Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity.

Abstract

Amyotrophic lateral sclerosis (ALS) is a severe adult motor neuron disease that causes progressive neuromuscular atrophy, muscle wasting, weakness, and depressive-like symptoms. Our previous research suggests that mercury levels are directly associated with ALS progression. MeHg+-induced ALS is characterised by oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, leading to demyelination and motor neuron death. The selection of MeHg+ as a potential neurotoxicant is based on our evidence that it has been connected to the development of ALS-like characteristics. It causes glutamate-mediated excitotoxicity, calcium-dependent neurotoxicity, and an ALS-like phenotype. Dysregulation of IGF-1/GLP-1 signalling has been associated with ALS progression. The bioactive amino acid 4-hydroxyisoleucine (HI) from Trigonella foenum graecum acts as an insulin mimic in rodents and increases insulin sensitivity. This study examined the neuroprotective effects of 4-HI on MeHg+-treated adult Wistar rats with ALS-like symptoms, emphasising brain IGF1/GLP-1 activation. Furthermore, we investigated the effect of 4-HI on MBP levels in rat brain homogenate, cerebrospinal fluid (CSF), blood plasma, and cell death indicators such as caspase-3, Bax, and Bcl-2. Rats were assessed for muscular strength, locomotor deficits, depressed behaviour, and spatial learning in the Morris water maze (MWM) to measure neurobehavioral abnormalities. Doses of 4-HI were given orally for 42 days in the MeHg+ rat model at 50 mg/kg or 100 mg/kg to ameliorate ALS-like neurological dysfunctions. Additionally, neurotransmitters and oxidative stress markers were examined in rat brain homogenates. Our findings suggest that 4-HI has neuroprotective benefits in reducing MeHg+-induced behavioural, neurochemical, and histopathological abnormalities in ALS-like rats exposed to methylmercury.

• Authors: Ambika Shandilya, Sidharth Mehan, Sumit Kumar, Pranshul Sethi, Acharan S Narula, Abdulrahman Alshammari, Metab Alharbi, Abdullah F Alasmari
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 27 Issue 12 (Jun 16 2022) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 35745001 (Publication Type: Journal Article)

Chemical References

• 4-hydroxyisoleucine
• Methylmercury Compounds
• Isoleucine
• Insulin-Like Growth Factor I
• Glucagon-Like Peptide 1

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, genetics)
• Animals
• Glucagon-Like Peptide 1 (metabolism)
• Insulin-Like Growth Factor I (metabolism)
• Isoleucine (analogs & derivatives)
• Methylmercury Compounds (toxicity)
• Motor Neurons
• Rats
• Rats, Wistar