The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy

Brandt, Claudia; Hillmann, Petra; Noack, Andreas; Römermann, Kerstin; Öhler, Leon A.; Rageot, Denise; Beaufils, Florent; Melone, Anna; Sele, Alexander; Wymann, Matthias P.; Fabbro, Doriano; Löscher, Wolfgang

doi:10.1016/j.neuropharm.2018.08.002

Cited by 70 publications

(90 citation statements)

References 71 publications

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“…Treatment with AZD could successfully slow down the growth of tumors and gliomas by inhibiting the mTOR complex . Furthermore, the fact that another dual mTOR inhibitor (PQR620) was effectively able to improve epilepsy in a mouse model of chronic epilepsy, suggests that this dual mTOR inhibitor might have a beneficial effect. Comparable to rapamycin treatment, AZD8055 treatment resulted in a strong reduction of pS6 Ser240/244 .…”

Section: Discussionmentioning

confidence: 99%

“…However, detailed analysis of the EEG data did not reveal a difference in total number of seizures in the 2 h after drug injection compared to any of the other 2‐h windows within 24 h following injection. A second explanation could be that mTORC2 activation is neuroprotective instead and hence, a decrease in mTORC2 reduces the effectiveness of inhibiting mTORC1. The second specific drug that we tested, PF4708671, is a cell‐permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform).…”

Section: Discussionmentioning

confidence: 99%

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Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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“…Overall, rapamycin and other mTOR inhibitors, including everolimus, might be interesting candidates for preventing epilepsy in genetic disorders of the mTOR pathway, and the TBI study of Guo et al suggests an antiepileptogenic effect in TBI‐induced PTE, although these data need to be confirmed. One disadvantage of rapalogs such as rapamycin and everolimus is their poor brain penetration . Thus, novel mTOR inhibitors with improved brain penetration might be more suitable to evaluate whether mTOR inhibition in the brain has antiepileptogenic potential …”

Section: Rapamycin Everolimus and Other Mammalian Target Of Rapamycmentioning

confidence: 99%

“…5,230 However, in most studies the effect of rapamycin on development of SRS was determined either during the period of rapamycin treatment or following relatively short periods of rapamycin withdrawal. Because rapamycin has been reported to exert an antiseizure effect on SRS 231 and is eliminated extremely slowly from the brain following prolonged administration (with half-lives of ~300 hours in rodents 232,233 ), most if not all of the reported effects of rapamycin on SRS development may be due to antiseizure rather than antiepileptogenic effects. When sufficiently long periods of withdrawal from rapamycin treatment were used, no effect on development of SRS was observed.…”

Section: And Other Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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“…However, long-term rapamycin 237 pretreatment (3 hours) abolished haloperidol-induced catalepsy. One possibility for such delayed 238 action is due to the relatively poor brain penetrability of rapamycin and thus a delayed target 239 engagement (Brandt et al, 2018). Interestingly, a previous study indicated Fyn kinase had a role 240 in the regulation of haloperidol-induced catalepsy (Hattori et al, 2006).…”

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confidence: 99%

The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

Ramírez-Jarquín

Shahani

Pryor

et al. 2020

Preprint

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13The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase 14 protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from 15 embryonic development to aging. However, its brain tissue-specific roles remain less explored. 16Here, we have identified that the depletion of the mTOR gene in the mice striatum completely 17 prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor 18 (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. 19Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 20 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration 21 of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal 22 protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic 23 approach, we used a pharmacological method and determined that the mTORC1 inhibitor 24 rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We 25 consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent 26 manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that 27 striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-28 dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness. 29 30 31 KEY WORDS 32 Psychosis, Freezing, Extra pyramidal symptoms, Pre-clinical model, Medium spiny neurons, 33Tissue-specific regulation, Brain behavior 34 65 consistently trigger severe motor deficit and extrapyramidal side effects (EPS) (Klemm, 1989). 66Recent studies have indicated that coordinated signaling of both D1R and D2R is 67 responsible for the initiation and execution of motor activity (Sheng et al., 2019). Importantly, 68 3 mTOR phosphorylation is selectively increased in the striatum during L-DOPA-induced dyskinesia 69 (Eshraghi et al., 2020) and motor learning (Bergeron et al., 2014). However, the genetic evidence 70 for the physiological role of mTOR signaling in the striatum (or its role in D1R versus D2R MSNs 71 signaling) is currently unknown. Using genetic and pharmacological approaches, we investigated 72 the role of mTOR on striatal-mediated motor behaviors under basal and challenged conditions. 73 74 RESULTS 75 Striatal mTOR regulates motor behaviors 76 The role of mTOR signaling in the regulation of striatal motor functions under basal conditions 77 remains unclear. To address this question, we carried out conditional depletion of mTOR in the 78 striatum of adult mTOR flox/flox mice. We used an AAV1.hSyn.HI.WPRE.SV40 variant expressing 79 Cre-GFP (AAV-Cre-GFP) under the control of human synapsin promoter to deplete mTOR 80 preferentially in striatal neuronal cells (Kugler et al., 2003). We stereotaxically injected purified 81 virus (AAV-Cre-GFP or AAV-GFP) bilaterally into the striatum of 8-week-old mTOR ...

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The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy

Cited by 70 publications

References 71 publications

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

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