Fatty acid amide hydrolase inhibitor URB597 may protect against kainic acid–induced damage to hippocampal neurons: Dependence on the degree of injury

Mikheeva, I. B.; Shubina, Liubov; Matveeva, Nataliya; Pavlik, Luybov L.; Kitchigina, Valentina F.

doi:10.1016/j.eplepsyres.2017.09.017

Cited by 16 publications

(11 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, the mitochondrial cascade hypothesis supports the existence of a reinforcing cycle of mitochondrial dysfunction (including the impairment of oxidative phosphorylation, reactive oxygen species production, and the alteration of mitochondrial dynamics) that, together with Aβ formation, leads to AD pathogenesis and cognitive decline [ 48 , 49 ]. Recently, in an in vivo model of kainic acid-induced epilepticus status in rats, URB597 treatment was shown to revert the ultrastructural alterations in the ER, mitochondria, and hippocampal neurons in a way dependent on both degree of injury and URB597 treatment [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Grieco

Caris

Maggi

et al. 2021

IJMS

View full text Add to dashboard Cite

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Grieco

Caris

Maggi

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Alternative approaches to modulate the hyperexcitability with seizure via activation of CB1 and its ligands, include the pharmacological blockade of enzymes involved in the degradation of endogenous neuroprotectants; anandamide (also known as arachidonoylethanolamide [AEA]), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA). Several inhibitors of the fatty acid amide hydrolase (FAAH) which degrades AEA, PEA and OEA were developed and assessed for their anticonvulsant properties (Vilela et al, 2013 , 2014 ; Mikheeva et al, 2017 ). Although effective anticonvulsant properties were evidenced for many FAAH inhibitors, their biphasic effect has to be carefully considered to prevent pro-convulsant effects (Di Marzo et al, 1994 ).…”

Section: Introductionmentioning

confidence: 99%

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy

Post

Loch

Lerner

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

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 intensit...

show abstract

“…In contrast to the aforementioned effects of 2-AG, increase in the level of AEA by treatment with the FAAH inhibitor URB597 did not affect kindling epileptogenesis ( Wendt et al, 2011 ). As for SE-induced epileptogenesis, elevation of the AEA level is reported to exert different effects depending on the degree of elevation ( Table 1 )—a mild increase prevented ( Mikheeva et al, 2017 ) whereas a strong increase promoted cell death ( Clement et al, 2003 ).…”

Section: Epileptogenesismentioning

confidence: 99%

Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

Sugaya

Kano

2022

Front. Neural Circuits

View full text Add to dashboard Cite

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.

show abstract

Fatty acid amide hydrolase inhibitor URB597 may protect against kainic acid–induced damage to hippocampal neurons: Dependence on the degree of injury

Cited by 16 publications

References 59 publications

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy

Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

Contact Info

Product

Resources

About