Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy
Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibit...
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00067/full |
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| author | Julia M. Post Sebastian Loch Raissa Lerner Floortje Remmers Ermelinda Lomazzo Beat Lutz Laura Bindila |
| author_facet | Julia M. Post Sebastian Loch Raissa Lerner Floortje Remmers Ermelinda Lomazzo Beat Lutz Laura Bindila |
| author_sort | Julia M. Post |
| collection | DOAJ |
| description | Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use. Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy. Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties. Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant. In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA). KA-induced epilepsy in rodents is assumed to resemble to different extents human temporal lobe epilepsy (TLE) depending on the route of KA administration; intracerebral (i.c.) injection was recently shown to most closely mimic human TLE, while systemic KA administration causes more widespread pathological damage, both in brain and periphery. To explore the potential of PEA to exert therapeutic effects both in brain and periphery, acute and subchronic administration of PEA by intraperitoneal (i.p.) injection was assessed on mice with systemically administered KA. Specifically, we investigated: (i) neuroprotective and anticonvulsant properties of acute and subchronic PEA treatment in KA-induced seizure models, and (ii) temporal dynamics of eCB and eicosanoid (eiC) levels in hippocampus and plasma over 180 min post seizure induction in PEA-treated and non-treated KA-injected mice vs. vehicle injected mice. Finally, we compared the systemic PEA treatment with, and in combination with, pharmacological blockade of fatty acid amide hydrolase (FAAH) in brain and periphery, in terms of anticonvulsant properties and modulation of eCBs and eiCs. Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice. |
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| language | English |
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| spelling | doaj.art-b500016e820e4ca8a6ea782d657bd6162022-12-21T20:31:59ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-03-011110.3389/fnmol.2018.00067316288Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute EpilepsyJulia M. Post0Sebastian Loch1Raissa Lerner2Floortje Remmers3Ermelinda Lomazzo4Beat Lutz5Laura Bindila6nstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germanynstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, GermanyResearch on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use. Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy. Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties. Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant. In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA). KA-induced epilepsy in rodents is assumed to resemble to different extents human temporal lobe epilepsy (TLE) depending on the route of KA administration; intracerebral (i.c.) injection was recently shown to most closely mimic human TLE, while systemic KA administration causes more widespread pathological damage, both in brain and periphery. To explore the potential of PEA to exert therapeutic effects both in brain and periphery, acute and subchronic administration of PEA by intraperitoneal (i.p.) injection was assessed on mice with systemically administered KA. Specifically, we investigated: (i) neuroprotective and anticonvulsant properties of acute and subchronic PEA treatment in KA-induced seizure models, and (ii) temporal dynamics of eCB and eicosanoid (eiC) levels in hippocampus and plasma over 180 min post seizure induction in PEA-treated and non-treated KA-injected mice vs. vehicle injected mice. Finally, we compared the systemic PEA treatment with, and in combination with, pharmacological blockade of fatty acid amide hydrolase (FAAH) in brain and periphery, in terms of anticonvulsant properties and modulation of eCBs and eiCs. Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice.http://journal.frontiersin.org/article/10.3389/fnmol.2018.00067/fullpalmitoylethanolamideLC-MRMendocannabinoidseicosanoidslipidomicsepilepsy |
| spellingShingle | Julia M. Post Sebastian Loch Raissa Lerner Floortje Remmers Ermelinda Lomazzo Beat Lutz Laura Bindila Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy Frontiers in Molecular Neuroscience palmitoylethanolamide LC-MRM endocannabinoids eicosanoids lipidomics epilepsy |
| title | Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy |
| title_full | Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy |
| title_fullStr | Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy |
| title_full_unstemmed | Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy |
| title_short | Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy |
| title_sort | antiepileptogenic effect of subchronic palmitoylethanolamide treatment in a mouse model of acute epilepsy |
| topic | palmitoylethanolamide LC-MRM endocannabinoids eicosanoids lipidomics epilepsy |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00067/full |
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