Mice lacking L‐12/15‐lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis

Kanzler, Matthew A.; Dyke, Adam M. Van; He, Yan; Hewett, James A.; Hewett, Sandra J.

doi:10.1002/epi4.12221

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…The lack of response to DHA supplementation may be due to the different metabolism of EPA and DHA in the brain and the preferential incorporation of DHA into cell membrane phospholipids, with DHA accounting for up to 40% of all fatty acids in some regions of the brain [33], and EPA mostly subjected to beta-oxidation [34]. However, both EPA and DHA may undergo conversion to SPM in the brain as 15-LOX is expressed by neurons and microglia [35]. In a mouse model of depression, intracranial administration of RvE1-3 or RvD1-2 was associated with reduced symptoms [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Lamon‐Fava

Dunlop

Kinkead

et al. 2023

Neuropsychopharmacol.

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Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 μg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p < 0.05). Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations (p < 0.05) and IDS-C30 scores (p < 0.01). In summary, response rates were greater among patients with MDD randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with ω-3 fatty acid supplementation.

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Section: Discussionmentioning

confidence: 99%

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Lamon‐Fava

Dunlop

Kinkead

et al. 2023

Neuropsychopharmacol.

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“…Numerous studies have demonstrated its involvement in the pathogenesis of human diseases (Singh and Rao, 2019). In addition, mice lacking leukocyte-type 12/15-LOX were resistant to PTZ-induced epilepsy, which implied that 12/15-LOX might be involved in the process of epileptic seizures (Kanzler et al, 2018). In our study, the expression of 12/15-LOX was increased in the FAC- and erastin-treated HT22 cells and FeCl 3 -induced mice PTE model.…”

Section: Discussionmentioning

confidence: 99%

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis

Jia

et al. 2019

Front. Pharmacol.

119

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Posttraumatic epilepsy (PTE) is a prevalent type of acquired epilepsy secondary to traumatic brain injury, and is characterized by repeated seizures. Traditional antiepileptic drugs have minimal response in preventing posttraumatic epileptic seizures. It is essential for the development of new therapeutic strategy. Our previous work disclosed a potent neuroprotective role of baicalein, a flavonoid extracted from Scutellaria baicalensis Georgi, against inherited epilepsy in rats. Whether baicalein has protective potential in posttraumatic epileptic seizures and the possible molecular mechanism remain elusive. Additionally, the brain is vulnerable to lipid peroxidation-induced damage due to high consumption of oxygen and abundant polyunsaturated fatty acids in neuronal membranes. Our present investigation aimed to elucidate whether baicalein exerts neuroprotective effects on posttraumatic epileptic seizures by inhibiting ferroptosis, a newly discovered lipid peroxidation-dependent cell death modality. We found that baicalein significantly reduced seizure score, number of seizures, and average seizure duration in an iron chloride (FeCl 3 )-induced PTE mouse model. The neuroprotective effect of baicalein was also validated in a ferric ammonium citrate (FAC)-induced HT22 hippocampal neuron damage model. Moreover, in vitro , baicalein could remarkably decrease ferroptotic indices (lipid reactive oxygen species, 4-hydroxynonenal, and prostaglandin endoperoxide synthase 2) and inhibit the expression of 12/15-lipoxygenase (12/15-LOX) in an iron-induced HT22 cell damage model. These findings were also validated in a mouse PTE model. It was concluded that baicalein exerted neuroprotective effects against posttraumatic epileptic seizures via suppressing ferroptosis and 12/15-LOX was likely to be involved in baicalein’s neuroprotection.

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“…Samples were stored at −20 • C overnight. Total RNA was isolated and first-strand complementary DNA (cDNA) synthesized as described (Kanzler et al, 2018). cDNA samples were amplified for 40 cycles (95 • C for 15sec, 60 • C for 60sec, 95 • C for 15 sec, 60 • C for 15 sec and 95 • C for 50 sec) using Taq DNA polymerase (Invitrogen) and target specific mouse primers for c-fos (Mm00487425_m1, TaqMan Gene Expression Assays, Applied Biosystems, Foster City, CA) and hypoxanthine guanine phosphoribosyl transferase (HPRT, Mm01545399_m1, TaqMan Gene Expression Assays, Applied Biosystems).…”

Section: Behavioral Testsmentioning

confidence: 99%

Sex- and age-dependent contribution of System xc– to cognitive, sensory, and social behaviors revealed by comprehensive behavioral analyses of System xc– null mice

Frare

Pitt

Hewett

2023

Front. Behav. Neurosci.

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BackgroundSystem xc– (Sxc–) is an important heteromeric amino acid cystine/glutamate exchanger that plays a pivotal role in the CNS by importing cystine into cells while exporting glutamate. Although certain behaviors have been identified as altered in Sxc– null mutant mice, our understanding of the comprehensive impact of Sxc– on behavior remains incomplete.MethodsTo address this gap, we compared motor, sensory and social behaviors of male and female mice in mice null for Sxc– (SLC7A11sut/sut) with wildtype littermates (SLC7A11+/+) in a comprehensive and systematic manner to determine effects of genotype, sex, age, and their potential interactions.ResultsMotor performance was not affected by loss of Sxc– in both males and females, although it was impacted negatively by age. Motor learning was specifically disrupted in female mice lacking Sxc– at both 2 and 6 months of age. Further, female SLC7A11sut/sut mice at both ages exhibited impaired sociability, but normal spatial and recognition memory, as well as sensorimotor gating. Finally, pronounced open-space anxiety was displayed by female SLC7A11sut/sut when they were young. In contrast, young SLC7A11sut/sut male mice demonstrated normal sociability, delayed spatial learning, increased open-space anxiety and heightened sensitivity to noise. As they aged, anxiety and noise sensitivity abated but hyperactivity emerged.DiscussionWe find that the behavioral phenotypes of female SLC7A11sut/sut are similar to those observed in mouse models of autism spectrum disorder, while behaviors of male SLC7A11sut/sut resemble those seen in mouse models of attention deficit hyperactivity disorder. These results underscore the need for further investigation of SLC7A11 in neurodevelopment. By expanding our understanding of the potential involvement of Sxc–, we may gain additional insights into the mechanisms underlying complex neurodevelopmental conditions.

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Mice lacking L‐12/15‐lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis

Cited by 7 publications

References 49 publications

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis

Sex- and age-dependent contribution of System xc– to cognitive, sensory, and social behaviors revealed by comprehensive behavioral analyses of System xc– null mice

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