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New Therapeutic Targets for Neuroinflammation and Neurodegeneration
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New Therapeutic Targets for Neuroinflammation and Neurodegeneration

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: 20 April 2025 | Viewed by 1748

Special Issue Editors

Dr. Muhammad Sohail Khan

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Guest Editor
1. Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
2. Center for Precision Medicine, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Interests: Alzheimer's disease; traumatic brain injury; cerebral ischemia; natural flavonoids; gut dysbiosis mediated AD pathology; diabetes and neuroinflammation/degeneration
Dr. Cassie S. Mitchell

E-Mail Website
Guest Editor
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
Interests: predictive medicine; systems neuropathology; machine learning; computational neuroscience; big data; Alzheimer's disease; amyotrophic lateral sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease have attracted social attention. Due to the aging population structure, the incidence of neurodegenerative diseases is increasing, but, at the same time, there has been no breakthrough in the development of related drugs, which is very tortuous. Therefore, it is crucial to discover new drug targets for the treatment of neurodegenerative diseases.

Inflammatory response is a defense mechanism of the immune system when facing infection and damage, and the central nervous system is no exception. When faced with various signals, such as infection, brain damage, or toxins, immune cells in the nervous system, such as microglia, will be activated, producing a series of neuroinflammations. Normal neuroinflammatory response can repair damaged tissues and protect the nervous system, while abnormal neuroinflammatory response is closely related to the occurrence and progression of neurodegenerative diseases.

Dr. Muhammad Sohail Khan
Dr. Cassie S. Mitchell
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 100 words) can be sent to the Editorial Office for announcement on this website.

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.

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Keywords

  • neurodegenerative diseases
  • inflammatory response
  • nervous system
  • neuroinflammations

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Published Papers (2 papers)

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Research

32 pages, 14289 KiB  
Article
Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability
by Albert J. B. Lee, Sarah Bi, Eleanor Ridgeway, Irfan Al-Hussaini, Sakshi Deshpande, Adam Krueger, Ahad Khatri, Dennis Tsui, Jennifer Deng and Cassie S. Mitchell
Int. J. Mol. Sci. 2025, 26(3), 872; https://doi.org/10.3390/ijms26030872 - 21 Jan 2025
Viewed by 688
Abstract
Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback [...] Read more.
Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases. Full article
(This article belongs to the Special Issue New Therapeutic Targets for Neuroinflammation and Neurodegeneration)
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27 pages, 4435 KiB  
Article
Remote Ischemic Post-Conditioning (RIC) Mediates Anti-Inflammatory Signaling via Myeloid AMPKα1 in Murine Traumatic Optic Neuropathy (TON)
by Naseem Akhter, Jessica Contreras, Mairaj A. Ansari, Andrew F. Ducruet, Md Nasrul Hoda, Abdullah S. Ahmad, Laxman D. Gangwani, Kanchan Bhatia and Saif Ahmad
Int. J. Mol. Sci. 2024, 25(24), 13626; https://doi.org/10.3390/ijms252413626 - 19 Dec 2024
Viewed by 880
Abstract
Traumatic optic neuropathy (TON) has been regarded a vision-threatening condition caused by either ocular or blunt/penetrating head trauma, which is characterized by direct or indirect TON. Injury happens during sports, vehicle accidents and mainly in military war and combat exposure. Earlier, we have [...] Read more.
Traumatic optic neuropathy (TON) has been regarded a vision-threatening condition caused by either ocular or blunt/penetrating head trauma, which is characterized by direct or indirect TON. Injury happens during sports, vehicle accidents and mainly in military war and combat exposure. Earlier, we have demonstrated that remote ischemic post-conditioning (RIC) therapy is protective in TON, and here we report that AMPKα1 activation is crucial. AMPKα1 is the catalytic subunit of the heterotrimeric enzyme AMPK, the master regulator of cellular energetics and metabolism. The α1 isoform predominates in immune cells including macrophages (Mφs). Myeloid-specific AMPKα1 KO mice were generated by crossing AMPKα1Flox/Flox and LysMcre to carry out the study. We induced TON in mice by using a controlled impact system. Mice (mixed sex) were randomized in six experimental groups for Sham (mock); Sham (RIC); AMPKα1F/F (TON); AMPKα1F/F (TON+RIC); AMPKα1F/F LysMCre (TON); AMPKα1F/F LysMCre (TON+RIC). RIC therapy was given every day (5–7 days following TON). Data were generated by using Western blotting (pAMPKα1, ICAM1, Brn3 and GAP43), immunofluorescence (pAMPKα1, cd11b, TMEM119 and ICAM1), flow cytometry (CD11b, F4/80, CD68, CD206, IL-10 and LY6G), ELISA (TNF-α and IL-10) and transmission electron microscopy (TEM, for demyelination and axonal degeneration), and retinal oxygenation was measured by a Unisense sensor system. First, we observed retinal morphology with funduscopic images and found TON has vascular inflammation. H&E staining data suggested that TON increased retinal inflammation and RIC attenuates retinal ganglion cell death. Immunofluorescence and Western blot data showed increased microglial activation and decreased retinal ganglion cell (RGCs) marker Brn3 and axonal regeneration marker GAP43 expression in the TON [AMPKα1F/F] vs. Sham group, but TON+RIC [AMPKα1F/F] attenuated the expression level of these markers. Interestingly, higher microglia activation was observed in the myeloid AMPKα1F/F KO group following TON, and RIC therapy did not attenuate microglial expression. Flow cytometry, ELISA and retinal tissue oxygen data revealed that RIC therapy significantly reduced the pro-inflammatory signaling markers, increased anti-inflammatory macrophage polarization and improved oxygen level in the TON+RIC [AMPKα1F/F] group; however, RIC therapy did not reduce inflammatory signaling activation in the myeloid AMPKα1 KO mice. The transmission electron microscopy (TEM) data of the optic nerve showed increased demyelination and axonal degeneration in the TON [AMPKα1F/F] group, and RIC improved the myelination process in TON [AMPKα1F/F], but RIC had no significant effect in the AMPKα1 KO mice. The myeloid AMPKα1c deletion attenuated RIC induced anti-inflammatory macrophage polarization, and that suggests a molecular link between RIC and immune activation. Overall, these data suggest that RIC therapy provided protection against inflammation and neurodegeneration via myeloid AMPKα1 activation, but the deletion of myeloid AMPKα1 is not protective in TON. Further investigation of RIC and AMPKα1 signaling is warranted in TON. Full article
(This article belongs to the Special Issue New Therapeutic Targets for Neuroinflammation and Neurodegeneration)
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