Dihydroergotamine  affects spatial behavior and neurotransmission in the central nervous system of Wistar rats

Piechal, Agnieszka; Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Krzysztoforska, Kinga; Mirowska‐Guzel, Dagmara; Widy-Tyszkiewicz, Ewa

doi:10.26444/aaem/126020

Cited by 4 publications

(3 citation statements)

References 44 publications

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“…Another explanation of the lack of effect of famotidine on reversing the beneficial effects of DHE on spatial memory in the present study is associated with changes in other neurotransmitter systems produced by DHE, which can contribute to their effect on memory. Piechal A. et al, 2021 demonstrated that administration of DHE to adult male Wistar Albino Glaxo rats produced changes in the concentration of monoaminergic neurotransmitters and their metabolites in the prefrontal cortex, striatum, cerebellum, medulla oblongata, and spinal cord [35]. Due to the above commentaries, it is necessary to continue with the exploration of DHE's effects on memory in additional behavioral assays.…”

Section: Discussionmentioning

confidence: 99%

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model

Hernández-Rodríguez,

Mera Jiménez,

Nicolás-Vázquez

et al. 2024

IJMS

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The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

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Section: Discussionmentioning

confidence: 99%

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model

Hernández-Rodríguez,

Mera Jiménez,

Nicolás-Vázquez

et al. 2024

IJMS

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“…Although oral administration of dihydroergotamine to adult male Wistar Albino Glaxo did not influence the learning processes, dihydroergotamine treatment produced changes in the concentration of monoaminergic neurotransmitters and their metabolites in the prefrontal cortex, striatum, cerebellum, medulla oblongata and spinal cord [ 35 ]. In a similar way, although vilazodone has not shown improvements in visuospatial memory in healthy middle-aged female mice, its effects on animal models of cognitive impairment have not been explored [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing to Inhibit Histamine N-Methyl Transferase

et al. 2023

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Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer’s disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme–drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 μM and 45.01 μM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.

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“…The chemical structure of DHE is similar to that of many natural neurotransmitters, including epinephrine, norepinephrine, dopamine, and serotonin[ 26 ]. It can modulate noradrenergic, serotonergic, and dopaminergic neurotransmission[ 34 ]. DHE is an adrenergic receptor antagonist used to treat severe orthostatic hypotension, migraine, and headache[ 26 ], which can bind with various receptors.…”

Section: Discussionmentioning

confidence: 99%

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type II receptor

Zheng¹,

Yuan²,

Dong³

et al. 2023

World J Gastroenterol

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BACKGROUND The transforming growth factor β (TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type II receptor (TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway. AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis. METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

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Dihydroergotamine affects spatial behavior and neurotransmission in the central nervous system of Wistar rats

Abstract: affects spatial behavior and neurotransmission in the central nervous system of Wistar rats. Ann Agric Environ Med.

Cited by 4 publications

References 44 publications

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model

Drug Repurposing to Inhibit Histamine N-Methyl Transferase

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type II receptor

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