Repurposing of cholesterol-lowering agents in status epilepticus: A neuroprotective effect of simvastatin

Hanin, Aurélie; Delphine, Roussel; Lecas, Sarah; Baudin, Paul; Navarro, Vincent

doi:10.1016/j.yebeh.2023.109133

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…Although the effects of statins are mainly at the systemic level, these drugs, in particular the lipophilic simvastatin which appears the most effective at crossing the BBB, are proposed as neuroprotective in the early stages of AD thanks to their hypocholesterolemic activity, and antioxidant and anti-inflammatory properties [49][50][51]. Statins can indeed inhibit neuroinflammation and associated neurodegenerative complications through inhibition of microglia and astrocyte activation, and of the release of pro-inflammatory cytokines [52,53]. Moreover, it has been shown that statin pharmacotherapy could be mainly beneficial for AD patients with dyslipidemia [54], for instance in patients with homozygous ApoE4 genotype [55].…”

Section: Discussionmentioning

confidence: 99%

Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease

Staurenghi,

Testa,

Leoni

et al. 2024

Antioxidants

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Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer’s disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.

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Section: Discussionmentioning

confidence: 99%

Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease

Staurenghi,

Testa,

Leoni

et al. 2024

Antioxidants

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“… 15 In animal models of status epilepticus, hippocampal astrogliosis has been observed, leading to increased expression of astroglia activation markers such as GFAP and S100B, after several days of seizures. 41 , 42 Reactive microglia can influence astrocyte function by secreting cytokines and chemokines, 43 potentially driving astrocytes from a neuroprotective “A2” to a neurotoxic “A1” phenotype. 28 , 44 By overexpressing genes such as HOMER1 , microglia can also play a pivotal protective role in inhibiting astrocyte-related inflammation.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE)

Hanin,

Zhang,

Huttner

et al. 2024

Neurol Neuroimmunol Neuroinflamm

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Background and Objectives New-onset refractory status epilepticus (NORSE) occurs in previously healthy children or adults, often followed by refractory epilepsy and poor outcomes. The mechanisms that transform a normal brain into an epileptic one capable of seizing for prolonged periods despite treatment remain unclear. Nonetheless, several pieces of evidence suggest that immune dysregulation could contribute to hyperexcitability and modulate NORSE sequelae. Methods We used single-nucleus RNA sequencing to delineate the composition and phenotypic states of the CNS of 4 patients with NORSE, to better understand the relationship between hyperexcitability and immune disturbances. We compared them with 4 patients with chronic temporal lobe epilepsy (TLE) and 2 controls with no known neurologic disorder. Results Patients with NORSE and TLE exhibited a significantly higher proportion of excitatory neurons compared with controls, with no discernible difference in inhibitory GABAergic neurons. When examining the ratio between excitatory neurons and GABAergic neurons for each patient individually, we observed a higher ratio in patients with acute NORSE or TLE compared with controls. Furthermore, a negative correlation was found between the ratio of excitatory to GABAergic neurons and the proportion of GABAergic neurons. The ratio between excitatory neurons and GABAergic neurons correlated with the proportion of resident or infiltrating macrophages, suggesting the influence of microglial reactivity on neuronal excitability. Both patients with NORSE and TLE exhibited increased expression of genes associated with microglia activation, phagocytic activity, and NLRP3 inflammasome activation. However, patients with NORSE had decreased expression of genes related to the downregulation of the inflammatory response, potentially explaining the severity of their presentation. Microglial activation in patients with NORSE also correlated with astrocyte reactivity, possibly leading to higher degrees of demyelination. Discussion Our study sheds light on the complex cellular dynamics in NORSE, revealing the potential roles of microglia, infiltrating macrophages, and astrocytes in hyperexcitability and demyelination, offering potential avenues for future research targeting the identified pathways.

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“…One of the drugs that was demonstrated to solubilize at high strength in this vehicle was simvastatin, a lipophilic statin with low oral availability. This is a drug with pleiotropic effects and many potential applications beyond the control of dyslipidemia, like anti-cancer [ 23 ], anti-fibrotic [ 24 ], neuroprotective [ 25 , 26 ], and bone regeneration [ 27 ] applications, among others. Some of these applications could benefit from an alternative liquid formulation for, for example, intranasal administration, which has the potential to enhance brain delivery [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity

Pires,

Fernandes,

Nina

et al. 2023

Pharmaceutics

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Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.

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Repurposing of cholesterol-lowering agents in status epilepticus: A neuroprotective effect of simvastatin

Cited by 6 publications

References 33 publications

Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease

Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE)

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity

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