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Blood-Brain Barrier in CNS Injury and Repair 2022

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 37595

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Special Issue Editors

Prof. Dr. Hari Shanker Sharma

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Guest Editor

Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, 751 85 Uppsala, Sweden
Interests: blood–brain barrier; brain edema; neurochemistry; neurophysiology; neuropathology; nanoneuroscience; nanoneuropharmacology; neuroregeneration; central nervous system injury; traumatic brain injury; neurorepair; military medicine; Alzheimer’s disease; Parkinson’s disease; neurotrophic factors
Special Issues, Collections and Topics in MDPI journals

Dr. Aruna Sharma

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Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, 751 85 Uppsala, Sweden
Interests: military medicine; high altitude brain pathology; blood–brain barrier; nanodrug delivery; stem cells; neuroregeneration; nanowired drug delivery; neurodegeneration; behavioural physiology; neurochemistry; Alzheimer’s disease; Parkinson’s disease; brain pathology; neurorepair
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nuno Vale

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Department of Community Medicine, Health Information and Decision, Faculty of Medicine, University of Porto, Rua Dr. Plácido da Costa, 4200-450, Porto, Portugal
Interests: in silico pharmacology; PBPK; drug metabolism; drug combination; drug delivery; peptides; ADME; DMPK; pharmacokinetic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The blood–brain barrier (BBB) regulates the fluid environment of the brain strictly within a narrow limit. The BBB is anatomically positioned within the endothelial cells of the cerebral capillaries that are connected with tight junctions. Thus, the passage of substances, drugs, proteins, and other large molecules is severely restricted at the BBB. However, all kinds of brain diseases following trauma, ischemia, strenuous activity stress, psychiatric illnesses and/or psychostimulant overuse, etc. are associated with the breakdown of the BBB to large molecules, e.g., proteins. Additionally, several neurological diseases, e.g., Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as amyotrophic lateral sclerosis, neuropathic pain, liver cirrhosis, hypertension and/or diabetes, and related chronic disorders are associated with the breakdown of the BBB. Furthermore, BBB breakdown allows the passage of serum proteins and other toxins into the fluid microenvironment of the central nervous system (CNS), resulting in cerebral edema formation and subsequent cellular injuries. Interestingly, no suitable therapeutic strategies have yet been worked out to treat such neurological diseases. This Special Issue will present new developments in the field of BBB research to improve current therapeutic measures as well as provide a platform to discuss the use of nanomedicine in several CNS diseases for the benefit of mankind. We ask experts in the field to contribute their latest research, perspectives, or reviews on this fascinating and rapidly progressing topic.

Prof. Dr. Hari Shanker Sharma
Dr. Aruna Sharma
Prof. Dr. Nuno Vale
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

blood–brain barrier
brain edema
neurodegeneration
neurorepair
cerebral blood flow
blood–spinal cord barrier
blood–CSF-barrier
Alzheimer’s disease
Parkinson’s disease
psychostimulants
brain pathology
nanomedicine

Published Papers (12 papers)

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Research

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20 pages, 1018 KiB

Open AccessArticle

Does the Blood–Brain Barrier Integrity Change in Regard to the Onset of Fetal Growth Restriction?

by Natalia Misan, Sławomir Michalak, Katarzyna Kapska, Krystyna Osztynowicz, Mariola Ropacka-Lesiak and Katarzyna Kawka-Paciorkowska

Int. J. Mol. Sci. 2023, 24(3), 1965; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031965 - 19 Jan 2023

Cited by 2 | Viewed by 1420

Abstract

The aim of the study was to determine whether early-onset and late-onset fetal growth restriction (FGR) differentially affects the blood–brain barrier integrity. Furthermore, the purpose of the study was to investigate the relationship between the blood–brain barrier breakdown and neurological disorders in FGR newborns. To evaluate the serum tight junction (TJ) proteins and the placental TJ proteins expression, an ELISA method was used. A significant difference in serum OCLN concentrations was noticed in pregnancies complicated by the early-onset FGR, in relation to the intraventricular hemorrhage (IVH) occurrence in newborns. No significant differences in concentrations of the NR1 subunit of the N-methyl-d-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), zonula occludens-1 (zo-1), the CLN5/zo-1 ratio, and the placental expression of OCLN, CLN5, claudin-4 (CLN4), zo-1 were noticed between groups. The early-onset FGR was associated with a higher release of NME1 into the maternal circulation in relation to the brain-sparing effect and premature delivery. Additionally, in late-onset FGR, the higher release of the S100B into the maternal serum in regard to fetal distress was observed. Furthermore, there was a higher release of zo-1 into the maternal circulation in relation to newborns’ moderate acidosis in late-onset FGR. Blood–brain barrier disintegration is not dependent on pregnancy advancement at the time of FGR diagnosis. NME1 may serve as a biomarker useful in the prediction of fetal circulatory centralization and extremely low birth weight in pregnancies complicated by the early-onset FGR. Moreover, the serum zo-1 concentration may have prognostic value for moderate neonatal acidosis in late-onset FGR pregnancies. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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15 pages, 4948 KiB

Open AccessArticle

Mycobacterium tuberculosis Cell Wall Antigens Induce the Formation of Immune Complexes and the Development of Vasculitis in an Experimental Murine Model

by Flaubert Alexis Pérez-Noriega, Citlaltepetl Salinas-Lara, Carlos Sánchez-Garibay, José Jiram Torres-Ruíz, José Luis Maravillas-Montero, Mauricio Castañón-Arreola, María Elena Hernández-Campos, Cesar Rodríguez-Balderas, Beatriz Victoria Basurto-López, Carlos Peñafiel-Salgado, Ana Paola Espinosa-García, José Alberto Choreño-Parra, Martha Lilia Tena-Suck, Luis O. Soto-Rojas, Elsa Y. León-Marroquín, José Pablo Romero-López and Manuel Castillejos-López

Int. J. Mol. Sci. 2023, 24(2), 1242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021242 - 08 Jan 2023

Viewed by 1953

Abstract

Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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12 pages, 1375 KiB

Open AccessArticle

Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study

by Allegra Conti, Francoise Geffroy, Hermes A. S. Kamimura, Anthony Novell, Nicolas Tournier, Sébastien Mériaux and Benoit Larrat

Int. J. Mol. Sci. 2022, 23(24), 15488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415488 - 07 Dec 2022

Cited by 5 | Viewed by 1226

Abstract

The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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18 pages, 818 KiB

Open AccessArticle

Blood-Brain Barrier Disintegration in Growth-Restricted Fetuses with Brain Sparing Effect

by Natalia Misan, Sławomir Michalak, Katarzyna Kapska, Krystyna Osztynowicz and Mariola Ropacka-Lesiak

Int. J. Mol. Sci. 2022, 23(20), 12349; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012349 - 15 Oct 2022

Cited by 7 | Viewed by 1819

Abstract

The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein – 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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15 pages, 2970 KiB

Open AccessArticle

Cytoskeleton Elements Contribute to Prion Peptide-Induced Endothelial Barrier Breakdown in a Blood–Brain Barrier In Vitro System

by Itzik Cooper, Katayun Cohen-Kashi Malina, Yishai Levin, Alexandra Gabashvili, Boaz Mohar, Alfredo Cagnotto, Mario Salmona and Vivian I. Teichberg

Int. J. Mol. Sci. 2022, 23(20), 12126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012126 - 12 Oct 2022

Viewed by 1156

Abstract

The mechanisms involved in the interaction of PrP 106-126, a peptide corresponding to the prion protein amyloidogenic region, with the blood–brain barrier (BBB) were studied. PrP 106-126 treatment that was previously shown to impair BBB function, reduced cAMP levels in cultured brain endothelial cells, increased nitric oxide (NO) levels, and changed the activation mode of the small GTPases Rac1 (inactivation) and RhoA (activation). The latter are well established regulators of endothelial barrier properties that act via cytoskeletal elements. Indeed, liquid chromatography-mass spectrometry (LC-MS)-based proteomic profiling study revealed extensive changes in expression of cytoskeleton-related proteins. These results shed light on the nature of the interaction between the prion peptide PrP 106-126 and the BBB and emphasize the importance of the cytoskeleton in endothelium response to prion- induced stress. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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22 pages, 6587 KiB

Open AccessArticle

Growth Hormone (GH) Crosses the Blood–Brain Barrier (BBB) and Induces Neuroprotective Effects in the Embryonic Chicken Cerebellum after a Hypoxic Injury

by Rosario Baltazar-Lara, Janeth Mora Zenil, Martha Carranza, José Ávila-Mendoza, Carlos G. Martínez-Moreno, Carlos Arámburo and Maricela Luna

Int. J. Mol. Sci. 2022, 23(19), 11546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911546 - 30 Sep 2022

Cited by 5 | Viewed by 2074

Abstract

Several motor, sensory, cognitive, and behavioral dysfunctions are associated with neural lesions occurring after a hypoxic injury (HI) in preterm infants. Growth hormone (GH) expression is upregulated in several brain areas when exposed to HI conditions, suggesting actions as a local neurotrophic factor. It is known that GH, either exogenous and/or locally expressed, exerts neuroprotective and regenerative actions in cerebellar neurons in response to HI. However, it is still controversial whether GH can cross the blood–brain barrier (BBB), and if its effects are exerted directly or if they are mediated by other neurotrophic factors. Here, we found that in ovo microinjection of Cy3-labeled chicken GH resulted in a wide distribution of fluorescence within several brain areas in the chicken embryo (choroid plexus, cortex, hypothalamus, periventricular areas, hippocampus, and cerebellum) in both normoxic and hypoxic conditions. In the cerebellum, Cy3-GH and GH receptor (GHR) co-localized in the granular and Purkinje layers and in deep cerebellar nuclei under hypoxic conditions, suggesting direct actions. Histological analysis showed that hypoxia provoked a significant modification in the size and organization of cerebellar layers; however, GH administration restored the width of external granular layer (EGL) and molecular layer (ML) and improved the Purkinje and granular neurons survival. Additionally, GH treatment provoked a significant reduction in apoptosis and lipoperoxidation; decreased the mRNA expression of the inflammatory mediators (TNFα, IL-6, IL-1β, and iNOS); and upregulated the expression of several neurotrophic factors (IGF-1, VEGF, and BDNF). Interestingly, we also found an upregulation of cerebellar GH and GHR mRNA expression, which suggests the existence of an endogenous protective mechanism in response to hypoxia. Overall, the results demonstrate that, in the chicken embryo exposed to hypoxia, GH crosses the BBB and reaches the cerebellum, where it exerts antiapoptotic, antioxidative, anti-inflammatory, neuroprotective, and neuroregenerative actions. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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16 pages, 7122 KiB

Open AccessArticle

Mycobacterium tuberculosis Infection Induces BCSFB Disruption but No BBB Disruption In Vivo: Implications in the Pathophysiology of Tuberculous Meningitis

by Carlos Sánchez-Garibay, Citlaltepetl Salinas-Lara, Marcos Artemio Gómez-López, Luis O. Soto-Rojas, Nidia Karen Castillón-Benavides, Omar Jorge Castillón-Benavides, María Elena Hernández-Campos, Rogelio Hernández-Pando, Brenda Marquina-Castillo, Manuel Alejandro Flores-Barrada, José Alberto Choreño-Parra, Juan Carlos León-Contreras, Martha Lilia Tena-Suck, Dulce Adriana Mata-Espinosa, Porfirio Nava, Jessica Medina-Mendoza and Cesar Augusto Rodríguez-Balderas

Int. J. Mol. Sci. 2022, 23(12), 6436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126436 - 09 Jun 2022

Cited by 7 | Viewed by 2802

Abstract

Central nervous system (CNS) tuberculosis is the most lethal and devastating form among the diseases caused by Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis bacilli enter the CNS are still unclear. However, the BBB and the BCSFB have been proposed as possible routes of access into the brain. We previously reported that certain strains of M. tuberculosis possess an enhanced ability to cause secondary CNS infection in a mouse model of progressive pulmonary tuberculosis. Here, we evaluated the morphostructural and molecular integrity of CNS barriers. For this purpose, we analyzed through transmission electron microscopy the ultrastructure of brain parenchymal microvessels and choroid plexus epithelium from animals infected with two mycobacterial strains. Additionally, we determined the expression of junctional proteins and cytokines by immunological techniques. The results showed that the presence of M. tuberculosis induced disruption of the BCSFB but no disruption of the BBB, and that the severity of such damage was related to the strain used, suggesting that variations in the ability to cause CNS disease among distinct strains of bacteria may also be linked to their capacity to cause direct or indirect disruption of these barriers. Understanding the pathophysiological mechanisms involved in CNS tuberculosis may facilitate the establishment of new biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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13 pages, 6516 KiB

Open AccessArticle

Cell Model of Depression: Reduction of Cell Stress with Mirtazapine

by Ana Salomé Correia, Sónia Fraga, João Paulo Teixeira and Nuno Vale

Int. J. Mol. Sci. 2022, 23(9), 4942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094942 - 29 Apr 2022

Cited by 12 | Viewed by 2654

Abstract

Depression is a very prevalent and complex disease. This condition is associated with a high rate of relapse, making its treatment a challenge. Thus, an intensive investigation of this disease and its treatment is necessary. In this work, through cell viability assays (MTT and neutral red assays) and alkaline comet assays, we aimed to test the induction of stress in human SH-SY5Y cells through the application of hydrocortisone and hydrogen peroxide and to test the reversal or attenuation of this stress through the application of mirtazapine to the cells. Our results demonstrated that hydrogen peroxide, and not hydrocortisone, can induce cellular stress, as evidenced by DNA damage and a global cellular viability reduction, which were alleviated by the antidepressant mirtazapine. The establishment of a cellular model of depression through stress induction is important to study new possibilities of treatment of this disease using cell cultures. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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13 pages, 2790 KiB

Open AccessArticle

Syndecan-3 as a Novel Biomarker in Alzheimer’s Disease

by Anett Hudák, Annamária Letoha, Csaba Vizler and Tamás Letoha

Int. J. Mol. Sci. 2022, 23(6), 3407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063407 - 21 Mar 2022

Cited by 6 | Viewed by 3855

Abstract

Early diagnosis of Alzheimer’s disease (AD) is of paramount importance in preserving the patient’s mental and physical health in a fairly manageable condition for a longer period. Reliable AD detection requires novel biomarkers indicating central nervous system (CNS) degeneration in the periphery. Members of the syndecan family of transmembrane proteoglycans are emerging new targets in inflammatory and neurodegenerative disorders. Reviewing the growing scientific evidence on the involvement of syndecans in the pathomechanism of AD, we analyzed the expression of the neuronal syndecan, syndecan-3 (SDC3), in experimental models of neurodegeneration. Initial in vitro studies showed that prolonged treatment of tumor necrosis factor-alpha (TNF-α) increases SDC3 expression in model neuronal and brain microvascular endothelial cell lines. In vivo studies revealed elevated concentrations of TNF-α in the blood and brain of APPSWE-Tau transgenic mice, along with increased SDC3 concentration in the brain and the liver. Primary brain endothelial cells and peripheral blood monocytes isolated from APPSWE-Tau mice exhibited increased SDC3 expression than wild-type controls. SDC3 expression of blood-derived monocytes showed a positive correlation with amyloid plaque load in the brain, demonstrating that SDC3 on monocytes is a good indicator of amyloid pathology in the brain. Given the well-established role of blood tests, the SDC3 expression of monocytes could serve as a novel biomarker for early AD detection. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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12 pages, 5514 KiB

Open AccessArticle

Severe Acute Hepatic Dysfunction Induced by Ammonium Acetate Treatment Results in Choroid Plexus Swelling and Ventricle Enlargement in the Brain

by Kazuhiko Nakadate and Sumito Kamata

Int. J. Mol. Sci. 2022, 23(4), 2010; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042010 - 11 Feb 2022

Cited by 7 | Viewed by 1900

Abstract

Hepatic encephalopathy is a major cause of liver failure. However, the pathophysiological role of ventricle enlargement in brain edema remains unclear. Here, we used an acute hepatic encephalopathy mouse model to examine the sequential pathological changes in the brain associated with this condition. We collected tissue samples from experimental animals treated with ammonium acetate at 3 and 24 h post-injection. Despite the normalization of the animal’s ammonia levels, samples taken at 24 h after injection exhibited distinct enlargement of lateral ventricles. The choroid plexus samples obtained at 3 h post-ammonium acetate treatment indicated enlargement; however, this swelling was reduced at the later timepoint. The aquaporin-1 proteins that regulate the choroid plexus were localized both in the apical membrane and the cytoplasm of the epithelia in the control; however, they translocated to the apical membranes of the epithelia in response to ammonia treatment. Therefore, severe acute hepatic encephalopathy induced by ammonium acetate administration caused enlargement of the ventricles, through swelling of the choroid plexus and aquaporin-1 transport and aggregation within the apical membranes. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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Review

Jump to: Research

21 pages, 709 KiB

Open AccessReview

Understanding Lamotrigine’s Role in the CNS and Possible Future Evolution

by Bárbara Costa and Nuno Vale

Int. J. Mol. Sci. 2023, 24(7), 6050; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076050 - 23 Mar 2023

Cited by 6 | Viewed by 5386

Abstract

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG’s unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG’s potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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17 pages, 1207 KiB

Open AccessReview

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

by Ana Salomé Correia and Nuno Vale

Int. J. Mol. Sci. 2022, 23(15), 8493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158493 - 31 Jul 2022

Cited by 63 | Viewed by 9565

Abstract

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways. Full article

(This article belongs to the Special Issue Blood-Brain Barrier in CNS Injury and Repair 2022)

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