Metabotropic glutamate receptors as a target for anticonvulsant and anxiolytic action in immature rats

Mareš, Pavel; Mikulecká, Anna; Tichá, Kateřina; Lojková-Janečková, Denisa; Kubová, Hana

doi:10.1111/j.1528-1167.2010.02604.x

Cited by 11 publications

(7 citation statements)

References 20 publications

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“…Retrograde activation of CB1Rs by cannabinoids and endocannabinoids hyperpolarizes presynaptic neurons and thus inhibits synaptic transmission [44], and several cannabinoids have even been shown to exhibit anticonvulsive activity [45], [46], [47], [48]. Therefore, seizures caused by K2 are possibly due to the antagonism of other inhibitory networks, such as GABA channels [49], and/or the activation of excitatory networks, such as metabotropic glutamate receptors (mGluRs) [50], Na + channels [51], and Ca 2+ channels [43]. Hallucinations, as well as psychosis in susceptible individuals with a previous personal and/or family psychiatric history [12], [13], have also been associated with K2 use.…”

Section: Discussionmentioning

confidence: 99%

“…The cardiovascular symptoms, as well as drug-induced anxiety, agitation and panic attacks, associated with K2 use could be caused by activation of α 1 , β 1 and β 2 adrenoceptors [55], [56]. Activation of mGluRs [50], as well as GABA channel blockade [57], may also be responsible for anxiety due to K2. Alteration of the receptor networks mentioned here are just a few examples of many possible that may result in severe adverse effects seen in an alarmingly large proportion of K2 users.…”

Section: Discussionmentioning

confidence: 99%

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Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

et al. 2011

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BackgroundK2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).Methods/Principal FindingsJWH-018, five potential monohydroxylated metabolites (M1–M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [3H]CP-55,940, and then for CB1R intrinsic efficacy using an [35S]GTPγS binding assay. JWH-018 and M1–M5 bound CB1Rs with high affinity, exhibiting Ki values that were lower than or equivalent to Δ9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Conclusions/SignificanceUnlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ9-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

et al. 2011

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“…Negative allosteric modulators (NAMs) of mGluR5 have been shown to alleviate long-term memory deficits, excessive repetitive behaviors, motor stereotypies, and social interaction abnormalities in various mouse models of autism (Seese et al, 2014;Silverman et al, 2012;Tian et al, 2015). In addition, mGluR5 NAMs have anticonvulsant and robust anxiolytic properties (Mares et al, 2010;Spooren and Gasparini, 2004). In experiments using slice preparations from Tsc2 +/ − mice, the prototypical mGluR5 NAM, MPEP, reduced ictal bursting and ameliorated aberrant plasticity (Potter et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

Kelly

Schaeffer

Dhamne

et al. 2017

Neuropsychopharmacol.

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Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy. This model uniquely enables the in vivo characterization and rescue of the electrographic seizures associated with TSC. We demonstrate that inhibition of mGluR5 corrects hyperactivity, seizures, and elevated de novo synaptic protein synthesis. Conversely, positive allosteric modulation of mGluR5 results in the exacerbation of hyperactivity and epileptic phenotypes. The data suggest a meaningful therapeutic potential for mGluR5 NAMs in TSC, which warrants clinical exploration and the continued development of mGluR5 therapies.

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“…There has been a trend towards moving AED pharmacological research in several new directions, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-inhibition [14,15], protein kinase inhibition [16,17], metabotropic glutamate receptor subtype signaling function modulation [18,19], carbonic anhydrase inhibition [20,21], gamma amino butyric acid receptor modulation [22,23], the mammalian target of rapamycin inhibition [24,25], inflammation inhibition through targeting interlukin-1b [26,27,28], transforming growth factor beta (TGF-β) [29], drug transporter system improvement, including P-glycoprotein [30], the activation of hyperpolarization cyclic nucleotide gated channels [31], the opening of voltage-gated Kv7 channels [32], exploration of the role of nuclear-related factor 2 modulators [33], Na-K-2Cl, K-Cl co-transport modulators [34], purinergic-receptor modulation, and the role of aberrant neurogenesis in epilepsy and cannabidiol mechanism exploration in epilepsy [35,36,37,38]. These investigations are contributing to a comprehensive overview of epileptogenesis and targeted treatment mechanisms [39].…”

Section: Introductionmentioning

confidence: 99%

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management

Krasniqi

Daci

2019

IJMS

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Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood–brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, the renin–angiotensin system (RAS) affects the brain’s physiological and pathological conditions, including epilepsy and its consequences. While there are a variety of available pharmacotherapeutic approaches, information on new pathways is in high demand and the achievement of treatment goals is greatly desired. Therefore, targeting the RAS presents an interesting opportunity to better understand this process. This has been supported by preclinical studies, primarily based on RAS enzyme, receptor-inhibition, and selective agonists, which are characterized by pleiotropic properties. Although there are some antiepileptic drugs (AEDs) that interfere with RAS, the main targeted therapy of this pathway contributes in synergy with AEDs. However, the RAS-targeted treatment alone, or in combination with AEDs, requires clinical studies to contribute to, and clarify, the evidence on epilepsy management. There is also a genetic association between RAS and epilepsy, and an involvement of pharmacogenetics in RAS, so there are possibilities for the development of new diagnostic and personalized treatments for epilepsy.

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Metabotropic glutamate receptors as a target for anticonvulsant and anxiolytic action in immature rats

Cited by 11 publications

References 20 publications

Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management

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