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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
- Source :
- Neuropharmacology. 140:107-120
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- The mTOR signaling pathway has emerged as a possible therapeutic target for epilepsy. Clinical trials have shown that mTOR inhibitors such as everolimus reduce seizures in tuberous sclerosis complex patients with intractable epilepsy. Furthermore, accumulating preclinical data suggest that mTOR inhibitors may have anti-seizure or anti-epileptogenic actions in other types of epilepsy. However, the chronic use of rapalogs such as everolimus is limited by poor tolerability, particularly by immunosuppression, poor brain penetration and induction of feedback loops which might contribute to their limited therapeutic efficacy. Here we describe two novel, brain-permeable and well tolerated small molecule 1,3,5-triazine derivatives, the catalytic mTORC1/C2 inhibitor PQR620 and the dual pan-PI3K/mTOR inhibitor PQR530. These derivatives were compared with the mTORC1 inhibitors rapamycin and everolimus as well as the anti-seizure drugs phenobarbital and levetiracetam. The anti-seizure potential of these compounds was determined by evaluating the electroconvulsive seizure threshold in normal and epileptic mice. Rapamycin and everolimus only poorly penetrated into the brain (brain:plasma ratio 0.0057 for rapamycin and 0.016 for everolimus). In contrast, the novel compounds rapidly entered the brain, reaching brain:plasma ratios of ∼1.6. Furthermore, they significantly decreased phosphorylation of S6 ribosomal protein in the hippocampus of normal and epileptic mice, demonstrating effective mTOR inhibition. PQR620 and PQR530 significantly increased seizure threshold at tolerable doses. The effect of PQR620 was more marked in epileptic vs. nonepileptic mice, matching the efficacy of levetiracetam. Overall, the novel compounds described here have the potential to overcome the disadvantages of rapalogs for treatment of epilepsy and mTORopathies directly connected to mutations in the mTOR signaling cascade.
- Subjects :
- Ribosomal Proteins
0301 basic medicine
Levetiracetam
Pyridines
Morpholines
Mechanistic Target of Rapamycin Complex 2
mTORC1
Mechanistic Target of Rapamycin Complex 1
Pharmacology
Blood–brain barrier
Hippocampus
Catalysis
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
Epilepsy
0302 clinical medicine
Seizures
medicine
Animals
Everolimus
Enzyme Inhibitors
Phosphorylation
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Sirolimus
Electroshock
Seizure threshold
Triazines
business.industry
medicine.disease
030104 developmental biology
medicine.anatomical_structure
Blood-Brain Barrier
Phenobarbital
Anticonvulsants
Female
business
Azabicyclo Compounds
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 140
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....2dfbc9c6b70d6b99927cfef73809c276