Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats

Torun, İbrahim Ethem; Kılınc, Yasemin Baranoglu; Kılınç, Erkan

doi:10.1590/0004-282x-anp-2021-0101

Cited by 7 publications

(2 citation statements)

References 35 publications

(51 reference statements)

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“…Some evidence suggests that this unique pharmacology may also play a direct role in reducing neuroinflammation and/or protecting or repairing myelin 52‐54 . Sigma1R was identified as a critical regulator of inflammation in a knockout Sigma1R mouse model, 52 and serotonin reduced levels of inflammatory cytokines in brain homogenates of rats after pentylenetetrazole‐induced seizures 55 . Sigma1R regulates myelination in the brain, with defects associated with neurodegenerative disorders (e.g., multiple sclerosis) 53,54,56 .…”

Section: Discussionmentioning

confidence: 99%

“…[52][53][54] Sigma1R was identified as a critical regulator of inflammation in a knockout Sigma1R mouse model, 52 and serotonin reduced levels of inflammatory cytokines in brain homogenates of rats after pentylenetetrazoleinduced seizures. 55 Sigma1R regulates myelination in the brain, with defects with neurodegenerative disorders (e.g., multiple sclerosis). 53,54,56 In a mouse model of spatial learning and memory, fenfluramine positively modulated Sigma1R to prevent dizocilpine-induced amnesia, 15 and later reports suggested that the neuro (active) steroids dehydroepiandrosterone sulfate and pregnenolone sulfate were endogenous ligands mediating these neuroprotective effects.…”

Section: Fenfluramine Impact On Myelin Degradationmentioning

confidence: 99%

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Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Cha,

Filatov,

Smith

et al. 2023

Epilepsia Open

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ObjectiveIn patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant scn1 DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (Scn1a+/− mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival.MethodsScn1a+/− DS mice were treated subcutaneously once daily with fenfluramine (15 mg/kg) or vehicle from postnatal day (PND) 7 until 35‐37. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D‐MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi‐quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1‐way ANOVA with post‐hoc Dunnett's test (D‐MBP, CD11b, and TUNEL) or Logrank Mantel‐Cox (survival).ResultsQuantitation of D‐MBP immunostaining per 0.1 mm2 unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle‐treated DS mice than in wild‐type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b + microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild‐type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b + microglia than vehicle‐treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild‐type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle‐treated DS mice. By PND 35‐37, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (P = 0.0291).SignificanceThis is the first report of anti‐neuroinflammation and pro‐survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction.Plain Language SummaryDravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine‐treated Dravet mice also lived longer than saline‐treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.

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Section: Discussionmentioning

confidence: 99%

Section: Fenfluramine Impact On Myelin Degradationmentioning

confidence: 99%

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Cha,

Filatov,

Smith

et al. 2023

Epilepsia Open

View full text Add to dashboard Cite

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Systemic inflammation as a biomarker of seizure propensity and a target for treatment to reduce seizure propensity

et al. 2023

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People with diabetes can wear a device that measures blood glucose and delivers just the amount of insulin needed to return the glucose level to within bounds.Currently, people with epilepsy do not have access to an equivalent wearable device that measures a systemic indicator of an impending seizure and delivers a rapidly acting medication or other intervention (e.g., an electrical stimulus) to terminate or prevent a seizure. Given that seizure susceptibility is reliably increased in systemic inflammatory states, we propose a novel closed-loop device where release of a fast-acting therapy is governed by sensors that quantify the magnitude of systemic inflammation. Here, we review the evidence that patients with epilepsy have raised levels of systemic indicators of inflammation than controls, and that some anti-inflammatory drugs have reduced seizure occurrence in animals and humans. We then consider the options of what might be incorporated into a responsive anti-seizure system.

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Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model

Okanari,

Teranishi,

Umeda

et al. 2024

Behavioural Brain Research

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Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats

Cited by 7 publications

References 35 publications

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome

Systemic inflammation as a biomarker of seizure propensity and a target for treatment to reduce seizure propensity

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model

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