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Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
- Source :
- Neurobiology of Disease, Vol 149, Iss, Pp 105227-(2021)
- Publication Year :
- 2020
-
Abstract
- Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no treatment available to prevent epilepsy. We recently proposed a multitargeted, network-based approach to prevent epileptogenesis by rationally combining clinically available drugs and provided first proof-of-concept that this strategy is effective. Here we evaluated eight novel rationally chosen combinations of 14 drugs with mechanisms that target different epileptogenic processes. The combinations consisted of 2-4 different drugs per combination and were administered systemically over 5 days during the latent epileptogenic period in the intrahippocampal kainate mouse model of acquired temporal lobe epilepsy, starting 6 h after kainate. Doses and dosing intervals were based on previous pharmacokinetic and tolerability studies in mice. The incidence and frequency of spontaneous electrographic and electroclinical seizures were recorded by continuous (24/7) video linked EEG monitoring done for seven days at 4 and 12 weeks post-kainate, i.e., long after termination of drug treatment. Compared to vehicle controls, the most effective drug combination consisted of low doses of levetiracetam, atorvastatin and ceftriaxone, which markedly reduced the incidence of electrographic seizures (by 60%; p
- Subjects :
- kainate
0301 basic medicine
Drug
Male
Levetiracetam
hippocampus
media_common.quotation_subject
Drug Evaluation, Preclinical
Kainate receptor
Pharmacology
Epileptogenesis
neuroinflammation
lcsh:RC321-571
03 medical and health sciences
Epilepsy
Mice
0302 clinical medicine
Drug Delivery Systems
Pharmacokinetics
Seizures
Atorvastatin
Medicine
Animals
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
media_common
Kainic Acid
business.industry
Ceftriaxone
Electroencephalography
blood-brain barrier
medicine.disease
030104 developmental biology
Treatment Outcome
Neurology
Tolerability
Anticonvulsants
Drug Therapy, Combination
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 1095953X
- Volume :
- 149
- Database :
- OpenAIRE
- Journal :
- Neurobiology of disease
- Accession number :
- edsair.doi.dedup.....4aaf7891f5e8f6fd3910fc19f4bd1868