A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

Solbrig, Marylou V.; Adrian, Russell; Baratta, Janie; Piomelli, Daniele; Giuffrida, Andrea

doi:10.1016/j.expneurol.2005.02.017

Cited by 25 publications

(12 citation statements)

References 34 publications

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“…However, by blocking CB1 receptor, rimonabant can act on GABAergic neurons stimulating GABA release (Naderi, 2005). This effect results in an induction of convulsive phenomena and epileptic activity in animal models of encephalopathy and Parkinson's disease (Bernard et al, 2005;Solbrig et al, 2005). These observations, together with the finding that rimonabant prevents the benefit effects of CB1 receptor agonists in genetic and pharmacologically induced Huntington's disease (Lastres-Becker et al, 2003;Centonze et al, 2005), suggest that the drug is not suited to the treatment of neurodegenerative diseases and motor-related disorders.…”

Section: Discussionmentioning

confidence: 86%

“…Despite the projectile findings on this issue, recently well reviewed (Fernandez Ruiz and Gonzales, 2005;Robson, 2005;Valverde et al, 2005;Walker and Hohmann, 2005;Pertwee, 2006), inconclusive results were reported on early study carried out with rimonabant. Rimonabant increased the frequency and duration of seizures in a rat model of viral encephalopathy (Borna disease virus rats) (Solbrig et al, 2005), whereas the hyperkinetic state (vertical activity) induced by L-DOPA was decreased by the subcutaneous injection of rimonabant in the reserpine-treated rat model of Parkinson's disease. On the other hand, discrepant results have been obtained about the effects of this compound on quinpirole-induced hyperactivity.…”

Section: Rimonabant-induced Effects On Neurodegenerative Disordersmentioning

confidence: 99%

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Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Bifulco¹,

Grimaldi²,

Gazzerro³

et al. 2007

Mol Pharmacol

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The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large-scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.Studies on the effect of marijuana psychoactive principle ⌬ 9 -tetrahydrocannabinol (THC) have evolved into the discovery and description of the endocannabinoid system. So far, this system is composed of two receptors (the widely expressed CB1 and the more restricted CB2), five endogenous lipid-like ligands [including the well known endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol], and the enzymes involved in their biosynthesis and degradation (for review, see Mechoulam et al., 1998;De Petrocellis et al., 2004;Di Marzo et al., 2004). Starting from the discovery of the endocannabinoid system, a number of studies have pointed out that altered endocannabinoid signaling and CB1 receptor expression are involved in several pathophysiological situations, ranging from neurological and psychiatric diseases to eating, cardiovascular, and reproductive disorders. More recently, it has been described that CB1 receptor stimulation by the endocannabinoid AEA can negatively modulate cancer cell proliferation in vitro (Bifulco et al., 2001 as well as tumor growth and metastatic spreading in vivo (Portella et al., 2003;Bifulco et al., 2006Bifulco et al., , 2007. CB1 or CB2 antagonistic or inverse agonistic compounds have been used to investigate the endocannabinoid network and its integration with other signaling transduction pathways (for review, see Lange and Kruse, 2005). The first highly selective CB1 receptor antagonist, rimonabant (SR141716; Acomplia) was discovered by Sanofi-Aventis (Bridgewater, NJ) (Rinaldi-Carmona et al., 1994). It showed a number of biological effects in vitro and in vivo in several pathological situations. An update on the pleiotropic effects of rimonabant does not exist, whereas the knowledge concerning endocannabinoid system has been expanded considerably; therefore, we critically analyze the current literature on the pharmacological potential of rimonabant. We aim to describe both We thank the Associazione Educazione e Ricerca Medica Salernitana (ERMES) for supporting our studies. A.S. was supported by a fellowship from Associazione Italiana Ricerca sul Cancro.Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 86%

Section: Rimonabant-induced Effects On Neurodegenerative Disordersmentioning

confidence: 99%

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Bifulco¹,

Grimaldi²,

Gazzerro³

et al. 2007

Mol Pharmacol

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“…Seizure activity increases the hippocampal level of anandamide in kainate-injected mice [34] and of 2-AG in pilocarpine-injected rats [35]. 2-AG has also been found to be increased in rat brain in response to picrotoxinin administration [36] and anandamide is increased in subthalamic nucleus of rats with virally induced dyskinesia and increased seizure susceptibility [37] while no changes have been reported for the phospholipid precursor of anandamide in cortex of PTZ-injected mice [38]. These above mentioned results suggest that changes in the levels of endocannabinoid compounds are related to the type of neurological conditions and that their protective role in pathological condition is different.…”

Section: Discussionmentioning

confidence: 90%

Modulation of Anticonvulsant Effects of Cannabinoid Compounds by GABA-A Receptor Agonist in Acute Pentylenetetrazole Model of Seizure in Rat

et al. 2011

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Cannabinoid system plays an important role in controlling neuronal excitability and brain function. On the other hand, modulation of gamma-aminobutyric acid (GABA) transmission is one of the initial strategies for the treatment of seizure. The aim of the present study was to evaluate possible interaction between cannabinoidergic and GABAergic systems in pentylenetetrazole (PTZ)-induced acute seizure in rat. Drugs were administered by intracerebroventricular (i.c.v.) administration 20 min before a single intraperitoneal (i.p.) injection of PTZ and the latency to the first generalized tonic-clonic seizure was measured. Both the cannabinoid receptor agonist WIN55212-2 (10, 30, 50 and 100 μg/rat) and the GABA-A receptor agonist isoguvacine (IGN; 10, 30 and 50 μg/rat) significantly increased the latency of seizure occurrence. Moreover, the fatty acid amide hydrolase inhibitor URB597 showed no anticonvulsive effect while the monoacyl glycerol lipase (MAGL) inhibitor URB602 (10, 50 and 100 μg/rat) protected rats against PTZ-induced seizure. Moreover, co-administration of IGN and cannabinoid compounds attenuated the anticonvulsant action of both WIN55212-2 and IGN in this model of seizure. Our data suggests that exogenous cannabinoid WIN55212-2 and MAGL inhibitor URB602 imply their antiseizure action in part through common brain receptorial system. Moreover, the antagonistic interaction of cannabinoids and IGN in protection against PTZ-induced seizure could suggest the involvement of GABAergic system in their anticonvulsant action.

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“…In rats with hippocampal dynorphin systems disrupted by virus, administration of the general opioid antagonist naloxone leads to limbic seizures (Solbrig et al, 2005(Solbrig et al, , 2006a(Solbrig et al, , 2006b). Naloxone treatment elicited rhythmic EEG discharges in BD virus-infected rats and grouped, synchronous discharges in HSV-1-infected rats.…”

Section: Discussionmentioning

confidence: 99%

Activators of potassium M currents have anticonvulsant actions in two rat models of encephalitis

Solbrig

Adrian

Wechsler

et al. 2007

European Journal of Pharmacology

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Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/ kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (I M ), we tested the effect of the I M augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures.

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A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

Cited by 25 publications

References 34 publications

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Modulation of Anticonvulsant Effects of Cannabinoid Compounds by GABA-A Receptor Agonist in Acute Pentylenetetrazole Model of Seizure in Rat

Activators of potassium M currents have anticonvulsant actions in two rat models of encephalitis

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