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Neuroprotective Strategies 2024

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 3858

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Special Issue Editor

Prof. Dr. Katalin Prokai-Tatrai

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Guest Editor

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
Interests: drug design of central nervous system agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; CNS-selective estrogen therapy; neuroprotection; proteomics
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Special Issue Information

Dear Colleagues,

We started the “Neuroprotective Strategies” collection jointly with Molecules in 2009. It was a great success; a large number of reviews and original research articles were published in the inaugural volume. Since then, the International Journal of Molecular Sciences has successfully continued this collection, covering neuroprotection broadly, including, but not limited to, preclinical/basic science assessments of various animal models relevant to diseases and agents with potential or perceived translation values. We open up the “Neuroprotective Strategies” Topical Collection to thought-provoking comments, opinions and perspectives, in addition to our traditional reviews and research articles in this field. We especially encourage submissions that address critical issues having prevented successful clinical translations of promising laboratory data. The limitations of in vitro studies and preclinical animal models to mirror multiple pathologies underlying human neurodegenerative diseases, lack of drug-likeness of experimental agents, the need to consider absorption, distribution, metabolism, elimination, toxicology (ADMET) and pharmacokinetics even in the early stage of drug discovery, and obstacles of drug delivery to the CNS are only some of the issues that come to mind regarding this matter. Critical reviews on relevant patent literature are also welcome. I give thanks for past contributions and look forward to receiving future contributions on the promising and challenging aspects of the field. The following links: https://www.mdpi.com/journal/ijms/special_issues/Neuroprotective_strategies_collection point to already published papers within this Special Issue.

Prof. Dr. Katalin Prokai-Tatrai
Guest Editor

Manuscript Submission Information

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Keywords

age-related neurodegeneration
blood–brain barrier
CNS injury
cognition and dementia
drug delivery and drug-likeness
inflammation
in silico drug design and disease models
ischemia and reperfusion
oxidative stress
peripheral nervous system
stem cell
structure–activity relationship
translational medicine

Published Papers (4 papers)

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Research

25 pages, 18703 KiB

Open AccessArticle

Protecting the Brain: Novel Strategies for Preventing Breast Cancer Brain Metastases through Selective Estrogen Receptor β Agonists and In Vitro Blood–Brain Barrier Models

by Janine Kirchner, Elisabeth Völker, Sergey Shityakov, Shigehira Saji and Carola Y. Förster

Int. J. Mol. Sci. 2024, 25(6), 3379; https://doi.org/10.3390/ijms25063379 - 16 Mar 2024

Viewed by 511

Abstract

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood–brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2024)

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13 pages, 1018 KiB

Open AccessArticle

Principal Component Analysis (PCA) of Molecular Descriptors for Improving Permeation through the Blood–Brain Barrier of Quercetin Analogues

by Nebojša Pavlović, Nastasija Milošević Sopta, Darko Mitrović, Dragana Zaklan, Ana Tomas Petrović, Nebojša Stilinović and Saša Vukmirović

Int. J. Mol. Sci. 2024, 25(1), 192; https://doi.org/10.3390/ijms25010192 - 22 Dec 2023

Viewed by 768

Abstract

Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood–brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking. Principal component analysis (PCA) was applied to identify the molecular descriptors contributing to efficient permeation through the BBB. Among 34 quercetin analogues, 19 compounds were found to form more stable complexes with IPMK, and the vast majority were found to be more lipophilic than quercetin. Using two distinct in silico techniques, insufficient BBB permeation was determined for all quercetin analogues. However, using the PCA method, the descriptors related to intrinsic solubility and lipophilicity (logP) were identified as mainly responsible for clustering four quercetin analogues (trihydroxyflavones) with the highest BBB permeability. The application of PCA revealed that quercetin analogues could be classified with respect to their structural characteristics, which may be utilized in further analogue syntheses and lead optimization of BBB-penetrating IPMK modulators as neuroprotective agents. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2024)

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15 pages, 2148 KiB

Open AccessArticle

Differential Effects of Hypothermia and SZR72 on Cerebral Kynurenine and Kynurenic Acid in a Piglet Model of Hypoxic–Ischemic Encephalopathy

by Ferenc Domoki, Valéria Tóth-Szűki, Viktória Kovács, Gábor Remzső, Tímea Körmöczi, László Vécsei and Róbert Berkecz

Int. J. Mol. Sci. 2023, 24(19), 14522; https://doi.org/10.3390/ijms241914522 - 25 Sep 2023

Viewed by 701

Abstract

Kynurenic acid (KYNA), an endogenous neuroprotectant with antiexcitotoxic, antioxidant, and anti-inflammatory effects, is synthesized through the tryptophan-kynurenine (KYN) pathway. We investigated whether brain KYN or KYNA levels were affected by asphyxia in a translational piglet model of hypoxic–ischemic encephalopathy (HIE). We also studied brain levels of the putative blood–brain barrier (BBB) permeable neuroprotective KYNA analogue SZR72, and whether SZR72 or therapeutic hypothermia (TH) modified KYN or KYNA levels. KYN, KYNA, and SZR72 levels were determined using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry in five brain regions 24 h after 20 min of asphyxia in vehicle-, SZR72- and TH-treated newborn piglets (n = 6-6-6) and naive controls (n = 4). Endogenous brain KYN levels (median range 311.2–965.6 pmol/g) exceeded KYNA concentrations (4.5–6.0 pmol/g) ~100-fold. Asphyxia significantly increased cerebral KYN and KYNA levels in all regions (1512.0–3273.9 and 16.9–21.2 pmol/g, respectively), increasing the KYN/Tryptophan-, but retaining the KYNA/KYN ratio. SZR72 treatment resulted in very high cerebral SZR72 levels (13.2–33.2 nmol/g); however, KYN and KYNA levels remained similar to those of the vehicle-treated animals. However, TH virtually ameliorated asphyxia-induced elevations in brain KYN and KYNA levels. The present study reports for the first time that the KYN pathway is altered during HIE development in the piglet. SZR72 readily crosses the BBB in piglets but fails to affect cerebral KYNA levels. Beneficial effects of TH may include restoration of the tryptophan metabolism to pre-asphyxia levels. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2024)

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17 pages, 2446 KiB

Open AccessArticle

Quetiapine Moderates Doxorubicin-Induced Cognitive Deficits: Influence of Oxidative Stress, Neuroinflammation, and Cellular Apoptosis

by Vasudevan Mani and Bander Shehail Alshammeri

Int. J. Mol. Sci. 2023, 24(14), 11525; https://doi.org/10.3390/ijms241411525 - 16 Jul 2023

Cited by 2 | Viewed by 1338

Abstract

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2024)

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