title: Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy.
abstract: OBJECTIVE
  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: Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro, Via T. Campanella 115, Catanzaro, Italy.
authors: Rita
authors: R
authors: Citraro
authors: Francesca
authors: F
authors: Scicchitano
authors: Salvatore
authors: S
authors: De Fazio
authors: Riccardo
authors: R
authors: Raggio
authors: Paolo
authors: P
authors: Mainardi
authors: Emilio
authors: E
authors: Perucca
authors: Giovambattista
authors: G
authors: De Sarro
authors: Emilio
authors: E
authors: Russo
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D002220:Carbamazepine / Q000008:administration & dosage / Q000627:therapeutic use; D003292:Convulsants / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy*; D020195:Epilepsy, Reflex / Q000188:drug therapy / Q000235:genetics; D005260:Female; D007768:Lactalbumin / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy*; D012701:Serotonin / Q000096:biosynthesis / Q000502:physiology; D014364:Tryptophan / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000596:Amino Acids; D003292:Convulsants; D010862:Pilocarpine; D012701:Serotonin; D002220:Carbamazepine; D014364:Tryptophan; D007768:Lactalbumin