Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity
Abstract
:1. Introduction
2. Material and Methods
2.1. Experimental Animals
2.2. Chemicals and Drugs
2.3. Experimental Animal Model of Methylmercury-Induced ALS-Like Rats
2.4. Protocol Schedule of Animal Experimentation
2.5. Parameters Evaluated
2.5.1. Assessment of Weight Variations
Assessment of Body Weight
Assessment of Relative Brain–Body Weight Ratio
2.6. BehaviourParameters
2.6.1. Grip Strength Test (GST)
2.6.2. Open Field Test (OFT) Assessment
2.6.3. Forced Swim Test (FST)
2.6.4. Morris Water Maze (MWM) Task
2.7. Neurochemical Parameters
2.7.1. Collection and Preparation of Biological Samples
2.7.2. Assessment of Cellular and Molecular Markers
2.7.3. Assessment of Apoptotic Markers
2.7.4. Assessment of Neurotransmitter Levels
2.7.5. Assessment of Inflammatory Cytokine Levels
2.7.6. Assessment of Oxidative Stress Markers
2.7.7. Assessment of Acetylcholinesterase Enzyme Level
2.7.8. Assessment of Gross Pathology and Demyelination Volume in Rat Brain
2.7.9. Assessment of Histopathological Changes
2.8. Statistical Analysis
3. Results
3.1. Effect of 4-Hydroxyisoleucine in the Restoration of Weight Variations after Methyl Mercury-Exposure in Rats
3.1.1. Improved Body Weight after Long-Term Administration of 4-Hydroxyisoleucine
3.1.2. Improvement in Relative Brain–Body Weight Ratio after Long-Term Administration of 4-Hydroxyisoleucine
3.2. Effect of 4-Hydroxyisoleucine in the Amelioration of Neurobehavioral Abnormalities after Methyl Mercury Exposure in Rats
3.2.1. Improved Grip Strength after Long-Term Administration of 4-Hydroxyisoleucine
3.2.2. Improved Locomotion and Restored Anxiety-Like Behaviour after Long-Term Administration of 4-Hydroxyisoleucine
3.2.3. Decreased Depression-Like Behaviour after Long-Term Administration of 4-Hydroxyisoleucine
3.2.4. Improved Memory and Cognition after Long-Term Administration of 4-Hydroxyisoleucine
3.3. Effect of 4-Hydroxyisoleucine on Neurochemical Alterations after Methyl MercuryExposure in Rats
3.3.1. Increased Level of IGF-1 after Long-Term Administration of 4-Hydroxyisoleucine
3.3.2. Increased Level of GLP-1 after Long-Term Administration of 4-Hydroxyisoleucine
3.3.3. Restored Level of Myelin Basic Protein after Long-Term Administration of 4-Hydroxysoleucine
3.3.4. Decreased Levels of Caspase-3 and Bax as well asIncreased Bcl-2 Levels after Long-Term Administration of 4-Hydroxyisoleucine
3.3.5. Restoration of Neurotransmitter Levels after Long-Term Administration of 4-Hydroxyisoleucine
3.3.6. Reduction in Neuroinflammatory Cytokines after Long-Term Administration of 4-Hydroxyisoleucine
3.3.7. Restored Antioxidant Levels after Long-Term Administration of 4-Hydroxyisoleucine
3.4. Effect of 4-HI on Gross Pathological Alterations and Demyelination Volume after Methyl MercuryExposure in Rats
3.4.1. Improvement in Whole-Brain Morphological Alterations after Long-Term Administration of 4-Hydroxyisoleucine
3.4.2. Reduced Pathological Abnormalities in Brain Sections after Long-Term Administration of 4-Hydroxyisoleucine
3.4.3. Reduced Demyelination Volume after Long-Term Administration of 4-Hydroxyisoleucine
3.4.4. Effect of 4-HI onMethyl-Mercury-Induced Histopathological Changes
4. Discussion
Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Ach | Acetylcholine |
AchE | Acetylcholinesterase |
AkT | Protein kinase B |
ALS | Amyotrophic lateral sclerosis |
ALT | Alanine transaminase |
ANOVA | Analysis of variance |
AST | Aspartate transaminase |
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 |
CNS | Central nervous system |
CSF | Cerebrospinal fluid |
ELT | Escape latency time |
FST | Forced swim test |
GABA | Gamma amino butyric acid |
GLP-1 | Glucagon like peptide-1 |
GLP-1R | Glucagon like peptide-1 receptor |
GLUT | Glucose transporter |
GSH | Reduced glutathione |
GST | Grip strength test |
HDL | High-density lipoprotein |
IBD | Intestinal bowel disease |
IGF-1 | Insulin-like growth factor-1 |
IGF-1R | Insulin-like growth factor-1 receptor |
IL-1β | Interleukin-1β |
IRS-1 | Insulin receptor substrate-1 |
LDH | Lactate dehydrogenase |
LDL | Low-density lipoprotein |
LPS | Lipopolysaccharide |
MBP | Myelin basic protein |
MDA | Malondialdehyde |
MeHg | Methylmercury |
MND | Motor neuron disease |
MS | Multiple sclerosis |
MWM | Morris water maze |
NGF | Nerve growth factor |
NO2 | Nitrite |
ODC | Oligodendrocytes |
PC12 | Pheochromocytoma cell 12 |
PI3K | Phosphoinositol 3-kinase |
rh-IGF-1 | Recombinant human-IGF-1 |
ROS | Reactive oxygen species |
SMA | Spontaneous motor activity |
SOD-1 | Superoxide dismutase 1 |
TACE | TNF-α converting enzyme |
TG | Triglycerides |
TNF-α | Tumor necrosis factor-α |
TSTQ | Time spent in target quadrant |
4-HI | 4-hydroxyisoleucine |
5-HIAA | 5-hydroxy indole acetic acid |
5-HT | Serotonin |
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Shandilya, A.; Mehan, S.; Kumar, S.; Sethi, P.; Narula, A.S.; Alshammari, A.; Alharbi, M.; Alasmari, A.F. Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity. Molecules 2022, 27, 3878. https://doi.org/10.3390/molecules27123878
Shandilya A, Mehan S, Kumar S, Sethi P, Narula AS, Alshammari A, Alharbi M, Alasmari AF. Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity. Molecules. 2022; 27(12):3878. https://doi.org/10.3390/molecules27123878
Chicago/Turabian StyleShandilya, Ambika, Sidharth Mehan, Sumit Kumar, Pranshul Sethi, Acharan S. Narula, Abdulrahman Alshammari, Metab Alharbi, and Abdullah F. Alasmari. 2022. "Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity" Molecules 27, no. 12: 3878. https://doi.org/10.3390/molecules27123878