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Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—3rd Edition
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Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—3rd Edition

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 3902

Special Issue Editors

Prof. Dr. Ramunė Morkūnienė

E-Mail Website
Guest Editor
1. Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
2. Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
Interests: cell death; energy metabolism; mitochondria; inflammation; neurodegenerative disorders; ischemia/reperfusion; amyloid proteins; brain cell cultures
Special Issues, Collections and Topics in MDPI journals
Dr. Dalia M. Kopustinskiene

E-Mail Website
Guest Editor
Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
Interests: protective and toxic mechanisms of bioactive compounds; ischemia; anoxia; stress conditions; cellular energy turnover; mitochondrial functions; ion channels; computer modeling in drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The world’s population is aging. Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, etc. In addition, aging is the strongest risk factor for ischemic stroke, and brain ischemia could progress and lead to the development of neurodegeneration. Both pathologies are life-threatening and may cause death or severe complications. Consequently, new therapies are constantly being sought out; one of the research directions explores the search for effective neuroprotective agents. Oxidative stress, mitochondrial injury, and inflammation activation leading to brain cell death have been suggested as key mechanisms of irreversible damage in many neurological disorders. The accumulation of several oxidation products in neurons during aging and pathological conditions supports the idea that the presence of natural antioxidant biomolecules may be a beneficial alternative therapy for neurodegeneration and other related diseases. Consequently, mitochondria-targeted or inflammatory response-regulated bioactive compounds may be promising candidate therapeutics for the prevention of brain cell death. We would like to invite you to submit original research papers or review articles to this Special Issue on “Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease”, addressing any research topic highlighting the recent identification of synthetic or natural-based bioactive molecules that alleviate brain cell damage.

Prof. Dr. Ramunė Morkūnienė
Dr. Dalia M. Kopustinskiene
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • brain
  • neuroprotection
  • neurodegenerative diseases
  • ischemia
  • mitochondria
  • oxidative stress
  • inflammation
  • bioactive compounds

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Related Special Issues

Published Papers (3 papers)

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Research

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18 pages, 3074 KB  
Article
NXC736, a Functional Antagonist of S1P4, Attenuates Brain Injury in Mice with Permanent Ischemic Stroke
by Nikita Basnet, Supriya Tiwari, Kyung Hee Choi, Donghee Kim and Ji Woong Choi
Molecules 2025, 30(23), 4504; https://doi.org/10.3390/molecules30234504 - 21 Nov 2025
Viewed by 1120
Abstract
Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This [...] Read more.
Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This study demonstrated the neuroprotective effect of NXC736, a functional antagonist of sphingosine-1-phosphate receptor 4 (S1P4, currently in phase II clinical trials for alopecia areata), against acute injury in mice with permanent middle cerebral artery occlusion (pMCAO). pMCAO-challenged mice received oral NXC736 1 h after occlusion. NXC736 demonstrated substantial therapeutic activity against permanent ischemic stroke by attenuating pMCAO-induced acute brain infarction, neurological deficits, and apoptosis. Additionally, NXC736 reduced blood–brain barrier disruption and edema in the injured brain. Moreover, NXC736 reduced microglial activation and proliferation, oxidative stress, and suppressed pro-inflammatory cytokine expression, suggesting that the efficacy of NXC736 in permanent ischemic stroke is associated with the suppression of neuroinflammatory responses. Mechanistically, we found that NXC736-mediated neuroprotective effects were dependent on the inactivation of NF-κB and MAPKs, including ERK1/2, JNK, and p38. Collectively, our findings indicate that NXC736 is an effective neuroprotective drug for permanent ischemic brain stroke, highlighting S1P4 as a promising therapeutic target for ischemic stroke. Full article
(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—3rd Edition)
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17 pages, 856 KB  
Article
Discovery of Novel Benzamide-Based Sigma-1 Receptor Agonists with Enhanced Selectivity and Safety
by Pascal Carato, Bénédicte Oxombre, Séverine Ravez, Rajaa Boulahjar, Marion Donnier-Maréchal, Amélie Barczyk, Maxime Liberelle, Patrick Vermersch and Patricia Melnyk
Molecules 2025, 30(17), 3584; https://doi.org/10.3390/molecules30173584 - 2 Sep 2025
Viewed by 1738
Abstract
Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target [...] Read more.
Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to its role in neuroprotection and neuroinflammation. Building upon our previously identified S1R ligand (compound 1), we designed and synthesized six novel benzamide derivatives through pharmacomodulation to optimize affinity, selectivity, and safety profiles. Among these, compound 2 demonstrated superior S1R affinity, improved selectivity over the sigma-2 receptor (S2R), and favorable ADME properties, including enhanced permeability and markedly reduced in vitro cardiac toxicity compared to the lead compound. Functional assays confirmed the agonist activity of key derivatives, while safety evaluations revealed low cytotoxicity and minimal off-target receptor interactions. Collectively, these findings support compound 2 as a promising candidate for further preclinical development in S1R-related CNS disorders. Full article
(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—3rd Edition)
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Review

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28 pages, 2384 KB  
Review
Histological Insights into the Neuroprotective Effects of Antioxidant Peptides and Small Molecules in Cerebral Ischemia
by Sanda Jurja, Ticuta Negreanu-Pirjol, Mihaela Cezarina Mehedinți, Maria-Andrada Hincu, Anca Cristina Lepadatu and Bogdan-Stefan Negreanu-Pirjol
Molecules 2025, 30(23), 4529; https://doi.org/10.3390/molecules30234529 - 24 Nov 2025
Viewed by 646
Abstract
Cerebral ischemia represents a major mortality and disability cause; oxidative stress is the main intensifier mechanism of excitotoxicity, neuroinflammation, blood–brain barrier failure, and neuronal loss; under these circumstances, firm, mechanism-anchored neuroprotection is an absolute necessity. The work includes a exhaustive, PRISMA (Preferred reporting [...] Read more.
Cerebral ischemia represents a major mortality and disability cause; oxidative stress is the main intensifier mechanism of excitotoxicity, neuroinflammation, blood–brain barrier failure, and neuronal loss; under these circumstances, firm, mechanism-anchored neuroprotection is an absolute necessity. The work includes a exhaustive, PRISMA (Preferred reporting items for systematic review and meta-analysis)-adherent presentation of the effects of antioxidant peptides and small molecules on tissues, unifying disparate readouts into a coherent tissue-level narrative. A systematic interrogation was performed across major databases over a prespecified interval, applying transparent eligibility criteria to studies that quantified canonical endpoints—infarct volume, neuronal integrity (NeuN/MAP2), apoptosis (TUNEL/cleaved caspase-3), gliosis (GFAP/Iba1), and ultrastructural preservation. The evidence coalesces around a strikingly consistent signal: antioxidant strategies converge on smaller infarcts, robust preservation of neuronal markers, attenuation of apoptotic burden, dampened astroglial–microglial reactivity, and stabilization of mitochondrial and axonal architecture—patterns that align with antioxidative, anti-apoptotic, anti-inflammatory, and ferroptosis-modulating mechanisms. While early clinical data echo these benefits, translation is tempered by heterogeneity in models, timing and dosing windows, and outcome batteries. By consolidating the histological landscape and pinpointing where effects are durable versus contingent, this work elevates antioxidant peptide and small-molecule neuroprotection from promising fragments to an integrated framework and sets an actionable agenda—standardized histological endpoints, protocol harmonization, head-to-head comparisons of peptide versus small-molecule strategies, and adequately powered randomized trials embedded with mechanistic biomarkers to decisively test efficacy and accelerate clinical adoption. Full article
(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—3rd Edition)
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