Effects of intrahippocampal injection of kainate on cytokine expression in cortico-limbic system and the role of cannabinoid system in these effects
- 作者: Karan A.A.1, Spivak Y.S.1, Suleymanova E.М.1, Gerasimov K.A.1, Bolshakov А.P.1, Vinogradova L.V.1
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隶属关系:
- Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
- 期: 卷 18, 编号 4 (2023)
- 页面: 483-486
- 栏目: Conference proceedings
- URL: https://journal-vniispk.ru/2313-1829/article/view/256250
- DOI: https://doi.org/10.17816/gc623458
- ID: 256250
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详细
According to the International League Against Epilepsy, epilepsy is a chronic condition of the brain that is characterized by a predisposition to epileptic seizures along with related neurobiological, cognitive, psychological, and social consequences. This is a general definition that does not take into account the diversity of epilepsies, including different aetiology, symptoms and mechanisms of epileptogenesis, making the development of a unified disease model challenging. The modeling framework addresses this challenge by selecting a distinct type of epilepsy and its associated manifestations, including electrophysiological, morphological (mainly neurodegeneration), and behavioral aspects [1]. In this study, a status epilepticus model is used with intrahippocampal kainic acid administration to reproduce electrophysiological activity and neurodegeneration. The process of reproducing two aspects simultaneously brings the kainate model closer to the disease called “epilepsy”.
Neuroinflammation is a neurobiological process that is associated with a chronic brain condition that is characterized by a persistent susceptibility to epileptic seizures. Specifically, neuroinflammation is the response of the central nervous system (CNS) to various stimuli, including stroke, trauma, infection, autoimmune diseases, stress, and hyperexcitability of the neural network resulting from epileptic seizures. This response involves brain cells, specifically activated microglia and astrocytes, as well as neurons and brain vasculature cells, biosynthesizing and releasing molecules with inflammatory properties [2].
Currently, the study of neuroinflammation in relation to various pathological conditions includes an examination of the influence of the endocannabinoid system (ECS) [3]. However, research on epilepsy primarily focused on the ECS’s effects on network neuronal activity through CB1-mediated changes in synapse function (both excitatory and inhibitory), with only a limited number of studies exploring the interactions between the ECS and neuroinflammation [4].
This study analyzed neuroinflammatory dynamics after kainate administration and the effect of exogenous endocannabinoid receptor modulators on these dynamics. Neuroinflammation was evaluated through the measurement of expression levels of pro- and anti-inflammatory cytokines (IL1b, Il6, Cx3cl1, Ccl2, Tgfb1, Zc3h12a, Tnfa) in various areas including the ipsilateral ventral hippocampus, contralateral dorsal and ventral hippocampuses, neocortex, dura mater, cerebral and hippocampal meninges (undivided arachnoid and pia maters). Expression was quantified using quantitative PCR at 3 and 24 hours following convulsant injection. The study showed that seizures induced by kainate resulted in swift neuroinflammation development in the hippocampus, which resolved nearly entirely after 24 hours. A unique pattern of neuroinflammation was detected in the neocortex, with minor alterations at 3 hours and more pronounced modifications in the expression of inflammatory genes at 24 hours. Using the intrahippocampal kainate administration model, this study was the first to show a significantly delayed neuroinflammatory response in the neocortex compared to the hippocampus across a broad range of genes.
Both activation of the cannabinoid CB1 and CB2 receptors and inhibition of the cannabinoid CB1 receptor increased neuroinflammation. However, cannabinoid receptor activation showed a predominantly proinflammatory effect in the neocortex, while CB1 receptor inhibition had a stronger effect in the hippocampus. Our findings indicate that cannabinoid receptor modulators regulate the kainate-induced neuroinflammatory response in the neocortex and hippocampus differently. Moreover, the well-known anti-inflammatory effect of cannabinoids is evident only within a certain range of cannabinoid concentrations and the timing of drug administration. In some cases, however, cannabinoids may have the opposite effect of increasing neuroinflammation.
全文:
According to the International League Against Epilepsy, epilepsy is a chronic condition of the brain that is characterized by a predisposition to epileptic seizures along with related neurobiological, cognitive, psychological, and social consequences. This is a general definition that does not take into account the diversity of epilepsies, including different aetiology, symptoms and mechanisms of epileptogenesis, making the development of a unified disease model challenging. The modeling framework addresses this challenge by selecting a distinct type of epilepsy and its associated manifestations, including electrophysiological, morphological (mainly neurodegeneration), and behavioral aspects [1]. In this study, a status epilepticus model is used with intrahippocampal kainic acid administration to reproduce electrophysiological activity and neurodegeneration. The process of reproducing two aspects simultaneously brings the kainate model closer to the disease called “epilepsy”.
Neuroinflammation is a neurobiological process that is associated with a chronic brain condition that is characterized by a persistent susceptibility to epileptic seizures. Specifically, neuroinflammation is the response of the central nervous system (CNS) to various stimuli, including stroke, trauma, infection, autoimmune diseases, stress, and hyperexcitability of the neural network resulting from epileptic seizures. This response involves brain cells, specifically activated microglia and astrocytes, as well as neurons and brain vasculature cells, biosynthesizing and releasing molecules with inflammatory properties [2].
Currently, the study of neuroinflammation in relation to various pathological conditions includes an examination of the influence of the endocannabinoid system (ECS) [3]. However, research on epilepsy primarily focused on the ECS’s effects on network neuronal activity through CB1-mediated changes in synapse function (both excitatory and inhibitory), with only a limited number of studies exploring the interactions between the ECS and neuroinflammation [4].
This study analyzed neuroinflammatory dynamics after kainate administration and the effect of exogenous endocannabinoid receptor modulators on these dynamics. Neuroinflammation was evaluated through the measurement of expression levels of pro- and anti-inflammatory cytokines (IL1b, Il6, Cx3cl1, Ccl2, Tgfb1, Zc3h12a, Tnfa) in various areas including the ipsilateral ventral hippocampus, contralateral dorsal and ventral hippocampuses, neocortex, dura mater, cerebral and hippocampal meninges (undivided arachnoid and pia maters). Expression was quantified using quantitative PCR at 3 and 24 hours following convulsant injection. The study showed that seizures induced by kainate resulted in swift neuroinflammation development in the hippocampus, which resolved nearly entirely after 24 hours. A unique pattern of neuroinflammation was detected in the neocortex, with minor alterations at 3 hours and more pronounced modifications in the expression of inflammatory genes at 24 hours. Using the intrahippocampal kainate administration model, this study was the first to show a significantly delayed neuroinflammatory response in the neocortex compared to the hippocampus across a broad range of genes.
Both activation of the cannabinoid CB1 and CB2 receptors and inhibition of the cannabinoid CB1 receptor increased neuroinflammation. However, cannabinoid receptor activation showed a predominantly proinflammatory effect in the neocortex, while CB1 receptor inhibition had a stronger effect in the hippocampus. Our findings indicate that cannabinoid receptor modulators regulate the kainate-induced neuroinflammatory response in the neocortex and hippocampus differently. Moreover, the well-known anti-inflammatory effect of cannabinoids is evident only within a certain range of cannabinoid concentrations and the timing of drug administration. In some cases, however, cannabinoids may have the opposite effect of increasing neuroinflammation.
ADDITIONAL INFORMATION
Funding sources. The study was supported by the Russian Science Foundation, grant No. 22-15-00327.
Authors' contribution. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, and final approval of the version to be published and agree to be accountable for all aspects of the work.
Competing interests. The authors declare that they have no competing interests.
作者简介
A. Karan
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
编辑信件的主要联系方式.
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
Yu. Spivak
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
E. Suleymanova
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
K. Gerasimov
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
А. Bolshakov
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
L. Vinogradova
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: akartar.n@gmail.ru
俄罗斯联邦, Moscow
参考
- Engel JJr. International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42(6):796–803. doi: 10.1046/j.1528-1157.2001.10401.x
- Vezzani A, Conti M, De Luigi A, et al. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. Journal of Neuroscience. 1999;19(12):5054–5065. doi: 10.1523/JNEUROSCI.19-12-05054.1999
- Walter L, Stella N. Cannabinoids and neuroinflammation. British Journal of Pharmacology. 2004;141(5): 775–785. doi: 10.1038/sj.bjp.0705667
- Cheung KAK, Peiris H, Wallace G, et al. The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids. International Journal of Molecular Sciences. 2019;20(23):6079. doi: 10.3390/ijms20236079
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