Rapamycin provides anti‑epileptogenic effect in a rat model of post‑traumatic epilepsy via deactivation of mTOR signaling pathway

Wang, Feng; Chen, Fuxiang; Wang, Genbo; Wei, Shushan; Fang, Fu Min; Kang, Dezhi; Lin, Yuanxiang

doi:10.3892/etm.2018.6004

Cited by 8 publications

(9 citation statements)

References 32 publications

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“…Rapamycin inhibits mTORC1 and has been shown to have antiseizure effects . Treatment with rapamycin during or after the initial epileptogenic injury has shown to reduce the percentage of mice that developed post‐traumatic epilepsy and the frequency of spontaneous seizures, as well as neuronal degeneration . Similar results have also been shown in the post‐SE and neonatal hypoxia models of acquired epilepsy .…”

Section: Mechanistic Target Of Mammalian Rapamycin Pathwaymentioning

confidence: 54%

Neurodegenerative pathways as targets for acquired epilepsy therapy development

2020

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There is a growing body of clinical and experimental evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult may share common etiological mechanisms. Acquired epilepsy commonly develops as a comorbid condition in patients with neurodegenerative diseases such as Alzheimer's disease, although it is likely much under diagnosed in practice. Progressive neurodegeneration has also been described after traumatic brain injury, stroke, and other forms of brain insults. Moreover, recent evidence has shown that acquired epilepsy is often a progressive disorder that is associated with the development of drug resistance, cognitive decline, and worsening of other neuropsychiatric comorbidities. Therefore, new pharmacological therapies that target neurobiological pathways that underpin neurodegenerative diseases have potential to have both an anti-epileptogenic and diseasemodifying effect on the seizures in patients with acquired epilepsy, and also mitigate the progressive neurocognitive and neuropsychiatric comorbidities. Here, we review the neurodegenerative pathways that are plausible targets for the development of novel therapies that could prevent the development or modify the progression of acquired epilepsy, and the supporting published experimental and clinical evidence. K E Y W O R D SAMPA, amyloid-β, glutamate, mTOR, neuroinflammation, tau

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Section: Mechanistic Target Of Mammalian Rapamycin Pathwaymentioning

confidence: 54%

Neurodegenerative pathways as targets for acquired epilepsy therapy development

2020

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“…In addition to inflammatory changes, there are a variety of other molecular alterations after TBI that have been implicated in the development of PTE. The mTOR signaling pathway, a regulator of cell metabolism, proliferation, and differentiation, has also been implicated in both TBI recovery 34 and seizures 35 . Surgically resected tissue samples from patients with temporal lobe epilepsy show increased expression of phosphorylated proteins mTOR, s6, and Akt, consistent with mTOR overactivity 36 .…”

Section: Discussionmentioning

confidence: 99%

“…mTOR inhibition supports a causative role of this pathway in altered seizure susceptibility 37 . In rodent studies of PTE, the mTOR inhibitor, rapamycin, has demonstrated antiepileptogenic effects 34 . Although mTOR signaling alterations have been shown in various zebrafish models of seizures, 38–40 they have not been investigated in zebrafish TBI or PTE.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish model of posttraumatic epilepsy

et al. 2020

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Objective: Posttraumatic epilepsy (PTE) is defined as recurrent and unprovoked seizures occurring >1 week after traumatic brain injury (TBI). Animal studies of PTE are lengthy and expensive. In this study, we developed a cost-effective PTE animal model using zebrafish to bridge the gap between in vitro studies and low-throughput animal studies. Methods: We used two different sets of parameters (G1 and G2) to induce closedhead TBI in adult zebrafish using pulsed high-intensity focused ultrasound. Injured fish and naive controls were evaluated for behavioral deficits and spontaneous behavioral seizure activity up to 21 days postinjury (DPI). We also assessed behavioral seizure susceptibility to a subconvulsive dose of pentylenetetrazole (PTZ; 2.5 mmol•L-1) and recorded electrophysiological signals to confirm seizure activity up to 40 DPI. In addition, we investigated injury-related changes in the blood-brain barrier and expression levels of various proteins altered in rodent and human TBI. Results: The G2 parameters resulted in a more severe TBI, with a mortality rate of 25%, as well as motor dysfunction and heightened anxiety persisting at 21 DPI. One hundred percent of the G2 group showed spontaneous myocloniclike behavior, and 80% demonstrated tonic-clonic-like behavioral seizures by 21 DPI. Such activities were not detected in the naive group. After the application of 2.5 mmol•L-1 PTZ, 100% of injured zebrafish had cloniclike seizures at 21 DPI, versus 30% of the naive group. We also demonstrated electrographic seizure activity at 40 DPI, which was not detected in the naive controls. Lastly, we observed acute blood-brain barrier dysfunction and increased levels of HMGB1 and ratios of phosphorylated/total Akt and tau through 21 DPI. Significance: Together, the results indicate that severe TBI in the adult zebrafish leads to similar behavioral and physiological changes to those of more traditional models, including the development of PTE, and suggest this may be a useful model that can accelerate research in TBI/PTE.

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“…In a rat model of FeCl 2 -induced post-traumatic epilepsy (PTE), p-mTOR and p-P70S6K are increased significantly in the hippocampus and perilesional cortex [138]. Rapamycin administration decreases mTOR activity markers while reducing the frequency and number of behavioral seizures and epileptic brain injury [138].…”

Section: Ischemic/hemorragic Stroke and Brain Traumamentioning

confidence: 99%

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

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Rapamycin provides anti‑epileptogenic effect in a rat model of post‑traumatic epilepsy via deactivation of mTOR signaling pathway

Cited by 8 publications

References 32 publications

Neurodegenerative pathways as targets for acquired epilepsy therapy development

Neurodegenerative pathways as targets for acquired epilepsy therapy development

Zebrafish model of posttraumatic epilepsy

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

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