Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

Patel, Dipan; Wallis, Glenna; Fujinami, Robert S.; Wilcox, Karen S.; Smith, Michael L.

doi:10.1002/epi4.12351

Cited by 24 publications

(15 citation statements)

References 39 publications

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“…and subcutaneous pentylenetetrazole models, the kainic acid model, the 6-Hz test, the corneal kindling model, and a central nervous system infection (Theiler murine encephalomyelitis virus) model. [12][13][14][15] CBD has yet to be evaluated, however, in the amygdala-kindling model, a validated preclinical model of FIASs. 16 The present study therefore was designed to assess the antiseizure effects of CBD in the amygdala-kindling model, using a dose-response paradigm.…”

Section: Introductionmentioning

confidence: 99%

Antiseizure effects of the cannabinoids in the amygdala‐kindling model

et al. 2021

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Objective Focal impaired awareness seizures (FIASs) are the most common seizure type in adults and are often refractory to medication. Management of FIASs is clinically challenging, and new interventions are needed for better seizure control. The amygdala‐kindling model is a preclinical model of FIASs with secondary generalization. The present study assessed the efficacy of cannabidiol (CBD), ∆9‐tetrahydrocannabinol (THC), and a combination of CBD and THC in a 15:1 ratio at suppressing focal and secondarily generalized seizures in the amygdala‐kindled rat. Methods Fully kindled, male Sprague Dawley rats, with bipolar electrodes implanted in the right amygdala, were given either CBD (0–320 mg/kg), THC (0–40 mg/kg), or a combination of CBD and THC (15:1 ratio, multiple doses) intraperitoneally. Suprathreshold kindling stimulation was administered 1 h (THC) or 2 h (CBD) after drug injection, and outcomes were assessed using focal electroencephalographic recording and the Racine seizure scale. Results CBD alone produced a partial suppression of both generalized seizures (median effective dose [ED50] = 283 mg/kg) and focal seizures (ED40 = 320 mg/kg) at doses that did not produce ataxia. THC alone also produced partial suppression of generalized (ED50 = 10 mg/kg) and focal (ED50 = 30 mg/kg) seizures, but doses of 10 mg/kg and above produced hypolocomotion, although not ataxia. The addition of a low dose of THC to CBD (15:1) left‐shifted the CBD dose–response curve, producing much lower ED50s for both generalized (ED50 = 26 + 1.73 mg/kg) and focal (ED50 = 40 + 2.66 mg/kg) seizures. No ataxia or hypolocomotion was seen at these doses of the CBD + THC combination. Significance CBD and THC both have antiseizure properties in the amygdala‐kindling model, although THC produces suppression of the amygdala focus only at doses that produce hypolocomotion. The addition of small amounts of THC greatly improves the effectiveness of CBD. A combination of CBD and THC might be useful for the management of FIASs.

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Section: Introductionmentioning

confidence: 99%

Antiseizure effects of the cannabinoids in the amygdala‐kindling model

et al. 2021

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“…Six‐ to 8‐week‐old C57BL/6J mice were anesthetized with isoflurane and injected intracortically with 2 × 10 5 plaque‐forming units of the Daniels strain of TMEV or PBS as previously described 17 . Acute behavioral seizures were induced twice daily 2–7 days postinfection (dpi) by shaking the cage to agitate the mice.…”

Section: Methodsmentioning

confidence: 99%

Gut metabolite S‐equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus‐induced acute seizures

et al. 2021

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Objective A growing body of evidence indicates a potential role for the gut–brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)‐induced seizures, and to evaluate the effect of microbial metabolite S‐equol on neuronal physiology as well as TMEV‐induced neuronal hyperexcitability ex vivo. Methods We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0–7 days postinfection (dpi). Fecal samples were collected at 5–7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole‐cell patch‐clamp recordings in cortical neurons to investigate the effect of exogenous S‐equol on cell intrinsic properties and neuronal hyperexcitability. Results We demonstrated that gut microbiota diversity is significantly altered in TMEV‐infected mice at 5–7 dpi, exhibiting separation in beta diversity in TMEV‐infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV‐infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S‐equol‐producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S‐equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV‐infected mice, and exogenous application of microbial‐derived S‐equol ameliorated this TMEV‐induced hyperexcitability. Significance Our study presents the first evidence of microbial‐derived metabolite S‐equol as a potential mechanism for alteration of TMEV‐induced neuronal excitability. These findings provide new insight for the novel role of S‐equol and the gut–brain axis in epilepsy treatment.

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“…A CB1 and CB2 agonist, WIN55,212-2, significantly reduced the gp120-induced apoptosis in dopaminergic neurons by controlling its subsequent ROS production in microglia. Interestingly, the beneficial effects of cannabinoids on the nervous system are not only found in the case of HIV-1 infection, but also with Theiler's virus, which is specifically used as a model of demyelination [44,45]. As mentioned earlier, cannabinoids can affect the inflammatory response, which is detrimental in the case of influenza [36].…”

Section: Cannabinoids and Viral Infections: Potential Role Of Mitochomentioning

confidence: 98%

Cannabinoid-Induced Immunomodulation during Viral Infections: A Focus on Mitochondria

Beji

Loucif

Telittchenko

et al. 2020

Viruses

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This review examines the impact of cannabinoids on viral infections, as well as its effects on the mitochondria of the nervous and immune system. The paper conveys information about the beneficial and negative impacts of cannabinoids on viral infections, especially HIV-1. These include effects on the inflammatory response as well as neuroprotective effects. We also explore non-apoptotic mitochondrial pathways modulated by the activity of cannabinoids, resulting in modifications to cellular functions. As a large part of the literature derives from studies of the nervous system, we first compile the information related to mitochondrial functions in this system, particularly through the CB1 receptor. Finally, we reflect on how this knowledge could complement what has been demonstrated in the immune system, especially in the context of the CB2 receptor and Ca2+ uptake. The overall conclusion of the review is that cannabinoids have the potential to affect a broad range of cell types through mitochondrial modulation, be it through receptor-specific action or not, and that this pathway has a potential implication in cases of viral infection.

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Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

Cited by 24 publications

References 39 publications

Antiseizure effects of the cannabinoids in the amygdala‐kindling model

Antiseizure effects of the cannabinoids in the amygdala‐kindling model

Gut metabolite S‐equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus‐induced acute seizures

Cannabinoid-Induced Immunomodulation during Viral Infections: A Focus on Mitochondria

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