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Enantiomeric N-substituted phthalimides with excitatory amino acids protect zebrafish larvae against PTZ-induced seizures

Campos-Rodriguez, Carolina LU ; Fredrik, Ek LU ; Juan, Eduardo Ramirez-San and Olsson, Roger LU (2020) In European Journal of Pharmacology 888.
Abstract

Epilepsy is a chronic neurological disease with high prevalence and adverse impacts on the quality of life of patients and caregivers. Up to one-third of individuals with epilepsy do not respond to current pharmacotherapy, underscoring the importance of identifying new molecules for epilepsy control. Thalidomide, the first synthetized phthalimide, is a neuroactive molecule with anti-seizure drug properties. The phthalimide group has been studied in some N-phthaloyl amino acids due to its pharmacological properties. Here we examine enantiomers of phthaloyl aspartate (R and S) and phthaloyl glutamate (R and S) for anti-seizure effects using zebrafish as a model. The zebrafish model is rapidly growing in use as a preclinical screening tool... (More)

Epilepsy is a chronic neurological disease with high prevalence and adverse impacts on the quality of life of patients and caregivers. Up to one-third of individuals with epilepsy do not respond to current pharmacotherapy, underscoring the importance of identifying new molecules for epilepsy control. Thalidomide, the first synthetized phthalimide, is a neuroactive molecule with anti-seizure drug properties. The phthalimide group has been studied in some N-phthaloyl amino acids due to its pharmacological properties. Here we examine enantiomers of phthaloyl aspartate (R and S) and phthaloyl glutamate (R and S) for anti-seizure effects using zebrafish as a model. The zebrafish model is rapidly growing in use as a preclinical screening tool for drug discovery in epilepsy. Pentylenetetrazol (PTZ) exposure was used to produce convulsive behavior in 7- and 10-days post-fertilization (dpf) zebrafish larvae; these ages correspond to before and after the blood-brain-barrier (BBB) is fully developed. Larvae were pre-treated for 60 min with: control, valproic acid sodium salt (SVP) 3 mM, or one of two concentrations of N-phthaloyl-R-glutamic acid (R-TGLU; 100, 316 μM) prior to PTZ addition. R-TGLU modified the locomotor phenotype and protected against PTZ in 7 and 10 dpf larvae at 316 μM, suggesting it crossed the BBB. We next tested the per se and anticonvulsant effect of the glutamate and aspartate phthalimides were tested at 237.1 and 316 μM concentration in 10dpf zebrafish. The four tested molecules produced an anticonvulsant effect at 237.1 μM concentration, however the behavioral changes that they induce suggest that they might act by different mechanisms.

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type
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publication status
published
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in
European Journal of Pharmacology
volume
888
article number
173489
publisher
Elsevier
external identifiers
  • scopus:85089703067
  • pmid:32822642
ISSN
1879-0712
DOI
10.1016/j.ejphar.2020.173489
language
English
LU publication?
yes
additional info
Copyright © 2020. Published by Elsevier B.V.
id
c5521772-355a-4e58-91b2-1a0a2041d0da
date added to LUP
2020-08-25 17:48:53
date last changed
2020-11-18 09:39:55
@article{c5521772-355a-4e58-91b2-1a0a2041d0da,
  abstract     = {<p>Epilepsy is a chronic neurological disease with high prevalence and adverse impacts on the quality of life of patients and caregivers. Up to one-third of individuals with epilepsy do not respond to current pharmacotherapy, underscoring the importance of identifying new molecules for epilepsy control. Thalidomide, the first synthetized phthalimide, is a neuroactive molecule with anti-seizure drug properties. The phthalimide group has been studied in some N-phthaloyl amino acids due to its pharmacological properties. Here we examine enantiomers of phthaloyl aspartate (R and S) and phthaloyl glutamate (R and S) for anti-seizure effects using zebrafish as a model. The zebrafish model is rapidly growing in use as a preclinical screening tool for drug discovery in epilepsy. Pentylenetetrazol (PTZ) exposure was used to produce convulsive behavior in 7- and 10-days post-fertilization (dpf) zebrafish larvae; these ages correspond to before and after the blood-brain-barrier (BBB) is fully developed. Larvae were pre-treated for 60 min with: control, valproic acid sodium salt (SVP) 3 mM, or one of two concentrations of N-phthaloyl-R-glutamic acid (R-TGLU; 100, 316 μM) prior to PTZ addition. R-TGLU modified the locomotor phenotype and protected against PTZ in 7 and 10 dpf larvae at 316 μM, suggesting it crossed the BBB. We next tested the per se and anticonvulsant effect of the glutamate and aspartate phthalimides were tested at 237.1 and 316 μM concentration in 10dpf zebrafish. The four tested molecules produced an anticonvulsant effect at 237.1 μM concentration, however the behavioral changes that they induce suggest that they might act by different mechanisms.</p>},
  author       = {Campos-Rodriguez, Carolina and Fredrik, Ek and Juan, Eduardo Ramirez-San and Olsson, Roger},
  issn         = {1879-0712},
  language     = {eng},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmacology},
  title        = {Enantiomeric N-substituted phthalimides with excitatory amino acids protect zebrafish larvae against PTZ-induced seizures},
  url          = {http://dx.doi.org/10.1016/j.ejphar.2020.173489},
  doi          = {10.1016/j.ejphar.2020.173489},
  volume       = {888},
  year         = {2020},
}