently known about the relationship between the interaction the gastrointestinal system and brain function and BD. Zonulin is the only known physiological modulator of tight junctions and is a biomarker for intestinal permeability (IP). Occludin is an integral transmembrane tight junction protein involved in the maintenance and assembly of such junctions. The current study aims to determine whether zonulin and occludin levels are altered in BD and whether they can serve as clinical biomarkers of disease.Methods Forty-four patients with BD and 44 healthy controls were included in this study. The Young Mania Rating Scale (YMRS) was used to determine the severity of manic symptoms, while the Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depressive symptoms, and the Brief Functioning Rating Scale (FAST) to assess functionality. Venous blood samples were taken from all participants and serum zonulin and occludin levels were measured.Results The mean serum zonulin and occludin levels of the patients were significantly higher compared to the healthy control group. There was no difference between manic, depressive, and euthymic patients in terms of zonulin and occludin levels. There was no correlation between the total number of attacks, duration of disease, YMRS, HDRS, FAST scores, and zonulin and occludin levels in the patient group. The groups were divided into three according to body mass index as normal, overweight, and obese. Zonulin and occludin levels increased as body mass index increased and were highest in the obese group.Conclusion The study shows that zonulin and occludin levels in BD increase independently of the disease stage. Consideration of the role of IP in the pathogenesis of BD may be helpful in determining the appropriate treatment modality.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Serum Zonulin and Occludin Levels in Bipolar Disorder

Zengil¹,

Laloğlu²

2023

Psychiatry Investig

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“…In future in vivo studies, it will be necessary to determine whether RBCLC or PLC better correlates with the responseassociated molecular signature. v) Correlations between intra-cerebral, plasma, and RBC lithium concentrations Lithium transport through the brain barriers is crucial to achieve adequate concentrations in the brain parenchyma, where it interacts with its pharmacological targets (Luo et al 2021). Regional permeability of the BBB and the blood cerebrospinal uid barrier (BCSFB) may represent variability factors affecting lithium exchanges between blood and brain, and brain distribution.…”

Section: Iv) Molecular Signaturesmentioning

confidence: 99%

Relevance of red blood cell Lithium concentration in the management of Lithium-treated bipolar and unipolar disorders: a systematic narrative review

COYAC,

JALABERT,

DECLEVES

et al. 2024

Preprint

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Background: Despite a variability in response and a narrow therapeutic index, lithium remains the gold standard treatment for bipolar disorders (BD), and a treatment of choice for non-bipolar mood disorders (MD). To date, the relevance of red blood cell (RBC) lithium monitoring remains unclear in the management of MD. This systematic review aims to provide a summary of areas in which the interest of lithium concentration monitoring was explored in the literature, and to discuss the relevance of such monitoring in the management of lithium-treated individuals. Methods: We conducted a systematic review, based on preferred reporting items for systematic reviews and Metanalysis (PRISMA) guidelines, of articles published between 1973 and February 2023, indexed in the following databases: EMBASE, MEDLINE, Cochrane Library. The search terms were combinations of the following headings: “Lithium AND Plasma AND Erythrocyte AND Mood disorders”. The systematic review protocol was published to PROSPERO (CRD42023406154). Results: Out of the 252 identified studies, 57 met the selection criteria. These studies primarily investigated the measurement of Red Blood Cell lithium concentration (RBCLC) in various areas: compliance (5 articles), SE/toxicity (13 articles), prediction of lithium response/therapeutic efficacy (17 articles), differences according to the type of MD (18 articles) and to the polarity of mood episodes (10 articles), associated clinical and socio-demographic factors (33 articles), and potential pathophysiological mechanisms (30 articles). The heterogeneity in methods and results, coupled with the limited amount of data, precludes any firm conclusion regarding the relevance of measuring RBCLC. However, the literature indicates a potential association between RBCLC and side effects (SE), particularly neurotoxicity. Surprisingly, the relevance of monitoring RBCLC is yet to be conclusively demonstrated, and its indications still require to be specified. In this context, we propose avenues of research aimed at exploring the relevance of measuring RBCLC. Conclusions: Despite decades of research on lithium, the relevance of monitoring RBCLC in the management of MD remains unclear. This underscores the imperative for high-quality research involving large representative samples.

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“…A well supported potential mechanism for lithium's effects on the BBB is through inhibition of GSK-3β. GSK-3β is thought to contribute to rearranging the subcellular distribution of tight junctions and inhibition of the Wnt/β-catenin pathway, which when activated serves to protect BBB integrity through increasing tight junction protein formation ( Luo et al., 2021 ).…”

Section: The Bbb and Pharmacologic Implications In Bdmentioning

confidence: 99%

“…In addition, lithium treatment was found to upregulate hippocampal claudin-5 and brain derived neurotrophic factor protein expression ( Taler et al., 2021 ). In vitro studies of lithium compounds have demonstrated variable effects on P-gp expression depending on the dosage administered, where low doses have been associated with inhibitory effects and doses outside the therapeutic range have been shown to induce P-gp expression ( Luo et al., 2021 ; Newman et al., 2017 ).…”

Section: The Bbb and Pharmacologic Implications In Bdmentioning

confidence: 99%

“…However, a recent review summarized current literature on “the role of brain barriers in the neurokinetics and pharmacodynamics of lithium” indicating that lithium may not only have an effect on the BBB, but patient BBB and blood-cerebrospinal fluid barrier integrity may also impact lithium response. More than half of patients with BD do not respond to lithium treatment, and lithium transport to and throughout the brain may play a role in patients' variable treatment responsivity ( Luo et al., 2021 ). In light of this, further study of lithium's interaction with the BBB and BBB-associated proteins such as GSK-3β in patients may serve as fruitful areas for drug development and personalized medicine.…”

Section: The Bbb and Pharmacologic Implications In Bdmentioning

confidence: 99%

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