Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure

Abstract

Abnormal and sometimes severe behavioral and molecular symptoms are usually observed in epileptic humans and animals. To address this issue, we examined the behavioral and molecular aspects of seizure evoked by pilocarpine. Autophagy can promote both cell survival and death, but there are controversial reports about the neuroprotective or neurodegenerative effects of autophagy in seizure. Cannabidiol has anticonvulsant properties in some animal models when used as a pretreatment. In this study, we investigated alteration of seizure scores, autophagy pathway proteins, and antioxidant status in hippocampal cells during the chronic phase of pilocarpine-induced epilepsy after treatment with cannabidiol. Cannabidiol (100 ng, intracerebroventricular injection) delayed the chronic phase of epilepsy. Single administration of cannabidiol during the chronic phase of seizure significantly diminished seizure scores such as mouth clonus, head nodding, monolateral and bilateral forelimb clonus and increased the activity of catalase enzyme and reduced glutathione content. Such a protective effect in the behavioral scores of epileptic rats was also observed after repeated administrations of cannabidiol at the onset of the silent phase. Moreover, the amount of Atg7, conjugation of Atg5/12, Atg12, and LC3II/LC3I ratio increased significantly in epileptic rats treated with repeated injections of cannabidiol. In short, our results suggest that post-treatment of Cannabidiol could enhance the induction of autophagy pathway and antioxidant defense in the chronic phase of epilepsy, which could be considered as the protective mechanisms of cannabidiol in a temporal lobe epilepsy model.

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

“…In fact, some SSRIs and mood stabilizers such as lithium increase autophagy in the brain (Heiseke et al, 2009; Gassen et al, 2014; Jia and Le, 2015). Although there are few studies relating CBD to autophagy in neuropsychiatric disorders, CBD can modulate this process (Koay et al, 2014; Yang et al, 2014; Hosseinzadeh et al, 2016). Specifically in the brain, CBD produced anticonvulsant effects concomitant to an activation of hippocampal autophagy pathway in the chronic phase of pilocarpine-induced seizure (Hosseinzadeh et al, 2016).…”

“…Although there are few studies relating CBD to autophagy in neuropsychiatric disorders, CBD can modulate this process (Koay et al, 2014; Yang et al, 2014; Hosseinzadeh et al, 2016). Specifically in the brain, CBD produced anticonvulsant effects concomitant to an activation of hippocampal autophagy pathway in the chronic phase of pilocarpine-induced seizure (Hosseinzadeh et al, 2016). In a genetic model of tauopathy, used to evaluate frontotemporal dementia, parkinsonism, and motor neuron disease, 1-month daily injections of Sativex®, a 1:1 mixture combination of CBD and THC, increased the ratio of reduced/oxidized glutathione and promoted autophagy in the brain (Casarejos et al, 2013).…”

Cannabidiol Attenuates Palmitic Acid-Induced Injury in Cultured Hepatocytes Through Promoting Autophagic Flux

“…In the tau disease mouse model, CBD treatment can increase the occurrence of autophagy flow, reduce the deposition of tau protein in the body, thereby alleviating the symptoms of [12]. In the chronic phase of seizure induced by pilocarpine, CBD can promote the occurrence of autophagic flow, thereby reducing the [13] of epilepsy. In alcohol induced fatty liver of mice, CBD also promotes the occurrence of autophagic flow in the liver, thereby alleviating liver injury [14].…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…Several studies support that CBD could be effective in the control of epilepsy . Results obtained from experimental models reveal that CBD reduces the seizure activity and delays the epileptogenesis process, effects associated with neuroprotection . CBD in oral solution (Epidiolex ® ) is considered a therapy to control seizures associated with the Lennox‐Gastaut syndrome, Dravet syndrome, and infantile spasms .…”