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Open AccessEditorial

Advanced Research in Neuroprotection

by Christos Bakirtzis and Evangelia Kesidou

Biomedicines 2026, 14(2), 450; https://doi.org/10.3390/biomedicines14020450 - 17 Feb 2026

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Abstract

In recent years, neurological research has focused on understudied neurological diseases, uncovering pathophysiological mechanisms and new therapeutic avenues [...] Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

Research

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20 pages, 8166 KB

Open AccessArticle

Comparative Investigation of the Effects of Adenosine Triphosphate, Melatonin, and Thiamine Pyrophosphate on Amiodarone-Induced Neuropathy and Neuropathic Pain in Male Rats

by Agah Abdullah Kahramanlar, Habip Burak Ozgodek, Ramazan Ince, Bulent Yavuzer, Ozlem Admis, Ali Sefa Mendil, Bilge Ekinci and Halis Suleyman

Biomedicines 2025, 13(12), 2965; https://doi.org/10.3390/biomedicines13122965 - 2 Dec 2025

Cited by 2 | Viewed by 994

Abstract

Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and [...] Read more.

Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and modulate inflammation, including adenosine triphosphate (ATP), melatonin, and thiamine pyrophosphate (TPP), may counteract these mechanisms; however, their relative neuroprotective potential in amiodarone-induced neuropathy remains unclear. This study aimed to comparatively evaluate the effects of ATP, melatonin, and TPP on amiodarone-induced peripheral neuropathy and neuropathic pain in rats. Methods: Thirty male albino Wistar rats were assigned to five groups: healthy; amiodarone (50 mg/kg/orally); amiodarone + ATP (5 mg/kg/intraperitoneally); amiodarone + melatonin (10 mg/kg/orally); or amiodarone + TPP (20 mg/kg/intraperitoneally). Treatments were given once daily for 14 days. Oxidative stress indices (malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT)) and proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 Beta (IL-1β), interleukin-6 (IL-6)) were quantified in sciatic nerve by Enzyme-Linked Immunosorbent Assay (ELISA). Paw withdrawal thresholds were measured with the Randall-Selitto test before and after treatment. Histopathology was performed using Hematoxylin-eosin staining. Results: Amiodarone exposure resulted in pronounced elevations in MDA and proinflammatory cytokine levels, accompanied by significant reductions in tGSH, SOD, CAT activities, and paw withdrawal thresholds. ATP, melatonin and TPP ameliorated these alterations to varying degrees. Among them, TPP provided the most robust antioxidant and anti-inflammatory effects, followed by ATP and melatonin. Histopathological examination confirmed most severe axonal degeneration, interstitial edema and Schwann cell proliferation in the amiodarone group, with substantial amelioration in the TPP-treated rats. Conclusions: Amiodarone induces neuropathic pain through oxidative and inflammatory injury to peripheral nerves. TPP exhibited superior neuroprotective efficacy compared with ATP and melatonin, highlighting its potential as a candidate therapeutic agent for amiodarone-related neuropathy. Further clinical research is warranted to support translational application of these findings. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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20 pages, 8550 KB

Open AccessArticle

Integrative Neoepitope Discovery in Glioblastoma via HLA Class I Profiling and AlphaFold2-Multimer

by Raquel Francés, Jenny Bonifacio-Mundaca, Íñigo Casafont, Christophe Desterke and Jorge Mata-Garrido

Biomedicines 2025, 13(11), 2715; https://doi.org/10.3390/biomedicines13112715 - 5 Nov 2025

Cited by 1 | Viewed by 1305

Abstract

Background/Objectives: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with limited therapeutic options. Neoantigen-based immunotherapy offers a promising avenue, but its efficacy primarily depends on the ability of somatic mutations to generate immunogenic peptides effectively presented by HLA class I molecules and [...] Read more.

Background/Objectives: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with limited therapeutic options. Neoantigen-based immunotherapy offers a promising avenue, but its efficacy primarily depends on the ability of somatic mutations to generate immunogenic peptides effectively presented by HLA class I molecules and recognized by cytotoxic T cells, in concert with innate immune mechanisms such as NK-cell activation and DAMP/PAMP signaling. This study aimed to characterize the MHC-I binding diversity of peptides derived from GBM-associated somatic variants, with a particular focus on interactions involving HLA-A68:01 and HLA-B15:01 alleles. These alleles were selected based on their ethnic prevalence and potential structural compatibility with neoepitopes. Methods: Somatic missense variants from TCGA-GBM were filtered using high-confidence genomic databases, including dbSNP, COSMIC, and MANE. Neoepitope prediction was performed across multiple HLA class I alleles using binding affinity algorithms (MHCflurry2). Peptide–HLA interactions were characterized through motif analysis and anchor residue enrichment. Structural modeling of peptide–HLA complexes was conducted using ColabFold (AlphaFold2-multimer v3) to evaluate conformational stability. The population frequency of selected HLA alleles was examined through epidemiological comparisons. Results: Canonical GBM driver mutations (e.g., EGFR, TP53, PIK3R1) are recurrent and biologically relevant, although pharmacological inhibition of EGFR alone has not consistently improved patient outcomes, underscoring the complex signaling redundancy in glioblastoma. HLA-A68:01 exhibited high binding affinity and favorable motif compatibility, supporting its potential for effective neoantigen presentation. HLA-B15:01 was identified as a viable presenter for the EGFR p.Arg108Lys variant. Structural modeling confirmed stable peptide insertion into the MHC-I binding groove, with high-confidence folding and preserved interface integrity. Ethnic distribution analysis revealed varying GBM incidence across populations expressing these alleles. Conclusions: This integrative analysis identified structurally validated, immunogenically promising neoantigens derived from GBM mutations, particularly for HLA-A68:01 and HLA-B15:01. These findings support allele-informed neoepitope prioritization in personalized immunotherapy, especially for patient populations with corresponding HLA genotypes and MHC-I presentation capacity. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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14 pages, 1981 KB

Open AccessArticle

Protective Role of Thiamine Pyrophosphate Against Erlotinib-Induced Oxidative and Inflammatory Damage in Rat Optic Nerve

by Ezgi Karatas, Bulent Yavuzer, Ozlem Demir, Esra Tuba Sezgin, Engin Hendem, Emine Cinici, Taha Abdulkadir Coban and Halis Suleyman

Biomedicines 2025, 13(11), 2614; https://doi.org/10.3390/biomedicines13112614 - 25 Oct 2025

Cited by 3 | Viewed by 969

Abstract

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib are widely used in non-small-cell lung cancer treatment, and accumulating evidence indicates they can markedly increase ocular toxicity. Nonetheless, whether erlotinib causes optic nerve injury has not been investigated before and [...] Read more.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib are widely used in non-small-cell lung cancer treatment, and accumulating evidence indicates they can markedly increase ocular toxicity. Nonetheless, whether erlotinib causes optic nerve injury has not been investigated before and remains a subject worth investigating. This study aimed to examine the impact of erlotinib on oxidative stress, inflammation, and histopathological changes in rat optic nerve tissue and evaluate the potential neuroprotective role of thiamine pyrophosphate (TPP). Methods: Twenty-four male Wistar rats were randomly assigned to four groups: healthy control, TPP alone, erlotinib alone, and erlotinib + TPP. Erlotinib (10 mg/kg, orally, on alternate days) and TPP (20 mg/kg, intraperitoneally, daily) were administered for two consecutive weeks. Optic nerve samples were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), followed by histopathological examination. Results: Erlotinib treatment significantly increased MDA, IL-1β, and TNF-α levels while reducing tGSH, SOD, and CAT activity, demonstrating oxidative stress and an inflammatory response. Co-administration of TPP ameliorated these changes by lowering reactive oxygen species, restoring antioxidant capacity, and attenuating inflammation. Histopathological alterations, including astrocyte degeneration, edema, and vascular congestion, were evident after erlotinib exposure but were significantly alleviated when TPP was administered concurrently. Conclusions: Erlotinib induces oxidative and inflammatory optic nerve injury, while TPP co-treatment offers significant neuroprotection. These findings support TPP as a potential adjunct to reduce EGFR-TKI-related ocular toxicity and highlight importance of redox modulation in limiting treatment-associated side effects. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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17 pages, 4098 KB

Open AccessArticle

Effects of Sildenafil on Cognitive Function Recovery and Neuronal Cell Death Protection after Transient Global Cerebral Ischemia in Gerbils

by Yeon Hee Yu, Gun Woo Kim, Yu Ran Lee, Dae-Kyoon Park, Beomjong Song and Duk-Soo Kim

Biomedicines 2024, 12(9), 2077; https://doi.org/10.3390/biomedicines12092077 - 12 Sep 2024

Cited by 3 | Viewed by 5078

Abstract

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, [...] Read more.

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil’s effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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28 pages, 6856 KB

Open AccessArticle

Regulatory Role and Cytoprotective Effects of Exogenous Recombinant SELENOM under Ischemia-like Conditions and Glutamate Excitotoxicity in Cortical Cells In Vitro

by Egor A. Turovsky, Egor Y. Plotnikov and Elena G. Varlamova

Biomedicines 2024, 12(8), 1756; https://doi.org/10.3390/biomedicines12081756 - 5 Aug 2024

Cited by 10 | Viewed by 1905

Abstract

Despite the successes in the prevention and treatment of strokes, it is still necessary to search for effective cytoprotectors that can suppress the damaging factors of cerebral ischemia. Among the known neuroprotectors, there are a number of drugs with a protein nature. In [...] Read more.

Despite the successes in the prevention and treatment of strokes, it is still necessary to search for effective cytoprotectors that can suppress the damaging factors of cerebral ischemia. Among the known neuroprotectors, there are a number of drugs with a protein nature. In the present study, we were able to obtain recombinant SELENOM, a resident of the endoplasmic reticulum that exhibits antioxidant properties in its structure and functions. The resulting SELENOM was tested in two brain injury (in vitro) models: under ischemia-like conditions (oxygen-glucose deprivation/reoxygenation, OGD/R) and glutamate excitotoxicity (GluTox). Using molecular biology methods, fluorescence microscopy, and immunocytochemistry, recombinant SELENOM was shown to dose-dependently suppress ROS production in cortical cells in toxic models, reduce the global increase in cytosolic calcium ([Ca²⁺]_i), and suppress necrosis and late stages of apoptosis. Activation of SELENOM’s cytoprotective properties occurs due to its penetration into cortical cells through actin-dependent transport and activation of the Ca²⁺ signaling system. The use of SELENOM resulted in increased antioxidant protection of cortical cells and suppression of the proinflammatory factors and cytokines expression. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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Review

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25 pages, 2139 KB

Open AccessReview

Next-Generation Drug Delivery for Neurotherapeutics: The Promise of Stimuli-Triggered Nanocarriers

by Radka Boyuklieva, Nikolay Zahariev, Plamen Simeonov, Dimitar Penkov and Plamen Katsarov

Biomedicines 2025, 13(6), 1464; https://doi.org/10.3390/biomedicines13061464 - 13 Jun 2025

Cited by 19 | Viewed by 3266

Abstract

Nanotherapeutics have emerged as novel unparalleled drug delivery systems (DDSs) for the treatment of neurodegenerative disorders. By applying different technological approaches, nanoparticles can be engineered to possess different functionalities. In recent years, the developed, stimuli-responsive nanocarriers stand out as novel complex DDSs ensuring [...] Read more.

Nanotherapeutics have emerged as novel unparalleled drug delivery systems (DDSs) for the treatment of neurodegenerative disorders. By applying different technological approaches, nanoparticles can be engineered to possess different functionalities. In recent years, the developed, stimuli-responsive nanocarriers stand out as novel complex DDSs ensuring selective and specific drug delivery in response to different endogenous and exogenous stimuli. Due to the multifaceted pathophysiology of the nervous system, a major challenge in modern neuropharmacology is the development of effective therapies ensuring high efficacy and low toxicity. Functionalization of the nanocarriers to react to specific microenvironmental changes in the nervous system tissues or external stimulations significantly enhances the efficacy of drug delivery. This review discusses the microenvironmental characteristics of some common neurological diseases in-depth and provides a comprehensive overview on the progress of the development of exogenous and endogenous stimuli-sensitive nanocarriers for the treatment of Alzheimer’s and Parkinson’s disease. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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23 pages, 636 KB

Open AccessReview

Identifying Biomarkers for Remyelination and Recovery in Multiple Sclerosis: A Measure of Progress

by Vito A. G. Ricigliano, Silvia Marenna, Serena Borrelli, Valentina Camera, Edgar Carnero Contentti, Natalia Szejko, Christos Bakirtzis, Sanja Gluscevic, Sara Samadzadeh, Hans-Peter Hartung, Krzysztof Selmaj, Bruno Stankoff, Giancarlo Comi and ECF Young Investigators/Fellows Initiative

Biomedicines 2025, 13(2), 357; https://doi.org/10.3390/biomedicines13020357 - 4 Feb 2025

Cited by 10 | Viewed by 6607

Abstract

Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the [...] Read more.

Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the remyelination process, where researchers are studying the effects of pharmacotherapy on myelin repair mechanisms. Multiple compounds are being tested for their potential to foster remyelination in different clinical settings through the application of less or more complex techniques to assess their efficacy. Objective: To review current methods and biomarkers to track myelin regeneration and recovery over time in people with MS (PwMS), with potential implications for promyelinating drug testing. Methods: Narrative review, based on a selection of PubMed articles discussing techniques to measure in vivo myelin repair and functional recovery in PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), are being implemented to track myelin repair, while other techniques like evoked potentials, functional MRI, and digital markers allow the assessment of functional recovery. These methods, alone or in combination, have been employed to obtain precise biomarkers of remyelination and recovery in various clinical trials on MS. Conclusions: Combining different techniques to identify myelin restoration in MS could yield novel biomarkers, enhancing the accuracy of clinical trial outcomes for remyelinating therapies in PwMS. Full article

(This article belongs to the Special Issue Advanced Research in Neuroprotection)

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