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Abstract: The aim of the present work was to evaluate the potential activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan (TRP), in two rodent models of epileptogenesis and we explored a possible mechanism of action. The effects of ALAC (oral administration) were tested in two standard epileptogenesis protocols, namely the pilocarpine post-status epilepticus model in mice and the WAG/Rij rat model of absence epileptogenesis. The mechanism of action was investigated by assessing the effects of ALAC in two seizure models (N-methyl-d-aspartate (NMDA) and pentylenetetrazol (PTZ) -induced seizures) including d-serine co-administration. ALAC showed protecting properties in both models of epileptogenesis, reducing spontaneous seizures development. In acute seizure models, ALAC possessed antiseizure properties at some of the doses tested (PTZ-seizures: >50% seizure-reduction between 250 and 375mg/kg; NMDA-seizures: >90% reduction at 250 and 500mg/kg). When a dose of d-serine ineffective per se was co-administered with ALAC, ALAC effects were significantly reversed in both models. ALAC is active in experimental models of seizure and epileptogenesis. Its effects are likely mediated by the inhibition of NMDA receptors at the glycine binding site, possibly secondarily to the in vivo enzymatic conversion of ALAC-generated tryptophan to kynurenic acid. However, other mechanisms of action contributing to ALAC effects cannot be excluded. [Copyright &y& Elsevier]

Abstract: Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2–3months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC, 10mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator. [Copyright &y& Elsevier]