Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

Tiwari, Shashi Kant; Seth, Brashket; Agarwal, Swati; Yadav, Ashok; Karmakar, Madhumita; Gupta, Satish; Choubey, Vinay; Sharma, Abhay; Chaturvedi, Rajnish Kumar

doi:10.1074/jbc.m115.652586

Cited by 79 publications

(43 citation statements)

References 77 publications

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“…Primary culture of the hippocampal NSC NSC were isolated from the hippocampus of rat embryos (embryonic day 12) and cultured as in our earlier published studies (94). Briefly, hippocampal tissues were collected in cold Hanks' balanced salt solution and chopped into small pieces followed by incubation in 0.25% trypsin for 30 min at 37°C.…”

Section: Carbofuran Exerts Anti-neurogenic Effects Through Tgf-␤/smadmentioning

confidence: 99%

Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

Seth

Yadav

Agarwal

et al. 2017

Journal of Biological Chemistry

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The widely used carbamate pesticide carbofuran causes neurophysiological and neurobehavioral deficits in rodents and humans and therefore poses serious health hazards around the world. Previously, we reported that gestational carbofuran exposure has detrimental effects on hippocampal neurogenesis, the generation of new neurons from neural stem cells (NSC), in offspring. However, the underlying cellular and molecular mechanisms for carbofuran-impaired neurogenesis remain unknown. Herein, we observed that chronic carbofuran exposure from gestational day 7 to postnatal day 21 altered expression of genes and transcription factors and levels of proteins involved in neurogenesis and the TGF-β pathway ( TGF-β; SMAD-2, -3, and -7; and SMURF-2) in the rat hippocampus. We found that carbofuran increases TGF-β signaling ( increased phosphorylated SMAD-2/3 and reduced SMAD-7 expression) in the hippocampus, which reduced NSC proliferation because of increased p21 levels and reduced cyclin D1 levels. Moreover, the carbofuran-altered TGF-β signaling impaired neuronal differentiation (BrdU/DCX and BrdU/NeuN cells) and increased apoptosis and neurodegeneration in the hippocampus. Blockade of the TGF-β pathway with the specific inhibitor SB431542 and via SMAD-3 siRNA prevented carbofuran-mediated inhibition of neurogenesis in both hippocampal NSC cultures and the hippocampus, suggesting the specific involvement of this pathway. Of note, both and studies indicated that TGF-β pathway attenuation reverses carbofuran's inhibitory effects on neurogenesis and associated learning and memory deficits. These results suggest that carbofuran inhibits NSC proliferation and neuronal differentiation by altering TGF-β signaling. Therefore, we conclude that TGF-β may represent a potential therapeutic target against carbofuran-mediated neurotoxicity and neurogenesis disruption.

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Section: Carbofuran Exerts Anti-neurogenic Effects Through Tgf-␤/smadmentioning

confidence: 99%

Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

Seth

Yadav

Agarwal

et al. 2017

Journal of Biological Chemistry

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“…By analyzing the Tau-interacting proteome, we revealed that PI3K-p85 is the key regulator of Taumediated AHN. Although accumulating studies have shown that PI3K-AKT signaling regulates hippocampal neuron survival and proliferation in the DG upon exposure to external chronic stress, the role of PI3K-AKT signaling in cocaine memory formation has not been completely elucidated [17,47]. Only one study published to date reported an association of human Tau with PI3K-p85 in COS-7 cells, and the replacement of a few amino acid residues of human Tau drastically decreased its binding with PI3K-p85 [21].…”

Section: The Interaction Of 4r Tau With Pi3k-p85 Modulates Pi3k-akt Smentioning

confidence: 99%

4R Tau Modulates Cocaine-Associated Memory Through Adult Hippocampal Neurogenesis

Wang

et al. 2020

Preprint

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Background: Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation; however, the underlying mechanism is not fully understood.Methods: Conditioned place preference (CPP), self-administration and locomotor activity were used to investigate the role of Tau in cocaine-associated memory formation. Virus-mediated gene transfer, western blot, immunohistochemistry, flow cytometry analysis, Tau-interacting proteomics, co-immunoprecipitation, and mutation of 4R Tau were performed. Results: Hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Conclusions: 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction.

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“…One aspect that needs further research is the impact of the administration of AEDs on embryonic and postnatal neurogenesis. In recent years, studies done in vitro and in vivo with rodent models of epilepsy and in humans have highlighted some of the consequences [ 78 , 79 , 80 ]. A study performed in pregnant mice treated with valproic acid has shown that, in the offspring, embryonic neurogenesis is untimely upregulated, leading to an increase in cell proliferation, which in the adult, will consequently deplete the NSC pool and decrease the levels of adult neurogenesis in the hippocampus.…”

Section: Adult Neurogenesis and Neural Stem/progenitor Cellsmentioning

confidence: 99%

“…This study also reported abnormal morphology and activity of hippocampal neurons [ 78 ]. In vitro, rat NSCs treated with ethosuximide, an AED used for absence epilepsy, were shown to have increased cell proliferation and neuronal differentiation [ 79 ]. Importantly, embryonic exposure to AEDs has worse outcomes than exposure in adulthood, with most animals presenting impaired spatial memory and cognitive deficits, resulting from neuronal death and structural changes in the rodent brain (reviewed in References [ 81 , 82 ]).…”

Section: Adult Neurogenesis and Neural Stem/progenitor Cellsmentioning

confidence: 99%

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

Lourenço

Ribeiro-Rodrigues

Sebastião

et al. 2020

IJMS

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Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.

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Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

Cited by 79 publications

References 77 publications

Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

4R Tau Modulates Cocaine-Associated Memory Through Adult Hippocampal Neurogenesis

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

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