CB1 receptor antagonism prevents long-term hyperexcitability after head injury by regulation of dynorphin-KOR system and mGluR5 in rat hippocampus

Wang, Xiu; Wang, Yao; Zhang, Chao; Liu, Chang; Zhao, Baotian; Wei, Naili; Zhang, Jianguo; Zhang, Kai

doi:10.1016/j.brainres.2016.05.055

Cited by 18 publications

(15 citation statements)

References 48 publications

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“…A similar effect was observed in a model of traumatic brain injury induced by lateral fluid percussion in rats where a single rapid administration of SR141716A (1, 2 or 10 mg/kg, i.p.) attenuated long-term seizures susceptibility and suppressed the epileptogenic process [109,110]. It is notable that, in some cases, SR141716A treatment is only effective when administered prior to or during the insult used to trigger epileptogenesis; e.g.…”

Section: Resultsmentioning

confidence: 99%

“…However, a single dose of SR141716A (1 and 10 mg/kg, i.p) administered 7 days after the induction of febrile seizures in immature (P8) rats attenuated the maximal electrical shock-induced seizures stage [111]. SR141716A appears to limit hyperexcitability and epileptogenesis by inhibiting the long-term postsynaptic mGluR5 receptor overexpression and activating the dynorphin-KOR system [110]. Since seizures-induced neuronal depolarization stimulates sustained 2-AG synthesis at the postsynaptic membrane as a protective mechanism, this intense and sustained activation of endocannabinoid signaling could lead to subsequent downregulation of presynaptic CB 1 R expression in principal cells [112].…”

Section: Resultsmentioning

confidence: 99%

“…Since seizures-induced neuronal depolarization stimulates sustained 2-AG synthesis at the postsynaptic membrane as a protective mechanism, this intense and sustained activation of endocannabinoid signaling could lead to subsequent downregulation of presynaptic CB 1 R expression in principal cells [112]. Therefore, the positive effect of SR141716A in the inhibition of epileptogenesis might be attributed to the early prevention of the downregulation of the endocannabinoid system and potentiation of the dynorphin-KOR system to preserve the neuronal function [78, 110]. In contrast to the above studies, SR141716A (10 mg/kg, i.p.)…”

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

162

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%

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

162

139

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“…To reproduce the favorable effects reported by Chen et al (2007), Echegoyen et al (2009, and Wang et al (2016) in a model of complex febrile seizures in P11 rats induced by hyperthermia and in the lateral fluid-percussion injury model of TBI in adult rats, we administered SR141716 treatment as a single dose at 2 min post-injury. We demonstrated no favorable disease-modifying or antiepileptogenic effects.…”

Section: Atipamezole But Not Sr141716a Improved Post-tbi Behavioralmentioning

confidence: 99%

“…To investigate, whether the expected favourable effects on recovery would be specific to 2-adrenergic receptor blockage, we also assessed the effect of another neurostimulant, the cannabinoid receptor 1 (CB1) antagonist SR141716A (Rimonabant®), on post-TBI recovery and epileptogenesis. Selection of SR141716A as a comparator treatment was based on previous observations of Echegoyen et al (2009) and Wang et al (2016) who reported its antiepileptogenic effects after TBI.…”

Section: Introductionmentioning

confidence: 99%

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

et al. 2017

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Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.

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Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury

Dulla

Pitkänen

2021

Neurotherapeutics

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CB1 receptor antagonism prevents long-term hyperexcitability after head injury by regulation of dynorphin-KOR system and mGluR5 in rat hippocampus

Cited by 18 publications

References 48 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

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury

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