Disturbances of brain cholesterol metabolism: A new excitotoxic process associated with status epilepticus

Hanin, Aurélie; Baudin, Paul; Demeret, Sophie; Delphine, Roussel; Lecas, Sarah; Teyssou, Elisa; Damiano, Maria; Luis, David; Lambrecq, Virginie; Frazzini, Valério; Decavèle, Maxens; Plu, Isabelle; Bonnefont‐Rousselot, Dominique; Bittar, Randa; Lamari, Foudil; Navarro, Vincent

doi:10.1016/j.nbd.2021.105346

Cited by 14 publications

(11 citation statements)

References 49 publications

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“…Whole-blood samples were collected from an arterial catheter to measure radioactivity in whole blood and plasma. Samples were centrifuged, and 100 l of whole blood and plasma was measured in a gamma counter at 10,20,30,40,50,60,75,90,105,120,150,180,210,240, 600, 900, 1200, 1800, 2700, 3920, 4500, and 5400 s after 18 F-CHL-2205 injection. Plasma radiometabolite analysis was performed by collecting additional arterial blood samples (1.0 to 2.5 ml) at 2, 10, 30, 60, and 90 min after injection.…”

Section: Pet/ct and Mri Studies In Rhesus Monkeysmentioning

confidence: 99%

“…Some studies suggested that patients with mild cognitive impairments (MCIs) and early stages of AD present with augmented concentrations of 24-hydroxycholesterol in the plasma, whereas others found no differences between healthy individuals and individuals with AD ( 26 , 27 ). Beyond AD, 24-hydroxycholesterol has been suggested as a potential biomarker for HD ( 28 ), autism ( 29 ), epilepsy ( 30 ), depression ( 31 ), and Parkinson’s disease ( 32 ). A critical consideration is that 24-hydroxycholesterol is highly susceptible to metabolism in the liver ( 33 , 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Assessment of cholesterol homeostasis in the living human brain

et al. 2022

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Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18 F-CHL-2205 ( 18 F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.

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Section: Pet/ct and Mri Studies In Rhesus Monkeysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessment of cholesterol homeostasis in the living human brain

et al. 2022

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“…Following extraction in n -hexane, the dried residue of free sterols was derivatized, dissolved in methanol, and injected into the ultra performance liquid chromatography coupled with mass spectroscopy/MS system, consisting in a Triple Quadrupole Mass Spectrometer (TQD-Waters) equipped with an electrospray ionization probe and coupled to an ultra performance liquid chromatography Acquity system (Waters). 22 A calibration curve was obtained by a mixture of zymosterol, lanosterol (0.25 µg/mL each), and cholesterol (50 µg/mL). Sterol levels were normalized to protein concentration (bicinchoninic acid assay).…”

Section: Methodsmentioning

confidence: 99%

Teriflunomide Promotes Oligodendroglial 8,9-Unsaturated Sterol Accumulation and CNS Remyelination

Martin

Aigrot

Lamari

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesTo test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models.MethodsThe effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting–sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein–GFP-nitroreductase (Mbp:GFP-NTR) transgenic Xenopus laevis demyelinated by metronidazole and in adult mice demyelinated by lysolecithin.ResultsIn cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination.DiscussionTF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis.

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“…For instance, cholesterol-lowering drugs could prevent harmful cholesterol accumulation in neurons after the onset of SE. [22][23][24] Similarly, the ketogenic diet, which shifts the body's energy metabolism from glucose-based to fat-based energy generation, has proven effective in treating drug-resistant childhood epilepsy and reducing the duration of SE in patients with super-refractory SE. [25][26][27] The benefits of the ketogenic diet may also stem from altered tryptophan-kynurenine metabolism and increased production of the N-methyl-d-aspartate (NMDA) receptor antagonist, kynurenic acid.…”

Section: Introductionmentioning

confidence: 99%

“…Targeting these metabolic pathways may hold promise for neuroprotective treatments. For instance, cholesterol‐lowering drugs could prevent harmful cholesterol accumulation in neurons after the onset of SE 22–24 . Similarly, the ketogenic diet, which shifts the body's energy metabolism from glucose‐based to fat‐based energy generation, has proven effective in treating drug‐resistant childhood epilepsy and reducing the duration of SE in patients with super‐refractory SE 25–27 .…”

Section: Introductionmentioning

confidence: 99%

Metabolomic changes in adults with status epilepticus: A human case–control study

Hanin,

Chollet,

Demeret

et al. 2024

Epilepsia

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ObjectiveStatus epilepticus (SE) is a life‐threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long‐term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury.MethodsWe conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways.ResultsWe identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N‐acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N‐methyl‐d‐aspartate (NMDA) receptor agonist with pro‐inflammatory properties.SignificanceThis study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.

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Disturbances of brain cholesterol metabolism: A new excitotoxic process associated with status epilepticus

Cited by 14 publications

References 49 publications

Assessment of cholesterol homeostasis in the living human brain

Assessment of cholesterol homeostasis in the living human brain

Teriflunomide Promotes Oligodendroglial 8,9-Unsaturated Sterol Accumulation and CNS Remyelination

Metabolomic changes in adults with status epilepticus: A human case–control study

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