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Nrf2/HO-1 Signaling Activator Acetyl-11-keto-beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS

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Abstract

Methylmercury (MeHg) is a potent neurotoxin that causes neurotoxicity and neuronal cell death. MeHg exposure also leads to oligodendrocyte destruction, glial cell overactivation, and demyelination of motor neurons in the motor cortex and spinal cord. As a result, MeHg plays an important role in the progression of amyotrophic lateral sclerosis (ALS)-like neurocomplications. ALS is a fatal neurodegenerative disorder in which neuroinflammation is the leading cause of further CNS demyelination. Nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway was thought to be a potential target for neuroprotection in ALS. Acetyl-11-keto-beta-boswellic acid (AKBA) is a multi-component pentacyclic triterpenoid mixture derived from Boswellia serrata with anti-inflammatory and antioxidant properties. The research aimed to investigate whether AKBA, as a Nrf2 / HO-1 activator, can provide protection against ALS. Thus, we explored the role of AKBA on the Nrf2/HO-1 signaling pathway in a MeHg-induced experimental ALS model. In this study, ALS was induced in Wistar rats by oral gavage of MeHg 5 mg/kg for 21 days. An open field test, force swim test, and grip strength were performed to observe experimental rats' motor coordination behaviors. In contrast, a morris water maze was performed for learning and memory. Administration of AKBA 50 mg/kg and AKBA 100 mg/kg continued from day 22 to 42. Neurochemical parameters were evaluated in the rat's brain homogenate. In the meantime, post-treatment with AKBA significantly improved behavioral, neurochemical, and gross pathological characteristics in the brain of rats by increasing the amount of Nrf2/HO-1 in brain tissue. Collectively, our findings indicated that AKBA could potentially avoid demyelination and encourage remyelination.

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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

Ach:

Acetylcholine

AchE:

Acetylcholinesterase

AD:

Alzheimer’s disease

AKBA:

Acetyl-11-keto-beta-bosellic acid

ALS:

Amyotrophic lateral sclerosis

ARE:

Antioxidant response element

Bcl-2:

B-cell lymphoma 2

Bzip:

Basic leucin zipper

Caspase-3:

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

CAT:

Catalase

FST:

Forced swim test

GABA:

Gamma amino butyric acid

GCL:

Glutamate cysteine ligase

GPx:

Glutathione peroxidase

GSH:

Glutathione

HD:

Huntington’s disease

HO-1:

Hemeoxygenase 1

IL:

Interleukin

LDH:

Lactate dehydrogenase

MBP:

Myelin basic protein

MDA:

Melanodialdehyde

MeHg:

Methylmercury

MS:

Multiple sclerosis

MWM:

Morris water maze

NIT:

Nitrite

NQO1:

NAD (P)H-quinone oxidoreductase 1

Nrf2:

Nuclear erythroid 2 related factor

OPC’S:

Oligodendrocytes

PD:

Parkinson’s disease

RNA:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOD1:

Superoxide dismutase 1

TSTQ:

Time spend in target quadrant

Txnrd1:

Thioredoxin reductase 1

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Acknowledgements

The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G.D. Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their great vision and support.

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  1. Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India

    Elizabeth Minj, Shubham Upadhayay & Sidharth Mehan

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  1. Elizabeth Minj
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All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy. EM: Contribution: Clinical and pre-clinical survey. SU: Contribution: Compilation of statistical research data, revision of research manuscript. SM: Contribution: Original research hypothesis, guide, and compilation of all manuscript data. All authors approved the final version of this study.

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Correspondence to Sidharth Mehan.

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Minj, E., Upadhayay, S. & Mehan, S. Nrf2/HO-1 Signaling Activator Acetyl-11-keto-beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS. Neurochem Res 46, 2867–2884 (2021). https://doi.org/10.1007/s11064-021-03366-2

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