A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

Chakravarty, Sumana; Maitra, Swati; Reddy, R. Gajendra; Das, Tapatee; Jhelum, Priya; Kootar, Scherazad; Rajan, Wenson D.; Samanta, Anumita; Samineni, Ramesh; Srihari, P.; Kernie, Steven G.; Mehta, Goverdhan; Kumar, Arvind

doi:10.1038/srep14134

Cited by 27 publications

(39 citation statements)

References 26 publications

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“…Neurotrophic factor-mediated TrkB signaling is important for the regulation of proliferation and enhanced neurogenesis of embryonic precursors, and for the maintenance of survival of neuronal populations 48 , 49 . TrkB signaling induces the production of the transcription factor, CREB, through the activation of protein kinase cascades; BDNF or NT4 expression coupled with CREB phosphorylation is thought to be one of the key modulatory mechanisms underlying neurogenesis 50 – 52 . We found that mBMSC and EA, especially EA, could influence the expression of neurotrophic factors such as BDNF and NT4, in turn stimulating the transactivation of CREB.…”

Section: Discussionmentioning

confidence: 99%

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke

Kim

Ahn

Pak

et al. 2018

Sci Rep

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The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced prominent atrophic changes in the striatum and led to proliferation of neural progenitor cells in the subventricular zone (SVZ) and the surrounding areas of the striatum (SVZ + striatum) of MCAO mice. The mBMSC and EA treatment markedly enhanced mature brain-derived neurotrophic factor (mBDNF) expression in the SVZ + striatum and hippocampus of mice with MCAO, and combined treatment enhanced neurotrophin-4 (NT4) expression. The number of mBDNF-and NT4-positive neurons in the SVZ + striatum and hippocampus increased following EA treatment. Combined treatment led to an increase in the expression levels of phosphorylated cAMP response element binding protein in the neuroblasts of the striatum. Our results indicate that combined MSC and EA treatment may lead to a better therapeutic effect via co-regulation of neurotrophic factors in the brain, by regulating neurogenesis more than single therapy.Endogenous neurogenesis is restricted in the adult mammalian brain; however, brain injury in pathologies such as stroke elicits a latent neurogenic program 1 . Successful neurogenesis in the brain provides an attractive therapeutic prospect for a variety of neurodegenerative diseases 2,3 . This self-renewal and multilineage differentiation from neuronal progenitor cells is regulated by a specific set of signals that comprises both cell-intrinsic programs and extrinsic factors 4,5 . Extrinsic factors influencing the stem cell niche allow trophic factors to persist and regulate the proliferation and differentiation of the progenitor cell population [3][4][5][6] .Mesenchymal stem cell (MSC) transplantation is considered a treatment for cerebral ischemia, because MSCs can be readily obtained from the patient and easily cultured in vitro, thereby leading to weak immunological reactions and improved safety [7][8][9][10] . Moreover, one hypothetical explanation for the efficacy of MSC transplantation is based on the trophic effect, which is mediated by various kinds of trophic factors produced by the MSCs themselves [11][12][13] . MSCs can secrete a variety of trophic factors with autocrine and paracrine modes of action under hypoxic or ischemic conditions [14][15][16] . MSCs also induce parenchymal cells in the brain to secrete endogenous trophic factors to promote functional recovery after stroke 9,16,17 . MSC transplantation has been shown to have a

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Section: Discussionmentioning

confidence: 99%

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke

Kim

Ahn

Pak

et al. 2018

Sci Rep

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“…From the neurotrophin or neurotrophic factor family, BDNF has been shown to play a critical role in maintaining proper neural functions. 38 , 41 , 42 An attenuation in its level in brain circuitry is observed in animal models of neuropsychiatric disorders, including depression, anxiety, and related mood disorders. 43 − 45 The treatment of animal models with antidepressants and anxiolytics has been shown to increase its level in the affected circuitry.…”

Section: Resultsmentioning

confidence: 99%

“… 13 − 15 In this direction, we and others have focused on the exploration of novel small molecules based on diverse natural product scaffolds and their simplified analogues for neuroactive functions. 16 , 17 This study is based on our effort in evaluating fellutamide B synthetic path intermediates for their in vitro and in vivo neuroactive properties.…”

Section: Introductionmentioning

confidence: 99%

Fellutamide B Synthetic Path Intermediates with in Vitro Neuroactive Function Shows Mood-Elevating Effect in Stress-Induced Zebrafish Model

et al. 2018

Self Cite

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Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A–D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A–D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders.

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“…Golgi Cox staining was carried out on brain sections of 100 μm thickness using a previous protocol ( Chakravarty et al, 2015 ). A total of six each of unstressed wild-type and Wdr13 -/0 mice, and, five wild-type and six Wdr13 -/0 socially isolated mice were studied.…”

Section: Methodsmentioning

confidence: 99%

Absence of Wdr13 Gene Predisposes Mice to Mild Social Isolation – Chronic Stress, Leading to Depression-Like Phenotype Associated With Differential Expression of Synaptic Proteins

Mitra

Kumar

Lakshmi

et al. 2018

Front. Mol. Neurosci.

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We earlier reported that the male mice lacking the Wdr13 gene (Wdr13-/0) showed mild anxiety, better memory retention, and up-regulation of synaptic proteins in the hippocampus. With increasing evidences from parallel studies in our laboratory about the possible role of Wdr13 in stress response, we investigated its role in brain. We observed that Wdr13 transcript gets up-regulated in the hippocampus of the wild-type mice exposed to stress. To further dissect its function, we analyzed the behavioral and molecular phenotypes of Wdr13-/0 mice when subjected to mild chronic psychological stress, namely; mild (attenuated) social isolation. We employed iTRAQ based quantitative proteomics, real time PCR and western blotting to investigate molecular changes. Three weeks of social isolation predisposed Wdr13-/0 mice to anhedonia, heightened anxiety-measured by Open field test (OFT), increased behavior despair- measured by Forced swim test (FST) and reduced dendritic branching along with decreased spine density of hippocampal CA1 neurons as compared to wild-type counterparts. This depression-like-phenotype was however ameliorated when treated with anti-depressant imipramine. Molecular analysis revealed that out of 1002 quantified proteins [1% False discovery rate (FDR), at-least two unique peptides], strikingly, a significant proportion of synaptic proteins including, SYN1, CAMK2A, and RAB3A were down-regulated in the socially isolated Wdr13-/0 mice as compared to its wild-type counterparts. This was in contrast to the elevated levels of these proteins in non-stressed mutants as compared to the controls. We hypothesized that a de-regulated transcription factor upstream of the synaptic genes might be responsible for the observed phenotype. Indeed, in the socially isolated Wdr13-/0 mice, there was an up-regulation of GATA1 – a transcription factor that negatively regulates synaptic genes and has been associated with Major Depression (MD) in humans. The present study demonstrates significant genotype × enviornment interaction for Wdr13 gene as shown by the reversal in the expression levels of several synaptic proteins in the mutant vis-à-vis wild-type mouse when exposed to social isolation stress.

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A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

Cited by 27 publications

References 26 publications

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke

Fellutamide B Synthetic Path Intermediates with in Vitro Neuroactive Function Shows Mood-Elevating Effect in Stress-Induced Zebrafish Model

Absence of Wdr13 Gene Predisposes Mice to Mild Social Isolation – Chronic Stress, Leading to Depression-Like Phenotype Associated With Differential Expression of Synaptic Proteins

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