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Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental...
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Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neurodegenerative Diseases".

Deadline for manuscript submissions: 13 June 2025 | Viewed by 6434

Special Issue Editor

Dr. Ansab Akhtar

E-Mail Website
Guest Editor
LSUHSC Neuroscience Center, New Orleans, LA, USA
Interests: pharmacology; neuroscience; preclinical research; Alzheimer’s disease; rodent models

Special Issue Information

Dear Colleagues,

Neurodegeneration is a multifactorial progressive phenomenon that primarily arises from neuronal loss in specific brain regions, which leads to various pathological manifestations including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis. Additionally, neurodevelopmental disorders such as autism, cerebral palsy, ADHD mainly occur in infants and children either due to brain damage or altered gene levels. Many of the genes and molecular pathways to be targeted require further exploration.

The etiological factors associated with neurodegenerative and neurodevelopmental disorders also include neuroinflammation, oxidative stress, mitochondrial dysfunction, brain insulin resistance and impairments of the energy metabolism. These cascades might further comprise several molecular bases that result in neurodegeneration or skewed neurodevelopment. Moreover, there are inconclusive findings regarding the pathogenesis of these diseases. Currently, it is only the symptoms of these diseases that are treated, without completely halting the progression of the disease.

This Special Issue will be focused on novel targets that influence the interconnected pathways of inflammation, oxidative stress, and metabolism directly or indirectly. Various potential pharmacological approaches and their mechanistic insights will be explored in order to reverse these detrimental features. Hence, we are soliciting papers that present cutting-edge research and review articles addressing molecular and cellular mechanisms that have not been explored in great detail previously. It is hoped that these can enhance our understanding of innovative therapeutic strategies and open avenues for future clinical research.

Dr. Ansab Akhtar
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 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

  • neuroinflammation
  • oxidative stress
  • mitochondrial dysfunction
  • metabolism
  • metabolomics
  • neurodegenerative diseases
  • neurodevelopmental diseases
  • pharmacological targets
  • potential drugs

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Published Papers (5 papers)

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Research

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14 pages, 1094 KiB  
Article
Vinpocetine, a Phosphodiesterase Type 1 Inhibitor, Mitigates Locomotor Hyperactivity in Female Mice Exposed to Lead During Development
by Ulisses C. Araujo, Fernanda Nunes, Bruno S. Gonçalves, Regina A. A. Gomes, Maria de Fátima R. Moreira, Andre Nunes-Freitas, Thomas E. Krahe, Yael de Abreu-Villaça, Alex C. Manhães and Cláudio C. Filgueiras
Brain Sci. 2025, 15(2), 150; https://doi.org/10.3390/brainsci15020150 - 2 Feb 2025
Viewed by 460
Abstract
Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP [...] Read more.
Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP levels, could mitigate locomotor hyperactivity in mice exposed to lead during early development. Methods Swiss mice were exposed to 90 ppm of lead in their drinking water throughout gestation and the first ten postnatal days. At postnatal day 10 (PN10), blood lead levels (BLLs) were about 30 µg/dL. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or a vehicle 4 h before the evaluation of locomotor activity in the open field. Results Lead-exposed males did not display differences in locomotor activity compared to controls, while lead-exposed females showed a significant increase in locomotion. Vinpocetine treatment significantly reversed the lead-induced hyperactivity in females. Conclusions These findings suggest that the cAMP and cGMP signaling pathways play a role in the hyperactivity induced by lead exposure. Full article
(This article belongs to the Special Issue Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions)
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15 pages, 2072 KiB  
Article
Eugenia uniflora Effects on the Depressive-like Behavior of MPTP-Exposed Female Rats: Apoptosis and α-Synuclein Modulation
by Anne Suély Pinto Savall, Jhuly Dorneles De Mello, Eduarda Monteiro Fidelis, Vandreza Cardoso Bortolotto, Mustafa Munir Mustafa Dahleh, Gustavo Petri Guerra, Marina Prigol, Robson Puntel, Jean Ramos Boldori, Cristiane Casagrande Denardin, Tuane Bazanella Sampaio and Simone Pinton
Brain Sci. 2025, 15(1), 41; https://doi.org/10.3390/brainsci15010041 - 3 Jan 2025
Viewed by 601
Abstract
Background: Parkinson’s disease (PD) is a neurodegenerative disorder marked by motor deficits and non-motor symptoms, such as depression, which are associated with dopaminergic loss and α-synuclein aggregation in the brain. Objectives: This study investigated the neuroprotective effects of a hydroalcoholic extract of the [...] Read more.
Background: Parkinson’s disease (PD) is a neurodegenerative disorder marked by motor deficits and non-motor symptoms, such as depression, which are associated with dopaminergic loss and α-synuclein aggregation in the brain. Objectives: This study investigated the neuroprotective effects of a hydroalcoholic extract of the purple fruit of Eugenia uniflora (PFEU) on motor ability and depressive-like behaviors in a PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in female Wistar rats. Methods: Rats received intranasal administration of MPTP or vehicle, followed by 14 days of oral administration of PFEU (300 or 2000 mg/kg, administered once daily) or vehicle. Depressive-like behavior was assessed using the splash and forced swimming tests, while motor ability was evaluated using the rotarod and open field tests. On day 15, hippocampal tissue was collected for immunoreactivity analysis. Results: MPTP treatment induced depressive-like behavior, which was significantly reversed by PFEU, as evidenced by increased grooming and decreased immobility. No motor coordination or locomotion deficits were observed. Furthermore, PFEU treatment prevented the MPTP-induced increase in hippocampal α-synuclein, p-p53, and Bax while restoring Bcl-2 levels, suggesting neuroprotective effects through the modulation of apoptotic pathways and α-synuclein. Conclusions: These findings support PFEU’s potential as a neuroprotective agent for MPTP-induced depressive-like behavior in female rats, highlighting its molecular mechanisms. Full article
(This article belongs to the Special Issue Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions)
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20 pages, 4640 KiB  
Article
In Vivo and Computational Studies on Sitagliptin’s Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer’s Disease
by Vasudevan Mani and Minhajul Arfeen
Brain Sci. 2024, 14(12), 1191; https://doi.org/10.3390/brainsci14121191 - 26 Nov 2024
Viewed by 915
Abstract
Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) [...] Read more.
Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article
(This article belongs to the Special Issue Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions)
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Review

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18 pages, 1006 KiB  
Review
Clearing Amyloid-Beta by Astrocytes: The Role of Rho GTPases Signaling Pathways as Potential Therapeutic Targets
by Gyeongah Park, Zhen Jin, Hui Lu and Jianyang Du
Brain Sci. 2024, 14(12), 1239; https://doi.org/10.3390/brainsci14121239 - 10 Dec 2024
Viewed by 876
Abstract
Astrocytes, vital support cells in the central nervous system (CNS), are crucial for maintaining neuronal health. In neurodegenerative diseases such as Alzheimer’s disease (AD), astrocytes play a key role in clearing toxic amyloid-β (Aβ) peptides. Aβ, a potent neuroinflammatory trigger, stimulates astrocytes to [...] Read more.
Astrocytes, vital support cells in the central nervous system (CNS), are crucial for maintaining neuronal health. In neurodegenerative diseases such as Alzheimer’s disease (AD), astrocytes play a key role in clearing toxic amyloid-β (Aβ) peptides. Aβ, a potent neuroinflammatory trigger, stimulates astrocytes to release excessive glutamate and inflammatory factors, exacerbating neuronal dysfunction and death. Recent studies underscore the role of Rho GTPases—particularly RhoA, Rac1, and Cdc42—in regulating Aβ clearance and neuroinflammation. These key regulators of cytoskeletal dynamics and intracellular signaling pathways function independently through distinct mechanisms but may converge to modulate inflammatory responses. Their influence on astrocyte structure and function extends to regulating endothelin-converting enzyme (ECE) activity, which modulates vasoactive peptides such as endothelin-1 (ET-1). Through these processes, Rho GTPases impact vascular permeability and neuroinflammation, contributing to AD pathogenesis by affecting both Aβ clearance and cerebrovascular interactions. Understanding the interplay between Rho GTPases and the cerebrovascular system provides fresh insights into AD pathogenesis. Targeting Rho GTPase signaling pathways in astrocytes could offer a promising therapeutic approach to mitigate neuroinflammation, enhance Aβ clearance, and slow disease progression, ultimately improving cognitive outcomes in AD patients. Full article
(This article belongs to the Special Issue Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions)
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23 pages, 2058 KiB  
Review
Indole-3-Carbinol and Its Derivatives as Neuroprotective Modulators
by Alka Ashok Singh, Dhananjay Yadav, Fazlurrahman Khan and Minseok Song
Brain Sci. 2024, 14(7), 674; https://doi.org/10.3390/brainsci14070674 - 2 Jul 2024
Cited by 3 | Viewed by 2577
Abstract
Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, [...] Read more.
Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF’s mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions)
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