Cannabinoids in Audiogenic Seizures: From Neuronal Networks to Future Perspectives for Epilepsy Treatment

Abstract

Cannabinoids and Cannabis-derived compounds have been receiving especial attention in the epilepsy research scenario. Pharmacological modulation of endocannabinoid system's components, like cannabinoid type 1 receptors (CB1R) and their bindings, are associated with seizures in preclinical models. CB1R expression and functionality were altered in humans and preclinical models of seizures. Additionally, Cannabis-derived compounds, like cannabidiol (CBD), present anticonvulsant activity in humans and in a great variety of animal models. Audiogenic seizures (AS) are induced in genetically susceptible animals by high-intensity sound stimulation. Audiogenic strains, like the Genetically Epilepsy Prone Rats, Wistar Audiogenic Rats, and Krushinsky-Molodkina, are useful tools to study epilepsy. In audiogenic susceptible animals, acute acoustic stimulation induces brainstem-dependent wild running and tonic-clonic seizures. However, during the chronic protocol of AS, the audiogenic kindling (AuK), limbic and cortical structures are recruited, and the initially brainstem-dependent seizures give rise to limbic seizures. The present study reviewed the effects of pharmacological modulation of the endocannabinoid system in audiogenic seizure susceptibility and expression. The effects of Cannabis-derived compounds in audiogenic seizures were also reviewed, with especial attention to CBD. CB1R activation, as well Cannabis-derived compounds, induced anticonvulsant effects against audiogenic seizures, but the effects of cannabinoids modulation and Cannabis-derived compounds still need to be verified in chronic audiogenic seizures. The effects of cannabinoids and Cannabis-derived compounds should be further investigated not only in audiogenic seizures, but also in epilepsy related comorbidities present in audiogenic strains, like anxiety, and depression.

Keywords: CB1 receptors; Cannabis-derived compounds; audiogenic seizures; cannabidiol; endocannabinoid system; epilepsy; genetically-developed strains; neuronal networks.

Figure 1

Representative CB1R immunostaining in limbic and cortical brain structures of Wistar Audiogenic Rats (WAR). It is possible to observe the increased CB1R immunostaining in limbic (hippocampus and amygdala) and cortical areas of WARs after acute audiogenic seizures (WAR AS) and chronic audiogenic seizures (WAR AuK). Wistar represents a control non-audiogenic strain. Image obtained from Lazarini-Lopes et al. (2020a).

Figure 2

Cannabinoid receptors type 1 (CB1R) in neuronal networks associated with acute and chronic audiogenic seizures. The inferior colliculus is the main brainstem structure related to sound perception and plays a key role in the genesis of audiogenic seizures. Inferior colliculus projects to different brainstem areas, like superior colliculus, periaqueductal gray matter, and brainstem reticular formation. This brainstem neuronal network is crucial to acute audiogenic seizures manifestation, that are behaviorally characterized by wild running followed by tonic-clonic seizures. The substantia nigra pars reticulata sends GABAergic projections to the mesencephalic tectum. This inhibitory projection is involved with the so-called endogenous anticonvulsant system. During the audiogenic kindling protocol, the chronic seizures, and the epileptogenic events lead to forebrain/limbic recruitment. The limbic recruitment during the chronic seizures involves projections from inferior colliculus to medial geniculate nucleus and then to the dorsal hippocampus and basolateral amygdala nucleus. This brainstem-limbic network is crucial to limbic motor seizures expression during the audiogenic kindling. Spinal cord neurons receive inputs from central neuronal networks and lead to audiogenic seizures' motor manifestation. The intensity of green color represents the amount of CB1R in each structure. Therefore, the endocannabinoid system is directly associated with brainstem and limbic neuronal networks responsible for tonic-clonic and limbic audiogenic seizures manifestation. IC, inferior colliculus; SC, superior colliculus; PAG, periaqueductal gray matter; BRF, brainstem reticular formation; SNr, substantia nigra pars reticulata; MGN, medial geniculate body; DH, dorsal hippocampus; AMG, amygdaloid complex (basolateral amygdala nucleus, BLA). Red arrows represent inhibitory projections, blue arrows represent excitatory projections.