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.

Amyotrophic lateral sclerosis (ALS) is the most prevalent adult motor neuron disease, characterized by progressive neuromuscular atrophy, heterogeneous muscle wasting, weakness, and behavioural despair-like symptoms, which are frequently associated with cognitive impairments. The neuropathological hallmarks of MeHg-induced ALS include oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, which ultimately leads to demyelination and motor neuron death. Numerous research studies have demonstrated that IGF-1/GLP-1 signaling dysregulation plays a significant role in ALS progression as it triggers programmed neuronal cell death, myelin sheath destruction, demyelination, glutamate excitotoxicity, pro-inflammatory cytokine release, and neuroinflammation. 4-hydroxyisoleucine (4-HI) is a unique bioactive amino acid derived from Trigonella foenum graecum, with insulin-mimetic and insulin-sensitizing properties in animal models. The objective of this study was to explore the neuroprotective potential of 4-HI on behavioural, molecular, neurochemical, and gross pathological alterations in MeHg-treated ALS-like rats, with a particular focus on its influence on IGF-1/GLP-1 upregulation in the brain. Furthermore, we investigated the effect of 4-HI on the concentration of myelin basic protein (MBP) in rat brain homogenate and CSF, and specific cell death markers such as caspase-3, Bax, and Bcl-2 in rat brain homogenate and blood plasma samples. In order to investigate the neurobehavioral abnormalities, rats were evaluated for muscular strength via the grip strength test (GST), locomotor deficits using open-field task (OFT), depressive behaviour with forced swim test (FST), and spatial learning in the Morris water maze (MWM) task. Chronic oral treatment with 4-HI at doses of 50 mg/kg and 100 mg/kg was given from days 22^nd to 42^nd of the experimental protocol to alleviate ALS-like symptoms in the MeHg model of rats. In addition to cellular, molecular, apoptotic, and neuroinflammatory assessments, neurotransmitter levels and oxidative stress indicators were examined in rat brain homogenates. The results of this study consistently show that 4-HI increases the level of neurotrophic growth factors such as IGF-1 and GLP-1 restores the altered neurochemical levels, and potentially prevents ALS-like gross pathological anomalies, including demyelination volume in the rat brain in a dose-dependent manner.