Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo

Wei, Liangpeng; Xue, Zhenyi; Lan, Baihui; Yuan, Shiyang; Li, Yuanyuan; Guo, Cunle; Zhang, Rongxin; Ding, Ran; Shen, Hui

doi:10.3389/fimmu.2021.691590

Cited by 8 publications

(4 citation statements)

References 55 publications

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“…This is in sharp contrast to findings in early states of neurological disorders, such as Alzheimer's Disease, Multiple Sclerosis and Huntington's Disease. Here, we and others reported firstly a shift towards hyperactivity [17][18][19][20][21][22] . Secondly, this dysregulation was limited to a subset of excitatory neurons exhibiting an increased firing rate.…”

Section: Distinct Functional Microarchitecture Characterized By Low-a...supporting

confidence: 54%

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Altahini,

Doering,

Kuchling

et al. 2023

Preprint

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IgG antibodies that bind to the N-methyl-D-aspartate receptors (NMDAR-Ab) can be detected in up to 1 % of healthy individuals. This suggests that a considerable subgroup of pregnant women is at risk of transferring NMDAR-antibodies to the fetus. We ask whether a transientin uteroexposure to human NMDAR-Ab can lead to neural network defects in adulthood. In mouse model of maternofetally transferred human NMDAR-Ab, at P51, corresponding to early adulthood in humans, we conducted two-photon calcium imaging in awake behaving mice. We found that microcircuits in NMDAR-Ab exposed mice exhibited a lower spontaneous activity and increased bursty firing. Upon visual stimulation, neurons in NMDAR-Ab exposed mice had a higher orientation selectivity. In NMDAR-Ab exposed mice, a large fraction of neurons active upon visual stimulation did not fire spontaneously, andvice versa. This dissociation is in sharp contrast to the operational principles in healthy networks, in which the majority of all neurons were co-active. These findings suggest that transientin uteroexposure to NMDAR-Ab shifts cortical microcircuits to a maladaptive state persisting into adulthood, characterized by a dissociation between spontaneous and visually evoked activity. Such dissociation has long been hypothesized to play a role in the development of psychosis.

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Section: Distinct Functional Microarchitecture Characterized By Low-a...supporting

confidence: 54%

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Altahini,

Doering,

Kuchling

et al. 2023

Preprint

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“…ZINC000013462928 is structurally similar to arctigenin and matairesinol with scores of 0.632 and 0.626, respectively. Both arctigenin and matairesinol have been reported to have neuroprotective, anti-diabetic and anti-depressive activities [ 134 , 135 , 136 ]. The predicted biological activities of the shortlisted compounds corroborate their potential anti-ADAR2 activity.…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

Broni

Striegel

Ashley

et al. 2023

IJMS

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Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from −81.304 to −1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (−1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [−873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) > 0.442 and probability of inactivity (Pi) < 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2.

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“…Its neuroprotective effects have been shown in primary cultures of rat cortical neurons 35 . A recent study reported a reversal of the abnormally high frequency of AMPA-mediated spontaneous excitatory postsynaptic currents to normal levels after ATG treatment 38 . Given the importance of AMPA and kainate receptors in the pathophysiology of many neurological disorders, we investigated whether ATG, TGN and MAT affect the electrically evoked field potentials of the rat CA1 hippocampus and neocortex ex vivo .…”

Section: Discussionmentioning

confidence: 99%

Anti-glutamatergic Effects of Three Lignan Compounds: Arctigenin, Matairesinol and Trachelogenin – An ex vivo Study on Rat Brain Slices

et al. 2023

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Arctigenin is a bioactive dibenzylbutyrolactone-type lignan exhibiting various pharmacological activities. The neuroprotective effects of arctigenin were demonstrated to be mediated via inhibition of AMPA and KA type glutamate receptors in the somatosensory cortex of the rat brain. The aim of this study was to compare the effects of arctigenin with matairesinol and trachelogenin on synaptic activity in ex vivo rat brain slices. Arctigenin, matairesinol and trachelogenin were isolated from Arctium lappa, Centaurea scabiosa and Cirsium arvense, respectively, and applied on brain slices via perfusion medium at the concentration range of 0.5-40 µM. The effects of the lignans were examined in the CA1 hippocampus and the somatosensory cortex by recording electrically evoked field potentials. Arctigenin and trachelogenin caused a significant dose-dependent decrease in the amplitude of hippocampal population spikes (POPS) and the slope of excitatory postsynaptic potentials (EPSPs), whereas matairesinol (1 µM and 10 µM) decreased EPSP slope but had no effect on POPS amplitude. Trachelogenin effect (0.5 µM, 10 µM, 20 µM) was comparable to arctigenin (1 µM, 20 µM, 40 µM) (p ˃ 0.05). In the neocortex, arctigenin (10 µM, 20 µM) and trachelogenin (10 µM) significantly decreased the amplitude of evoked potential early component, while matairesinol (1 µM and 10 µM) had no significant effect (p>0.05). The results suggest that trachelogenin and arctigenin act via inhibition of AMPA and KA receptors in the brain and trachelogenin has a higher potency than arctigenin. Thus, trachelogenin and arctigenin could serve as lead compounds in the development of neuroprotective drugs.

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Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo

Cited by 8 publications

References 55 publications

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

Anti-glutamatergic Effects of Three Lignan Compounds: Arctigenin, Matairesinol and Trachelogenin – An ex vivo Study on Rat Brain Slices

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