Effect of Harmane on the Convulsive Threshold in Epilepsy Models in Mice

Arıcıoğlu, Feyza; Yillar, Okan; Korcegez, Eylem; Berkman, Kemal

doi:10.1196/annals.1304.023

Cited by 15 publications

(11 citation statements)

References 14 publications

(27 reference statements)

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“…Previous reports have shown that intraperitoneal injection of harmine suppresses bone resorption in vivo 12 , but also induces significant neurotoxic effects 13 - 15 . To minimize the undesired side effects, harmine was prepared into oil-in-water oral emulsion for our in vivo study.…”

Section: Resultsmentioning

confidence: 96%

“…Intraperitoneal administration with harmine was able to suppress OVX-induced bone loss in mice 12 . However, it should be noted that intraperitoneal injection of harmine could cause serious central nervous system side effects 13 - 15 , 26 , which impede the development of harmine toward wider clinical applications 26 . In this study, we generated an oil-in-water harmine emulsion and found that the oral administration of harmine in emulsion form reduced harmine accumulation in the mouse brain.…”

Section: Discussionmentioning

confidence: 99%

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Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice

Huang¹,

Yin²,

Rao³

et al. 2018

Theranostics

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Recently, researchers identified a distinct vessel subtype called type H vessels that couple angiogenesis and osteogenesis. We previously found that type H vessels are reduced in ovariectomy (OVX)-induced osteoporotic mice, and preosteoclasts are able to secrete platelet-derived growth factor-BB (PDGF-BB) to stimulate type H vessel formation and thereby to promote osteogenesis. This study aimed to explore whether harmine, a β-carboline alkaloid, is capable of preventing bone loss in OVX mice by promoting preosteoclast PDGF-BB-induced type H vessel formation.Methods: The impact of harmine on osteoclastogenesis of RANKL-stimulated RAW264.7 cells was verified by gene expression analysis and tartrate-resistant acid phosphatase (TRAP) staining. Enzyme-linked immunosorbent assay (ELISA) was conducted to test PDGF-BB production by preosteoclasts. A series of angiogenesis-related assays in vitro were performed to assess the pro-angiogenic effects of the conditioned media from RANKL-stimulated RAW264.7 cells treated with or without harmine. Meanwhile, the role of PDGF-BB in this process was determined. In vivo, OVX mice were intragastrically administrated with harmine emulsion or an equal volume of vehicle. 2 months later, bone samples were collected for µCT, histological, immunohistochemical and immunofluorescent analyses to evaluate bone mass, osteogenic and osteoclastic activities, as well as the numbers of type H vessels. Bone marrow PDGF-BB concentrations were assessed by ELISA.Results: Exposure of RANKL-stimulated RAW264.7 cells to harmine enhanced the formation of preosteoclasts and the production of PDGF-BB. Harmine augmented the ability of RANKL-stimulated RAW264.7 cells to promote angiogenesis of endothelial cells, whereas the effect was blocked by PDGF-BB inhibition. In vivo, the oral administration of harmine emulsion to OVX mice resulted in enhanced trabecular bone mass and osteogenic responses, increased numbers of preosteoclasts, as well as reduced numbers of osteoclasts and fat cells. Moreover, OVX mice treated with harmine exhibited higher levels of bone marrow PDGF-BB and much more type H vessels in bone.Conclusion: Harmine may exert bone-sparing effects by suppression of osteoclast formation and promotion of preosteoclast PDGF-BB-induced angiogenesis.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice

Huang¹,

Yin²,

Rao³

et al. 2018

Theranostics

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“…Harmine is a harmala alkaloid (Figure 5A) and generally these alkaloids have a wide spectrum of pharmacological actions, including MAO inhibition, binding to benzodiazepine receptors, convulsive or anticonvulsive actions and tremorogenesis (Aricioglu et al, 2003; Glennon et al, 2000; Guan et al, 2001; Husbands et al, 2001; Kim et al, 1997; Lutes et al, 1988; Song et al, 2004). To gain some insight into the specificity of harmine’s ability to up-regulate glutamate transporter gene expression, we tested the activities of anumber of harmine analogs.…”

Section: Resultsmentioning

confidence: 99%

“…It is also present in common plant-derived foods and in human tissues (Guan et al, 2001). Known pharmacologic effects of harmine include hallucinogenesis (Sourkes, 1999), convulsive or anticonvulsive actions (Aricioglu et al, 2003), and tremor (Guan et al, 2001; Lutes et al, 1988). Several potential molecular targets for these central pharmacologic effects of harmine have been identified.…”

Section: Discussionmentioning

confidence: 99%

Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression

Sattler

Yang

et al. 2011

Neuropharmacology

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Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS). Glutamate transporter EAAT2 /GLT-1 is the physiologically dominant astroglial protein that inactivates synaptic glutamate. Previous studies have shown that EAAT2 dysfunction leads to excessive extracellular glutamate and may contribute to various neurological disorders including amyotrophic lateral sclerosis (ALS). The recent discovery of the neuroprotective properties of ceftriaxone, a beta lactam antibiotic, suggested that increasing EAAT2 /GLT-1 gene expression might be beneficial in ALS and other neurological/psychiatric disorders by augmenting astrocytic glutamate uptake. Here we report our efforts to develop a new screening assay for identifying compounds that activate EAAT2 gene expression. We generated fetal derived-human immortalized astroglial cells that are stably expressing a firefly luciferase reporter under the control of the human EAAT2 promoter. When screening a library of 1040 FDA approved compounds and natural products, we identified harmine, a naturally occurring beta-carboline alkaloid, as one of the top hits for activating the EAAT2 promoter. We further tested harmine in our in vitro cell culture systems and confirmed its ability to increase EAAT2/GLT1 gene expression and functional glutamate uptake activity. We next tested its efficacy in both wild type animals and in an ALS animal model of disease and demonstrated that harmine effectively increased GLT-1 protein and glutamate transporter activity in vivo. Our studies provide potential novel neurotherapeutics by modulating the activity of glutamate transporters via gene activation.

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“…However, the side effects, like neurotoxicity had also been noted for many years. Accumulating evidences indicated that harmine was also a tumorigenic agent, and can induce convulsion and Straub tail in mouse model (Ahmed et al, 1959;Saano et al, 1982;Aricioglu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

DH332, a Synthetic β-Carboline Alkaloid, Inhibits B Cell Lymphoma Growth by Activation of the Caspase Family

Gao

Ning²,

Ma³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Aim: The purpose of this study was to investigate anti-tumor effects and safety of DH332, a new β-carboline alkaloids derivatives in vitro and in vivo. Materials and Methods: The effects of DH332 on human (RAMOS RA.1) and mouse (J558) B lymphoma cell lines were detected using a CCK-8 kit (Cell Counting Kit-8), and apoptosis was detected by flow cytometry with PI/annexinV staining. Western blotting was used to detected caspase-3 and caspase-8. Neurotoxic and anti-tumor effects were evaluated in animal experiments. Results: DH332 exerts a lower neurotoxicity compared with harmine. It also possesses strong antitumor effects against two B cell lymphoma cell lines with low IC 50s . Moreover, DH332 could inhibit the proliferation and induce the apoptosis of RAMOS RA.1 and J558 cell lines in a dose-dependent manner. Our results suggest that DH332 triggers apoptosis by mainly activating the caspase signaling pathway. In vivo studies of tumor-bearing BALB/c mice showed that DH332 significantly inhibited growth of J558 xenograft tumors. Conclusions: DH332 exerts effective antitumor activity in vitro and in vivo, and has the potential to be a promising drug candidate for lymphoma therapy.

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Effect of Harmane on the Convulsive Threshold in Epilepsy Models in Mice

Cited by 15 publications

References 14 publications

Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice

Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice

Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression

DH332, a Synthetic β-Carboline Alkaloid, Inhibits B Cell Lymphoma Growth by Activation of the Caspase Family

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