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.

Cannabidiol and the central nervous system: translating into clinics

“…profile of CBD as anti-seizure medications are available (44,49,(199)(200)(201)(202)(203)(204)(205). The existing data suggest a beneficial response with CBD oil-based solution in patients across a broad range of epilepsy disorders and etiologies.…”

Increased TRPV1 Channels and FosB Protein Expression Are Associated with Chronic Epileptic Seizures and Anxiogenic-like Behaviors in a Preclinical Model of Temporal Lobe Epilepsy

“…Consequently, the diagnosis of epilepsies increases the chances of suicide and further diagnosis of anxiety, but the opposite is also true once patients with anxiety and depressive disorders have a higher risk of developing epilepsies in comparison to those who do not suffer from mood or anxiety disorders [ 3 , 5 , 6 , 12 , 13 ]. Additionally, it is worth noticing that brainstem and limbic structures, such as the periaqueductal gray matter (PAG), superior colliculus, basolateral amygdala nucleus (BLA), and hippocampus, are intrinsically involved with epileptic seizures manifestations [ 14 , 15 , 16 , 17 ], as well as with anxiogenic, emotional and defensive behaviors [ 18 , 19 , 20 , 21 ], indicating that neuroplastic and functional alterations in these neuronal networks can impact epilepsy and anxiety comorbidity.…”

Efeitos do tratamento com canabidiol (CBD) em modelos genéticos de epilepsias: estudos comportamentais, farmacológicos e eletrofisiológicos

“…Additionally, although the amygdala is mainly divided into different nuclei and subnuclei, the BLA complex presents the most prominent and homogenous CB1R expression, when compared to the other amygdaloid nuclei [71]. Furthermore, cannabinoids and endocannabinoid system's modulation are closely related with audiogenic seizure susceptibility and control in brainstem and limbic structures [72]. For these reasons, in the present study, CB1R expression was measured in the dorsal hippocampus and BLA.…”

“…SWDs mais longas e mais frequentesLazarini-Lopes et al, 2021a; Anexo E). Dessa maneira, a fim de analisar os efeitos do CBD em animais com crises de ausência severas e consistentes, WAG/Rijs de 10 meses de idade foram utiliados.…”

“…Na linhagem GAERS, o CBD apresentou efeito dose-dependente, com as doses de 30 de 145 100 mg/mecanismos, como o aumento da sinalização de cálcio e a inibição da FAAH, por meio destes mecanismo, CBD provoca um aumento da disponibilidade de anandamida e, consequentemente, um aumento da sinalização de CB1, o que está diretamente associado à efeitos anticrises em vários modelos experimentaisIANNOTTI et al, 2014;. Ademais, várias evidências indicam que CB1 tenha um papel crucial no controle das AGS por meio da modulação da excitabilidade mesencefálica e límbica/cortical(FUERTE-HORTIGÓN et al, 2021;LAZARINI-LOPES et al, 2021a), enquanto a modulação dos receptores CB1 da via tálamo-cortical é capaz de controlar as crises de ausência em ratos WAG/Rijs (.. Em WARs, foi demonstrado aumento de CB1 na camada molecular interna do giro denteado e o KA intensificou a imunomarcação de CB1 em áreas límbicas.De forma oposta, os efeitos antiepileptogênicos do CBD em mostrando que houve um aumento na duração média das SWDs após a administração aguda e sub-crônica de WIN55,212-2 (ROEBUCK et al, 2021). Efeitos similares foram observados após a administração de CBD, enquanto o THC induziu um aumento nas SWDs em GAERS (ROEBUCK et al, 2020).…”