Fingolimod enhances myelin repair of hippocampus in pentylenetetrazol-induced kindling model

Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP − ) and AD transgenic (APP + ) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP − mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.

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“…The doses used were based on analysis of data from earlier studies [44][45][46]. Animals were weighed to assess correct injection volume/dose.…”

Section: Animal Housing and Treatmentmentioning

confidence: 99%

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

et al. 2018

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“…These effects could also be the result of astrocyte S1P receptor modulation, however, further studies are needed to better clarify this hypothesis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 [13,23]. More recently, Gol et al [24] also demonstrated that fingolimod, through neuroprotective and anti-inflammatory effects, promotes myelin protection and remyelination improvement in the pentylenetetrazole (PTZ)-kindling mouse model of epilepsy. Particularly, the pre-treatment with fingolimod, 1h before PTZ-administration, resulted in decreased seizure onset, microglial activation and neuronal death in hippocampal areas, CA1 and CA3.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, fingolimod antiepileptic effects were confirmed in the PTZ-kindling mouse model with pretreatment reducing seizure development as well as protecting myelin and post-treatment reducing seizure severity as well as inducing remyelination in kindled mice [24]. Considering fingolimod potential effects in epilepsy/epileptogenesis and the lack of data on genetic epilepsy models and epilepsy comorbidities, we aimed in the present study, to evaluate the effects of some fingolimod treatments (acute, sub-chronic and early long-term treatment) in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity (dysthymia and decline in learning and memory performance) [25][26][27].…”

Section: Introductionmentioning

confidence: 93%

“…Two doses of fingolimod (1 and 3 mg/Kg/day; gift from Novartis Pharmaceutical Development, Basel, Switzerland) were used in this protocol section and were chosen according to previous studies [13,21,23,24]; the acute effects of fingolimod were always tested 1h after i.p. administration considering its known pharmacokinetic profile [44].…”

Section: Acute and Subchronic Proceduresmentioning

confidence: 99%

“…Therefore, these multiple relevant effects have prompted the study of fingolimod effects in other brain disorders [16] including Alzheimer's disease [22] and epilepsy [13,23,24].…”

Section: Introductionmentioning

confidence: 99%

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Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine‐1‐Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects

de Cuba,

de Goede,

Klaassen

et al. 2024

Clin Pharma and Therapeutics

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Current anti‐epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment‐resistant. Drugs targeting the sphingosine‐1‐phosphate receptor show potential anti‐convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti‐epileptic potential. TRV045 is a selective sphingosine‐1‐phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability. This randomized, double‐blind, placebo‐controlled, two‐way cross‐over, multiple‐dose study evaluated the effects of TRV045 on cortical excitability in healthy male adults, measured by pharmaco‐electroencephalography and transcranial magnetic stimulation (TMS). Subjects received TRV045 250 mg or placebo, once daily for 4 days, in randomized order. Endpoints were analyzed with a mixed effects model analysis of covariance. Twenty‐five of the 27 subjects completed the study. There was a significant increase in alpha power with eyes open after treatment with TRV045 on Day 1, increasing after 4 days of dosing. Less pronounced significant effects in beta, gamma, and delta power were observed after 4 days. For TMS‐Electromyography there was a non‐significant decreased post‐dose single‐pulse peak‐to‐peak amplitude on Day 1 only, and there were no effects on paired‐pulse parameters. Several significant TMS‐Electroencephalography clusters were seen after 4 days of dosing. These findings show that TRV045 has central nervous system activity with evolving effects following repeated dosing. These data support further studies to elucidate the mechanism of action of TRV045 and its potential anti‐epileptic effects.

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Fingolimod enhances myelin repair of hippocampus in pentylenetetrazol-induced kindling model

Cited by 47 publications

References 33 publications

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine‐1‐Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects

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