Drugs targeting nitric oxide synthase for migraine treatment

Barbanti, Piero; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Della-Morte, David

doi:10.1517/13543784.2014.918953

Cited by 37 publications

(27 citation statements)

References 61 publications

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“…The increased activity of central terminals of sensitized TG afferents can promote the upregulation of neuronal NOS (nNOS) in the postsynaptic neurons, which can both sensitize the second‐order neurons as well as the primary afferent terminals by retrograde diffusion of NO . Moreover, both NO and CGRP activate astrocytes and microglia .…”

Section: Role Of Trigeminal Cgrp In Migraine – Preclinical Evidencementioning

confidence: 99%

“…[156][157][158][159][160] In the TG, CGRP secreted from neurons can activate signaling cascades by interacting with the CGRP receptors present on satellite glia and on adjacent non-CGRPergic TG neurons, inducing NO production in these glia and neurons to cause release of additional CGRP and the activation of signaling cascades to increase production of proinflammatory mediators, thus sensitizing TG neurons. [161][162][163] Studies performed with primary TG cultures suggested the presence of a feed-forward loop that can increase both CGRP and NO production (Fig. 2).…”

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

“…161,164 The increased activity of central terminals of sensitized TG afferents can promote the upregulation of neuronal NOS (nNOS) in the postsynaptic neurons, which can both sensitize the second-order neurons as well as the primary afferent terminals by retrograde diffusion of NO. 57,163,165 Moreover, both NO and CGRP activate astrocytes and microglia. 57,163,165,166 Taken together, these studies indicate that both CGRP and NO contribute to central sensitization, and they do so in a way that can potentiate each other's activity (Fig.…”

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

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CGRP and the Trigeminal System in Migraine

et al. 2019

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Objective The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene‐related peptide (CGRP) within the context of the trigeminovascular system. Background Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system. Design This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points. Results The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second‐order neurons. A shift in central sensitization from activity‐dependent to activity‐independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder. Conclusions CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Addit...

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Section: Role Of Trigeminal Cgrp In Migraine – Preclinical Evidencementioning

confidence: 99%

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

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CGRP and the Trigeminal System in Migraine

et al. 2019

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“…have prevented their therapeutic use. [39][40][41] For instance, efforts are still in progress to improve the permeability of nNOS inhibitors. [42][43][44] Therefore, developing a clinically useful NOS inhibitor remains a strong challenge.…”

Section: Introductionmentioning

confidence: 99%

Solid‐Phase Synthesis of Substrate‐Based Dipeptides and Heterocyclic Pseudo‐dipeptides as Potential NO Synthase Inhibitors

et al. 2020

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More than 160 arginine analogues modified on the C‐terminus via either an amide bond or a heterocyclic moiety (1,2,4‐oxadiazole, 1,3,4‐oxadiazole and 1,2,4‐triazole) were prepared as potential inhibitors of NO synthases (NOS). A methodology involving formation of a thiocitrulline intermediate linked through its side‐chain on a solid support followed by modification of its carboxylate group was developed. Finally, the side‐chain thiourea group was either let unchanged, S‐alkylated (Me, Et) or guanidinylated (Me, Et) to yield respectively after TFA treatment the corresponding thiocitrulline, S‐Me/Et‐isothiocitrulline and N‐Me/Et‐arginine substrate analogues. They all were tested against three recombinant NOS isoforms. Several compounds containing a S‐Et‐ or a S‐Me‐Itc moiety and mainly belonging to both the dipeptide‐like and 1,2,4‐oxadiazole series were shown to inhibit nNOS and iNOS with IC50 in the 1–50 μM range. Spectral studies confirmed that these new compounds interacted at the heme active site. The more active compounds were found to inhibit intra‐cellular iNOS expressed in RAW264.7 and INS‐1 cells with similar efficiency than the reference compounds L‐NIL and SEIT.

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“…Moreover, another critical target for the inflammation suppressive activity regulated by andrographolide is the NO/inducible NOS (iNOS) pathway (Lim et al, 2012). The NO/iNOS system is involved in pain transmission, hyperalgesia, chronic pain, neuroinflammation and central sensitization (Barbanti et al, 2014). Despite the potent anti-inflammatory properties exhibited by AP, its anti-nociceptive and analgesic effects are still largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine

Greco

Siani

Demartini

et al. 2016

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Administration of nitroglycerin (NTG) to rats induces a hyperalgesic condition and neuronal activation of central structures involved in migraine pain. In order to identify therapeutic strategies for migraine pain, we evaluated the anti-nociceptive activity of Andrographis Paniculata (AP), a herbaceous plant, in the hyperalgesia induced by NTG administration in the formalin test. We also analyzed mRNA expression of cytokines in specific brain areas after AP treatment. Male Sprague-Dawley rats were pre-treated with AP extract 30 minutes before NTG or vehicle injection. The data show that AP extract significantly reduced NTG-induced hyperalgesia in phase II of the test, 4 hours after NTG injection. In addition, AP extract reduced IL-6 mRNA expression in the medulla and mesencephalon and also mRNA levels of TNFalpha in the mesencephalic region. These findings Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine suggest that AP extract may be a potential therapeutic approach in the treatment of general pain, and possibly of migraine.

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Drugs targeting nitric oxide synthase for migraine treatment

Cited by 37 publications

References 61 publications

CGRP and the Trigeminal System in Migraine

CGRP and the Trigeminal System in Migraine

Solid‐Phase Synthesis of Substrate‐Based Dipeptides and Heterocyclic Pseudo‐dipeptides as Potential NO Synthase Inhibitors

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine

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