Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage

Siddiqui, Ehraz Mehmood; Mehan, Sidharth; Upadhayay, Shubham; Khan, Andleeb; Halawi, Maryam; Halawi, Azhar Ahmed; Alsaffar, Rana M.

doi:10.1016/j.sjbs.2021.07.010

Cited by 18 publications

(4 citation statements)

References 108 publications

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“…It not only improves blood flow but also protects brain cells, thereby promoting nerve regeneration. 65 AKT is a serine/threonine protein kinase, and its main activation pathway is the PI3K-AKT signalling pathway. PI3K can activate and phosphorylate AKT, and AKT1 has great significance in cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

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Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC‐MS/MS methods for simultaneous determination of 19 main active components

Yin,

Lian,

et al. 2023

Phytochemical Analysis

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IntroductionGinkgo biloba extract (GBE) is an effective substance from traditional Chinese medicine (TCM) G. biloba for treating ischaemic stroke (IS). However, its active ingredients and mechanism of action remain unclear.ObjectivesThis study aimed to reveal the potential active component group and possible anti‐IS mechanism of GBE.Materials and methodsThe network pharmacology method was used to reveal the possible anti‐IS mechanism of these active ingredients in GBE. An ultra‐high‐performance liquid chromatography triple quadrupole electrospray tandem mass spectrometry (UPLC‐MS/MS) method was established for the simultaneous detection of the active ingredients of GBE.ResultsThe active components of GBE anti‐IS were screened by literature integration. Network pharmacology results showed that the anti‐IS effect of GBE is achieved through key active components such as protocatechuic acid, bilobalide, ginkgolide A, and so on. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the possible anti‐IS mechanism of GBE is regulating the PI3K‐Akt signalling pathway and other signal pathways closely related to inflammatory response and apoptosis regulation combined with AKT1, MAPK, TNF, ALB, CASP3, and other protein targets. Nineteen main constituents in seven batches of GBE were successfully analysed using the established UPLC‐MS/MS method, and the results showed that the content of protocatechuic acid, gallic acid, ginkgolide A, and so forth was relatively high, which was consistent with network pharmacology results, indicating that these ingredients may be the key active anti‐IS ingredients of GBE.ConclusionThis study revealed the key active components and the anti‐IS mechanism of GBE. It also provided a simple and sensitive method for the quality control of related preparations.

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Section: Discussionmentioning

confidence: 99%

“…ALB can also effectively protect cerebral nerve cells. It not only improves blood flow but also protects brain cells, thereby promoting nerve regeneration 65 . AKT is a serine/threonine protein kinase, and its main activation pathway is the PI3K‐AKT signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC‐MS/MS methods for simultaneous determination of 19 main active components

Yin,

Lian,

et al. 2023

Phytochemical Analysis

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“…The mixture was incubated for 10 minutes at room temperature in a dark closed space with absorbent at 540 nm equal volumes of Griess reagent, and the supernatant was combined. A standard curve for sodium nitrite quanti ed the nitrite level as mM/mg protein [59].…”

Section: Estimation Of Nitrite Protein Levelmentioning

confidence: 99%

Guggulsterone selectively modulates STAT-3, mTOR, and PPAR-gamma signalling in a methylmercury-exposed experimental neurotoxicity: Evidence from CSF, blood plasma and brain samples

Kumar,

Mehan,

Khan

et al. 2023

Preprint

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Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg+) causes ALS. In ALS, (MeHg+-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signalling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg+-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.

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“…All of the other compounds employed in the study were of analytical grade. An aqueous solution of 4-HI with 2% ethanol was orally administered in the volume of 10 ml/kg (Siddiqui et al, 2021;Gaur et al, 2012).…”

Section: Drugs and Chemicalsmentioning

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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Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage

Abstract: Graphical abstract

Cited by 18 publications

References 108 publications

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC‐MS/MS methods for simultaneous determination of 19 main active components

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC‐MS/MS methods for simultaneous determination of 19 main active components

Guggulsterone selectively modulates STAT-3, mTOR, and PPAR-gamma signalling in a methylmercury-exposed experimental neurotoxicity: Evidence from CSF, blood plasma and brain samples

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

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