Dopamine D1 receptor modulation of pilocarpine-induced convulsions

Barone, Paolo; Parashos, Sotirios A.; Palma, V.; Marı́n, Concepció; Campanella, G; Chase, Thomas N.

doi:10.1016/0306-4522(90)90314-t

Cited by 40 publications

(27 citation statements)

References 38 publications

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“…In line with the majority of data described for generalized seizures, D 1 -like receptor-activation results in seizure enhancement in the limbic pilocarpine model (Barone et al, 1990). Activation of hippocampal D 2 -like receptors, leading to inhibition of adenylyl cyclase (AC) via Gi coupling, consistently protected rodents against limbic motor seizures, supporting seizure facilitation via D 1 R-mediated increases in cyclic adenosine monophosphate (cAMP; Bozzi and Borrelli, 2013).…”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencesupporting

confidence: 79%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

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Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencesupporting

confidence: 79%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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“…We have found, however, that as well as facilitating locomotion in mice treated with reserpine, an alkaloid used to deplete brain dopamine and induce a state of akinesia not unlike that of Parkinson's disease, D1 agonists also cause the animals to convulse (AI-Tajir et al, 1990a). In addition, we and others have demonstrated that D1 agonists similarly lower the seizure threshold to the chemoconvulsant pilocarpine in normal animals (A1-Tajir et al, 1990a; Barone et al, 1990;Turski et al, 1990). There is some suggestion that this seizure-promoting effect of D1 agonists involves D1 receptors that are anatomically discrete from those mediating changes in the animal's motor behaviour (A1-Tajir et al, 1990b;Turski et al, 1990), but it is not yet clear if the structural determinants of proconvulsive activity are the same as those for motor enhancement.…”

Section: Introductionmentioning

confidence: 92%

“…Nevertheless, it is a moderately good seizure inducer (A1-Tajir et al, 1990a; Barone et al, 1990;Burke et al, 1990), It is possible, therefore, that full D1 agonists with improved bioavailability may not only have enhanced antiparkinson capabilities, but also induce fits more readily. It is known that small variations in the substituent groups attached to the benzazepine nucleus can markedly alter the compound's D1 binding affinity, as well as its ability to stimulate adenylyl cyclase (i.e.…”

Section: Introductionmentioning

confidence: 96%

Seizure promotion by D1 agonists does not correlate with other dopaminergic properties

Starr

1993

J Neural Transm Gen Sect

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A range of D1 receptor agonists were tested for their ability to facilitate limbic motor seizures induced by a subthreshold dose of the chemoconvulsant pilocarpine (100 mg/kg IP) in mice. ED50 values (mumol/kg) were calculated from log dose-probit analyses, giving relative proconvulsant potencies of SKF 82958 > CY 208-243 > SKF 77434 = SKF 75670 = SKF 80723 > SKF 38393. The compound SKF 82526, which poorly crosses the blood-brain barrier, did not lower the seizure threshold. Convulsions consisted of rearing and forepaw myoclonus, leading to status epilepticus at higher doses of the D1 agonists. No deaths were recorded. A maximum seizure incidence of 50% was obtained with SKF 75670, compared to 100% for the other compounds. Apart from SKF 82526, the D1 agonists all elicited behavioural signs of central D1 receptor stimulation, including motor restlessness, grooming and sniffing. There was no obvious relationship between the abilities of these D1 agonist drugs to promote epilepsy and their effects on unconditioned motor behaviour, or their affinities and efficacies at the striatal D1 receptor. It is concluded that a reduction of the seizure threshold is an inevitable consequence of central D1 receptor stimulation with existing D1 agonists.

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“…Moreover, the most pronounced effect of i.c.v administration of NPY on extracellular (EC) neurotransmitter levels in rat brain appears to be an increase in hippocampal dopamine content [151][152]. Behavioural and electrographic studies in rats have shown that dopamine controls hippocampal excitability via opposing actions at D 1 and D 2 receptors [153][154][155]. Seizure enhancement is presumed to be a specific feature of D 1 receptor stimulation, whereas D 2 receptor simulation is anticonvulsant [156][157].…”

Section: Anticonvulsant Mechanism Of Action Of Npymentioning

confidence: 96%

Clinical Potential of Neuropeptide Y Receptor Ligands in the Treatment of Epilepsy

Meurs¹,

Clinckers²,

Ebinger³

et al. 2007

CTMC

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A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y(2) and/or Y(5) receptors and blockade of Y(1) receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y(2) and/or Y(5) agonists, and possibly Y(1) antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y(1) antagonists that fulfill these criteria, but suitable Y(2) and/or Y(5) agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.

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Dopamine D1 receptor modulation of pilocarpine-induced convulsions

Cited by 40 publications

References 38 publications

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Seizure promotion by D1 agonists does not correlate with other dopaminergic properties

Clinical Potential of Neuropeptide Y Receptor Ligands in the Treatment of Epilepsy

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