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.

Full text

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
Mahshid Hosseinzadeh
1
&Sara Nikseresht
1
&Fariba Khodagholi
1,2
&Nima Naderi
1,3
&
Nader Maghsoudi
1,2
Received: 11 November 2015 /Accepted: 15 December 2015 /Published online: 6 January 2016
#Springer Science+Business Media New York 2016
Abstract Abnormal and sometimes severe behavioral and
molecular symptoms are usually observed in epileptic humans
and animals. To address this issue, we examined the behav-
ioral 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 neuro-
degenerative 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) de-
layed the chronic phase of epilepsy. Single administration of
cannabidiol during the chronic phase of seizure significantly
diminished seizure scores such as mouth clonus, head nod-
ding, monolateral and bilateral forelimb clonus and increased
the activity of catalase enzyme and reduced glutathione con-
tent. Such a protective effect in the behavioral scores of epi-
leptic 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. Inshort, our results suggest
that post-treatment of Cannabidiol could enhance the induc-
tion 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 ep-
ilepsy model.
Keywords Pilocarpine-induced seizure .Cannabidiol .
Autophagy .Antioxidant status
Introduction
One of the most common forms of partial epilepsy in humans is
temporal lobe epilepsy (TLE) (Engel, 2001). Characterization
of this model shows three phases: (a) a period of 24 h is known
as the acute phase that extended to limbic area and causes status
epilepticus (SE), (b) the second phase is a silent period where
electroencephalogram and behavior are both normal and vary
from 4 to 44 days, and (c) a third period known as chronic
phase is characterized by spontaneous recurrent seizures
(SRSs) (Cavalheiro, 1995,Aridaetal.1999). Localization of
seizure foci in the limbic system, particularly in the hippocam-
pus, is the main feature of TLE (Bartolomei et al. 2005).
Autophagy, one of the most important pathways that main-
tain cell homeostasis, can regulate important biological func-
tions such as cell survival, cell death, cell metabolism, devel-
opment, neuroprotection, and sometimes neurodegeneration
(Hochfeld et al. 2013). In this process, cytoplasmic compo-
nents are delivered to lysosomes to form autophagosomes. In
this process, a group of autophagy-related proteins (Atgs)
have vital roles (Levine and Klionsky, 2004,Meijer,2003).
Among these proteins, Atg5 initiates the process (Maiuri et al.
2007). The participation of two ubiquitin-like conjugation
*Nader Maghsoudi
nmaghsoudi@sbmu.ac.ir
1
Neuroscience Research Center, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
2
NeuroBiology Research Center, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
3
Department of Pharmacology and Toxicology, School of Pharmacy,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
J Mol Neurosci (2016) 58:432–440
DOI 10.1007/s12031-015-0703-6
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