Enhanced therapeutic potential of paeoniflorin and vitamin B12 in intracerebropeduncle ethidium bromide-induced multiple sclerosis-like pathology.

Overview

1. Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University), Jalandhar, Punjab, India
2. Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University), Jalandhar, Punjab, India
3. Narula Research, LLC, Chapel Hill, NC, United States

Abstract

The study investigates the neuroprotective potential of paeoniflorin (PNN) in mitigating the multifaceted pathology of multiple sclerosis (MS) in an ethidium bromide-induced (EBRO) rat model. A comprehensive approach utilizing in silico, in-vitro, and in-vivo methodologies reveals that PNN targets key molecular pathways implicated in MS, including the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3-Beta signaling cascade. PNN (50 mg/kg, 100 mg/kg, p.o.) administration, both as monotherapy and in combination with VB-12 (30 mg/kg, p.o.), demonstrated significant efficacy in reducing EBRO-induced neurodegeneration, demyelination, synaptic dysfunction, and neuroinflammation. Behavioral assessments such as the rotarod, beam crossing, and Morris water maze tests highlighted PNN capacity to restore motor coordination, spatial memory, and cognitive function. Combination therapy with VB12 (30) further enhanced these outcomes, demonstrating synergistic therapeutic benefits. Histological and molecular analyses revealed that PNN100 alleviates demyelination, reduces inflammatory cytokines TNF-α, IL-1β, and restores anti-inflammatory markers (IL-10) in brain homogenates, CSF, and blood plasma. Moreover, PNN normalized neurotransmitter imbalances, including elevated glutamate and reduced GABA, dopamine, serotonin, and acetylcholine levels, highlighting its role in restoring excitatory-inhibitory balance. ELISA studies confirmed PNN ability to modulate apoptotic markers Bax, Bcl-2, and Caspase-3 and upregulate neurotrophic factors GDNF, and GFRA1 while downregulating hyperactivated pathways like AKT, ERK1/2, and GSK3-Beta. Additionally, hematological parameters disrupted by EBRO were significantly restored by PNN, indicating its systemic anti-inflammatory and hematoprotective effects. This research provides the first evidence of PNN’s role in modulating the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3β pathway in MS. Its synergistic action with VB12 underscores its potential as a combinatorial therapeutic strategy. The findings pave the way for innovative treatment approaches to improve outcomes for MS patients by addressing neurodegeneration, inflammation, and systemic immune dysregulation.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• rcsb.org/structure/1agq, at PDB; found in the text, “Molecular docking”
• rcsb.org/structure/1q41, at PDB; found in the text, “Molecular docking”
• rcsb.org/structure/1q8d, at PDB; found in the text, “Molecular docking”
• rcsb.org/structure/2ivu, at PDB; found in the text, “Molecular docking”
• rcsb.org/structure/3o96, at PDB; found in the text, “Molecular docking”
• rcsb.org/structure/6gdq, at PDB; found in the text, “Molecular docking”

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 6 authors, 8 keywords, 156 references.

Cite

This paper

Khan, M. N., Mehan, S., Choudhary, D., Rana, R., Das Gupta, G., & Narula, A. S. (2026). Enhanced therapeutic potential of paeoniflorin and vitamin B12 in intracerebropeduncle ethidium bromide-induced multiple sclerosis-like pathology. Frontiers in pharmacology, 17, 1792674. https://doi.org/10.3389/fphar.2026.1792674

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1128/msystems.00416-26 [code]

Integrative multicohort analysis reveals consistent sex differences in gut microbiota of multiple sclerosis patients.

Journal: mSystems

In common: multiple sclerosis, clinical / translational, 1 reference

[2] doi:10.1007/s00401-026-03062-x

Genetic subtypes of multiple sclerosis severity are uncoupled from inflammatory lesion burden.

Journal: Acta neuropathologica

In common: multiple sclerosis, 1 reference

[3] doi:10.1162/imag.a.1251

Detection of slowly expanding lesions in people with multiple sclerosis using MRI: A scoping review.

Journal: Imaging neuroscience (Cambridge, Mass.)

In common: multiple sclerosis, 1 reference

[4] doi:10.1093/braincomms/fcag134 [code]

Neurophysiological, imaging and neurobiological markers of central fatigue in multiple sclerosis.

Journal: Brain communications

In common: multiple sclerosis, 1 reference

[5] doi:10.3389/fnetp.2026.1853254 [code]

Recovery in gait and posture: a network-based approach to the assessment of rehabilitation effectiveness after spinal cord injury.

Journal: Frontiers in network physiology

In common: clinical / translational, 1 reference

[6] doi:10.1007/s12035-026-06058-6

2-Phenyl-3-(Phenylselanyl)Benzofuran As a Promising Antidepressant Candidate: Mechanistic Insights Into Nitrergic Modulation and Subchronic Efficacy and Safety Profiling.

Journal: Molecular neurobiology

In common: 1 reference

[7] doi:10.1007/s00401-026-03035-0

Expression of GPR34 in microglia remains stable in human Alzheimer's disease.

Journal: Acta neuropathologica

In common: 1 reference

[8] doi:10.3389/fphar.2026.1773471

Preliminary exploration of acute limit toxicity testing for nicotinamide mononucleotide in the neonatal population.

Journal: Frontiers in pharmacology

In common: 1 reference

[9] doi:10.1021/acs.jmedchem.5c03413 [code]

Peptides Targeting GDNF Family Receptor Alpha 1 (GFRα1) Mimic Glial Cell Line-Derived Neurotrophic Factor (GDNF) Bioactivity.

Journal: Journal of medicinal chemistry

In common: 1 reference

[10] doi:10.1016/j.neurobiolaging.2026.04.007 [code]

The TREM2 R47H variant is associated with liver-plasma-brain axis dyshomeostasis in the 5xFAD mouse model of Alzheimer's disease.

Journal: Neurobiology of aging

In common: 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.