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Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples

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Abstract

Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg+) causes ALS. In ALS, MeHg+-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg+-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.

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Data Availability

All data generated or analyzed during this study are included in this article. There are no separate or additional files.

Abbreviations

AAS:

Atomic absorption spectroscopy

Ach:

Acetylcholine

AchE:

Acetylcholinesterase

ALS:

Amyotrophic lateral sclerosis

ALT:

Alanine transaminase

ANOVA:

Analysis of variance

Bax:

Bcl-2 associated X protein

Bcl-2:

B cell lymphoma-2

BDNF:

Brain-derived growth factor

cAMP:

Cyclic AMP

Caspase-3:

Cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate directed proteases-3

CAT:

Catalase

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ELT:

Escape latency time

FST:

Forced swim test

GABA:

Gamma amino butyric acid

GSH:

Reduced glutathione

GST:

Guggulsterone

IL-1β:

Interleukin-1β

JAK:

Janus kinase

LFB:

Luxol Fast Blue

MBP:

Myelin basic protein

MDA:

Malondialdehyde

MeHg:

Methylmercury

mTOR:

Mammalian target of rapamycin

MND:

Motor neuron disease

MWM:

Morris water maze

NEFL:

Neurofilament

NGF:

Nerve growth factor

NO2 :

Nitrite

ODC:

Oligodendrocytes

OPC:

Oligodendrocyte precursor cells

PPAR-gamma:

Peroxisome proliferator-activated receptors

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor-α

TSTQ:

Time spent in target quadrant

5-HT:

Serotonin

VitD3 :

Vitamin D3

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Acknowledgements

The authors thank Chairman Mr. Parveen Garg, ISF College of Pharmacy, Moga (Punjab), India, for their excellent vision and support.

Funding

This work was supported by DST-SERB, Govt. of India (Grant Number: CRG/2021/001009). This work was supported by institutional grants from the Institutional Animal Ethics Committee (IAEC) with registration no. 816/PO/ReBiBt8/S/04/CPCSEA as protocol no. ISFCP/IAEC/CPCSEA/Meeting No: 30/2021/Protocol No. 505 approved by RAB Committee, ISFCP, Moga, Punjab, India.

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  1. Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), NAAC Accredited “A” Grade College, GT Road, Ghal-Kalan, Moga, 142 001, Punjab, India

    Sumit Kumar, Sidharth Mehan & Zuber Khan

  2. IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India

    Sumit Kumar, Sidharth Mehan, Zuber Khan & Ghanshyam Das Gupta

  3. Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India

    Ghanshyam Das Gupta

  4. Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA

    Acharan S. Narula

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  1. Sumit Kumar
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Contributions

Investigation, original draft, formal analysis, S.K; revision, editing, visualization, G.D.G., Z.K., A.S.N.; conceptualization, resources, supervision, S.M. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of this work, ensuring integrity and accuracy. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sidharth Mehan.

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Kumar, S., Mehan, S., Khan, Z. et al. Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-023-03902-x

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