Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions

Shandilya, Ambika; Mehan, Sidharth

doi:10.1007/s10072-021-05328-6

Cited by 22 publications

(20 citation statements)

References 188 publications

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“… 78 , 79 Within the PNS, periaxin represents a SC‐specific protein of non‐compact myelin sheaths. 80 , 81 A loss of proper myelination represents a key feature of several devastating diseases like, for example multiple sclerosis, 82 amyotrophic lateral sclerosis 83 , 84 or Charcot‐Marie‐Tooth disease. 85 …”

Section: Discussionmentioning

confidence: 99%

Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis

Huang¹,

Zdora²,

Buhr

et al. 2021

J Cellular Molecular Medi

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Satellite glial cells (SGCs) of dorsal root ganglia (DRG) react in response to various injuries in the nervous system. This study investigates reactive changes within SGCs in a murine model for GM1‐gangliosidosis (GM1). DRG of homozygous β‐galactosidase‐knockout mice and homozygous C57BL/6 wild‐type mice were investigated performing immunostaining on formalin‐fixed, paraffin‐embedded tissue. A marked upregulation of glial fibrillary acidic protein (GFAP), the progenitor marker nestin and Ki67 within SGCs of diseased mice, starting after 4 months at the earliest GFAP, along with intracytoplasmic accumulation of ganglioside within neurons and deterioration of clinical signs was identified. Interestingly, nestin‐positive SGCs were detected after 8 months only. No changes regarding inwardly rectifying potassium channel 4.1, 2, 3‐cyclic nucleotide 3‐phosphodiesterase, Sox2, doublecortin, periaxin and caspase3 were observed in SGCs. Iba1 was only detected in close vicinity of SGCs indicating infiltrating or tissue‐resident macrophages. These results indicate that SGCs of DRG show phenotypical changes during the course of GM1, characterized by GFAP upregulation, proliferation and expression of a neural progenitor marker at a late time point. This points towards an important role of SGCs during neurodegenerative disorders and supports that SGCs represent a multipotent glial precursor cell line with high plasticity and functionality.

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Section: Discussionmentioning

confidence: 99%

Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis

Huang¹,

Zdora²,

Buhr

et al. 2021

J Cellular Molecular Medi

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“…Previous research has revealed that disruption of the IGF-1 and GLP-1 signaling pathways plays a detrimental role in the progression of ALS pathogenesis and related neurocomplications. The neurodegenerative symptoms of ALS, such as oligodendrocytic degradation, myelin degeneration, glial cell overactivation, immunological dysregulation, and neuronal excitation, are triggered by aberrant IGF-1/GLP-1 signaling (Shandilya and Mehan., 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant IGF-1/GLP-1 signaling is symptomatic of ALS-associated neurodegenerative manifestations. Downregulation of the IGF-1/GLP-1 signaling in CNS induces various neuropathological characteristics of ALS, such as genetic malfunction, demyelination, glial overactivation, immunological dysregulation, neuroin ammation, and neuronal excitation (Shandilya and Mehan., 2021).…”

Section: Introductionmentioning

confidence: 99%

IGF-1/GLP-1 Signaling Activator 4-hydroxyisoleucine (4-HI) Prevent Neurobehavioral and Neurochemical Defects in Methylmercury-induced Experimental Model of ALS: Insights From CSF, Blood Plasma and Brain Homogenate Samples in Rats

Shandilya

Mehan

2021

Preprint

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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 22nd to 42nd 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.

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“…A previous study reported that the upregulation of GLP-1 shows neuroprotection in the brain injury in rat brain after subarachnoid hemorrhage ( Park et al, 2011 , Tien et al, 2017 ). Psychological distress and other neurodegenerative brain disorders have also been reported to have decreased IGF-1, indicating the use of IGF-1 as a possible treatment ( Shandilya and Mehan, 2021 , Rodriguez-Perez et al, 2016 ). In the presence of glia, IGF-1 protecting neurons against neurotoxins related to glia directly mediated by IGF-1( Rodriguez-Perez et al, 2016 ; Nadjar et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…GLP-1 analogues can cross the BBB and have several effects on endogenous GLP-1( Athauda and Foltynie, 2016 ), such as anorexigenic and neuroprotective effects ( Cabou and Burcelin, 2011 ) in various neurodegenerative diseases. GLP-1 treatment has been shown to be effective in a variety of other neurodegenerative disorders, such as Alzheimer's disease ( Gengler et al 2012 ), Parkinson's disease ( Bertilsson et al 2008 ), Amyotrophic lateral sclerosis ( Shandilya and Mehan, 2021 ), Peripheral neuropathy ( Himeno et al 2011 ). Multiple sclerosis-related animal model studies ( Rossi et al, 2012 , Holt and Trapp, 2016 , Shiraishi et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage

Siddiqui

Mehan

Upadhayay

et al. 2021

Saudi Journal of Biological Sciences

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Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions

Cited by 22 publications

References 188 publications

Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis

Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis

IGF-1/GLP-1 Signaling Activator 4-hydroxyisoleucine (4-HI) Prevent Neurobehavioral and Neurochemical Defects in Methylmercury-induced Experimental Model of ALS: Insights From CSF, Blood Plasma and Brain Homogenate Samples in Rats

Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage

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Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions

Cited by 22 publications

References 188 publications

Phenotypical changes of satellite glial cells in a murine model of GM1‐gangliosidosis

Phenotypical changes of satellite glial cells in a murine model of GM1‐gangliosidosis

IGF-1/GLP-1 Signaling Activator 4-hydroxyisoleucine (4-HI) Prevent Neurobehavioral and Neurochemical Defects in Methylmercury-induced Experimental Model of ALS: Insights From CSF, Blood Plasma and Brain Homogenate Samples in Rats

Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage

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Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis

Phenotypical changes of satellite glial cells in a murine model of G_M1‐gangliosidosis