Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1‐receptor antagonist in the rat

Kalinichev, Mikhail; Bradford, Andrea M.; Bison, Silvia; Lucas, A.; Sartori, Ilaria; Garbati, Nicoletta; Andreetta, Filippo; Bate, Simon T.; Austin, Nigel; Jones, Declan N.C.; Read, Kevin D.; Alvaro, Giuseppe; Large, Charles H.

doi:10.1111/j.1528-1167.2009.02482.x

Cited by 14 publications

(14 citation statements)

References 36 publications

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“…Moreover, at the doses tested vofopitant did not produce CNS side effects, and it did not enhance side effects induced by high doses of lamotrigine. Analysis of the dose-effect relationship for GR-205,171 indicated that a high ([99 %) occupancy of NK-1 receptors is required for an effect to be observed, consistent with previous behavioral and human clinical studies with this pharmacologic class (Kalinichev et al 2010). The authors concluded that in patients with refractory epilepsy some benefit could be derived from adding treatment with a suitable NK-1 receptor antagonist to treatment with a sodium channel blocker.…”

Section: Seizurementioning

confidence: 57%

“…The authors found that vofopitant had no anticonvulsant efficacy by itself, but could enhance the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. This effect was mediated by NK-1 receptors (Kalinichev et al 2010). Moreover, at the doses tested vofopitant did not produce CNS side effects, and it did not enhance side effects induced by high doses of lamotrigine.…”

Section: Seizurementioning

confidence: 97%

“…However, this potential has not been fully explored in animals or humans. A recent study carried out in an animal experimental model has evaluated the efficacy of the NK-1 receptor antagonist, vofopitant (GR-205,171) (Table 1), both alone and in combination with different anticonvulsant drugs, because it is known that many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures (Kalinichev et al 2010). The authors found that vofopitant had no anticonvulsant efficacy by itself, but could enhance the anticonvulsant efficacy of lamotrigine and other sodium channel blockers.…”

Section: Seizurementioning

confidence: 99%

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Involvement of substance P and the NK-1 receptor in human pathology

2014

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The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also present in cells not belonging to the nervous system (immune cells, liver, lung, placenta, etc.). SP is located in all body fluids, such as blood, cerebrospinal fluid, breast milk, etc. i.e. it is ubiquitous in human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates many pathophysiological functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, vomiting, migraine, alcohol addiction, seizures and neurodegeneration. SP has been also implicated in pain, inflammation, hepatitis, hepatotoxicity, cholestasis, pruritus, myocarditis, bronchiolitis, abortus, bacteria and viral infection (e.g., HIV infection) and it plays an important role in cancer (e.g., tumor cell proliferation, antiapoptotic effects in tumor cells, angiogenesis, migration of tumor cells for invasion, infiltration and metastasis). This means that the SP/NK-1 receptor system is involved in the molecular bases of many human pathologies. Thus, knowledge of this system is the key for a better understanding and hence a better management of many human diseases. In this review, we update the involvement of the SP/NK-1 receptor system in the physiopathology of the above-mentioned pathologies and we suggest valuable future therapeutic interventions involving the use of NK-1 receptor antagonists, particularly in the treatment of emesis, depression, cancer, neural degeneration, inflammatory bowel disease, viral infection and pruritus, in which that system is upregulated.

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Section: Seizurementioning

confidence: 57%

Section: Seizurementioning

confidence: 97%

Section: Seizurementioning

confidence: 99%

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Involvement of substance P and the NK-1 receptor in human pathology

2014

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“…NK-1 receptor antagonists have been tested in animal models of epilepsy and were found effective. CP-122,721-1, attenuated kainate induced seizure activity [180] while GR205171 potentiated the anticonvulsant efficacy of sodium channel inhibitors [181]. Thus, research using NK-1 receptor antagonist in epilepsy is expected to intensify in the future [182].…”

Section: Substance Pmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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“…A recent study reported that aprepitant can decrease neuronal cell death and oxidative stress in bilateral common carotid artery-occluded rats [ 90 ]. Interestingly, GR205171 (vofopitant), a NK-1R antagonist, demonstrated potent antiepileptic effects as a Na + channel blocker, rather than exerting direct antiepileptic efficacy [ 91 ]. Thus, NK-1R antagonists may elicit synergistic effects with other traditional AEDs, which could be a promising target for treatment of refractory epilepsy.…”

Section: Introductionmentioning

confidence: 99%

The role of substance P in epilepsy and seizure disorders

Wang

Fan

et al. 2017

Oncotarget

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A range of evidence implicates the neuropeptide substance P (SP), a member of the tachykinin family, in emotional behavior, anxiety, pain, and inflammation. Recently, SP has been implicated in susceptibility to seizures, for which a potential proconvulsant role was indicated. Indeed, antagonists of a specific SP receptor, neurokinin-1 receptor, were found to attenuate kainic acid (KA)-induced seizure activity. However, detailed mechanisms of SP regulation in epilepsy remain obscure. In this review, we summarize the present literature to expound the role of SP in epilepsy, and provide hypotheses for potential mechanisms.

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Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1‐receptor antagonist in the rat

Cited by 14 publications

References 36 publications

Involvement of substance P and the NK-1 receptor in human pathology

Involvement of substance P and the NK-1 receptor in human pathology

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

The role of substance P in epilepsy and seizure disorders

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