Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy

Vinogradova, Lyudmila V.; Rijn, Clementina M. van

doi:10.1016/j.pharep.2014.12.002

Cited by 23 publications

(15 citation statements)

References 19 publications

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“…Chronic administration of the full CB 1 R agonist WIN55,212-2 (4 mg/kg/day, i.p., for 11 days, 30 min before stimulation) exhibited anti-epileptogenic properties in the amygdala kindling model of temporal lobe epilepsy in mice by delaying the progression of seizures severity [94]. A single dose of WIN55,212-2 (4 mg/kg, s.c.) administered at the start of the epileptogenic kindling process has also been shown to prolong seizures development by a period of two weeks in Krushinsky-Molodkina (KM) rats with genetic audiogenic epilepsy [95]. WIN 55,212-2 (10 μM) attenuated the frequency of excitatory postsynaptic currents in whole cell patch clamp recordings from granule cells in vitro and impeded recurrent excitation in the dentate gyrus of mice with pilocarpine-induced temporal lobe epilepsy (TLE), assessed after electric stimulation of mossy fibers in the hilus of hippocampal slices [96].…”

Section: Resultsmentioning

confidence: 99%

“…Collectively, understanding the role of the endocannabinoid system in epileptogenesis requires careful consideration of the dosing schedule, time window of drug administration, age of the animal, and underlying seizures network [95]. CB 1 R agonists demonstrate primarily anticonvulsive effects in chronic models, while CB 1 R antagonists exert mixed effects, based on drug timing and dosage.…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Rosenberg

Patra

Whalley

2017

Epilepsy & Behavior

168

139

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The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review's findings aim to drive future drug development ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Rosenberg

Patra

Whalley

2017

Epilepsy & Behavior

168

139

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“…In turn, results obtained from the treatment with cannabinoids WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) in the mouse olfactory epithelium in vivo indicated increased proliferation, but not neurogenesis nor non-neuronal cell generation [57]. Additionally, Vinogradowa and van Rijn [58] examined acute and long-term effects of another synthetic cannabinoid WIN55,212-2 in the early stage of audiogenic kindling. The results they obtained showed that WIN55,212-2 administered in a single dose one hour before the 4th seizure delayed the kindling process by two weeks, without any acute effect on audiogenic seizures.…”

Section: Discussionmentioning

confidence: 99%

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Andres-Mach

Zagaja

Haratym-Maj

et al. 2017

IJMS

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Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.

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“…Results from animal models for brain injuries suggest a seizure protective role of the endocannabinoid system. CB 1 agonists attenuate several types of seizures [18][19][20] and retard the development of amygdala kindling [21,22]. Additionally, the CB 1 agonist R(+)WIN55,212-2 (WIN) reduces status epilepticus and subsequent mortality in rats [23].…”

Section: Introductionmentioning

confidence: 99%

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

Perescis

Flipsen

Luijtelaar

et al. 2020

Epilepsy & Behavior

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A single injection of the cannabinoid agonist R(+)WIN55,212-2 (WIN) is known to cause an increase of the mean duration of spontaneously occurring spike-and-wave discharges (SWDs) in rats of the WAG/Rij strain, a genetic model for absence epilepsy. The aim of the present study was to establish whether repeated activation of CB 1 receptors with WIN leads to tolerance in its effect on SWD parameters, spectral density, and behavior over time. Adult male WAG/Rij rats (n = 16) were treated with WIN (6 mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2 weeks. Electroencephalogram (EEG) recordings, each lasting 24 h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2 weeks of treatment (subchronic treatment). The recordings were analyzed regarding incidence, durations of SWDs, and hazard rates of the durations of SWDs, the latter to describe SWD stopping probabilities. Putative changes in the spectral content of the EEG before and after WIN during active and passive behaviors were additionally investigated. Spike-and-wave discharge incidence was not affected by the acute and subchronic treatments. The mean duration of the SWDs was significantly longer than controls in the acute WIN-treated animals [11.9-s standard error of the mean (SEM): 0.64 compared with 8.4-s SEM: 0.25] as well as in subchronically treated animals (11.5-s SEM: 1.00 compared with 8.4-s SEM: 0.25). Hazard rates were significantly lower for WIN-treated animals at SWD durations in the 5.04-20.16-s range on both occasions. No effects of WIN on the frequency spectrum of the ongoing EEG were found, neither acutely nor after repeated administration. Evidence for tolerance was not found. The results on the mean duration and hazard rates suggest that stimulating the endocannabinoid system affects the SWD stopping mechanism, resulting in more long SWDs. We speculate that this effect is likely to be a direct result of CB 1 receptor agonism and a subsequent decrease in the availability of gamma-aminobutyric acid (GABA) in the reticular thalamic nucleus, which further weakens, in WAG/Rij rats already disturbed, the stopping mechanism of the SWDs.

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Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy

Abstract: This result suggests that short-term potentiation of the eCB system might modify the epileptogenic disease process in patients with a progressive course of epilepsy.

Cited by 23 publications

References 19 publications

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

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