Cannabinoids: A New Perspective on Epileptogenesis and Seizure Treatment in Early Life in Basic and Clinical Studies.

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. 2021 Jan 12;14:610484.

doi: 10.3389/fnbeh.2020.610484. eCollection 2020.

Affiliations

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Angélica Vega-García et al. Front Behav Neurosci. .

Abstract

Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.

Keywords: anti-inflammatory; cannabinoids; epileptogenesis; neurodevelopment; neuroprotection; pharmacokinetics.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1

Figure 1

Pharmacological effects of Δ9-THC and CBD. Δ9-THC is the main psychoactive component of C. sativa, which can behave as a selective agonist, partial agonist, inverse agonist, and antagonist of the Cb1 receptor, while when activating the Cb2 receptor it behaves as an inverse agonist. Activation of the Cb1 and Cb2 receptors stimulates GTPγS binding to cell membranes and inhibits cyclic AMP production. Also, Δ9-THC can inhibit 5HT3A receptor-mediated currents induced by 5-hydroxytryptamine (5HT); antagonizing receptor activation, possibly through an allosteric mechanism, by this same mechanism, Δ9-THC and CBD can enhance the activation of GlyR expressed in central tegmental area (ATV) neurons. Additionally, Δ9-THC activates the TRPV3 and TRPV4 receptors, which are nonselective calcium-permeable cation channels that, when activated, raise intracellular Ca2+ and consequently cause neuronal depolarization. Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a large number of stimuli. Unlike Δ9-THC, CBD does not activate CB1 and CB2 receptors, which likely accounts for its lack of psychotropic activity. However, CBD interacts with many other, nonendocannabinoid signaling systems. It is a “multi-target” drug. At low micromolar to submicromolar concentrations, CBD is a blocker of the equilibrative nucleoside transporter (ENT), the orphan G-protein-coupled receptor GPR55, and the TRP of melastatin type 8 (TRPM8) channel. At higher micromolar concentrations, CBD activates the TRP of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels while also inhibiting cellular uptake and fatty acid amide hydrolase—catalyzed degradation of anandamide.

Figure 2

Figure 2

Epileptogenesis and endocannabinoid system (eCBs). (A) Acute changes: increased intracellular Ca2+ flux, induction of early genes (IEGs) that alter synaptic function, decreased threshold to neuronal hyperexcitability, alteration of eCBs that modulates the balance between excitatory and inhibitory neurotransmission. (B) Sub-acute changes: synthesis of endocannabinoids (eCB) mediated by the increase in intracellular Ca2+, neuronal hyperexcitability and the demand for membrane phospholipids diacylglycerol lipase (DAGL) and N-acyl phosphatidyl ethanolamine-hydrolyzing phospholipase D (NAPE-PLD) to form 2-AG and AEA, respectively, and their degradation after the dissociation of CB1R and the activation of TRPTV1 by AEA, which triggers greater glutamate release and increases in intracellular Ca2+. The eCBs degrade rapidly, and 2-AG and AEA are catabolized by the enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively, which generate AA, PGs-Eas, PG-Gs, and Cox-2 to increase convulsive susceptibility, activation of astrocytes and microglia and increases in CB2R that promote the release of pro-inflammatory proteins IL1-β, Cox-2, TNF-α and iNOS, generating neuroinflammation, neuronal hyperexcitability, and neuronal death. (C,D) Chronic changes: neuronal death, the perpetuation of the neuroinflammatory response and dysregulation of eCBs that promote neurogenesis, formation of aberrant connections, expression of spontaneous seizures, and epilepsy.

Figure 3

Figure 3

Graph showing the mean ± SE of the latencies of Status epilepticus (SE) induced by KA. (A) Low doses: the 20 and 25 mg/kg CBD groups showed an increase of SE latencies with a significant difference ****p < 0.0001 compared with the KA group. However, the 30 and 35 mg/kg groups of CBD showed a reduction in SE latencies though with a significant difference, **p < 0.01 and ***p < 0.001, respectively, compared with the KA group. (B) The high-dose 40 and 60 mg/kg groups of CBD showed an increase in the latencies of SE with a significant difference, **p < 0.01 compared with the KA group. The 80 and 100 mg/kg CBD groups did not show significant differences compared with the KA group. One-way ANOVA followed by Bonferroni’s post hoc test, p < 0.05 (unpublished data).

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