Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy.

Abstract

PURPOSE:

To evaluate the potential anticonvulsant activity of α-lactalbumin (ALAC), a whey protein rich in tryptophan (TRP) relative to other large neutral amino acids (LNAAs), in rodent models of seizures and epilepsy.

METHODS:

The effects of ALAC administered per os were evaluated by standard protocols against audiogenic seizures in Genetic Epilepsy Prone Rats (GEPR-9 rats), maximal electroshock (MES)-induced seizures in rats, pilocarpine-induced seizures in mice, spontaneous chronic seizures in mice exposed to pilocarpine-induced status epilepticus (SE), and absence seizures in WAG/Rij rats. In some models, carbamazepine (CBZ) was included as an active control. Plasma TRP/LNAAs ratios were measured by GC-MS.

RESULTS:

Single doses of ALAC up to 500 or 6000 mg/kg were devoid of anticonvulsant activity in all models tested. Conversely, 5- and 12-day treatment with ALAC (250-1000 mg/kg/day) in GEPR rats reduced dose-dependently seizure scores and prolonged latency to clonus onset, with full persistence of the effect for up to 12h. ALAC (125-500 mg/kg/day for 15 days) protected against seizures induced by 250 mg/kg pilocarpine, but was less effective against higher pilocarpine doses. Similarly to CBZ, ALAC (125-500 mg/kg/day for 15 days) was also effective against spontaneous seizures in the post-pilocarpine SE model. ALAC (up to 6000 mg/kg/day for 12 days) did not prevent MES-induced seizures, although it reduced the duration of tonic extension at doses between 250 and 1000 mg/kg/day. Absence seizures in WAG/Rij rats were not significantly affected by ALAC. Plasma TRP/LNAAS ratios increased 2- to 3-fold after dosing with ALAC (250 mg/kg/day) for 7 and 14 days, respectively.

CONCLUSIONS:

ALAC exerts significant protective activity against seizures in animal models, the effect being especially prominent against audiogenic seizures in GEPR-9 rats, seizures induced by low-dose pilocarpine in mice, and spontaneous seizures in mice exposed to pilocarpine-induced SE. This action is likely to be mediated by increased availability of TRP in the brain, with a consequent increase in 5-HT mediated transmission.

• Authors: Rita Citraro, Francesca Scicchitano, Salvatore De Fazio, Riccardo Raggio, Paolo Mainardi, Emilio Perucca, Giovambattista De Sarro, Emilio Russo
• Journal: Epilepsy research (Epilepsy Res) Vol. 95 Issue 1-2 Pg. 60-9 (Jun 2011) ISSN: 1872-6844 [Electronic] Netherlands
• PMID: 21458955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids
• Convulsants
• Pilocarpine
• Serotonin
• Carbamazepine
• Tryptophan
• Lactalbumin

Topics

• Amino Acids (blood)
• Animals
• Carbamazepine (administration & dosage, therapeutic use)
• Convulsants (toxicity)
• Drug Evaluation, Preclinical
• Electroshock (adverse effects)
• Epilepsy (drug therapy)
• Epilepsy, Reflex (drug therapy, genetics)
• Female
• Lactalbumin (chemistry, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Pilocarpine (toxicity)
• Rats
• Rats, Mutant Strains
• Rats, Wistar
• Seizures (drug therapy)
• Serotonin (biosynthesis, physiology)
• Tryptophan (blood, pharmacokinetics)