ABSTRACT
Title
Preclinical antiepileptic and antiepileptogenic effects of alpha-lactoalbumin, a whey protein rich in tryptophan.
Authors
R. Citraro1, S. De Fazio1, F. Scicchitano, S. Chimirri1, A. Urzino1, M. Menniti1, R. Marra2, G. De Sarro1, E. Russo1
1Dept of Experimental and Clinical Medicine, School of Medicine, University “Magna Graecia” of Catanzaro, Catanzaro, Italy. 2National Council of Research, Institute of Neurological Science, Catanzaro, Italy
1Dept of Experimental and Clinical Medicine, School of Medicine, University “Magna Graecia” of Catanzaro, Catanzaro, Italy. 2National Council of Research, Institute of Neurological Science, Catanzaro, Italy
Abstract
Serotonin (5-HT) is involved in several physiological functions in the central nervous system (CNS) such as control of appetite, sleep, memory and learning, temperature regulation, mood, behaviour, maturation of neuronal and glial cells, synaptic connections and neuronal excitability (Barnes and Sharp, 1999; Bagdy et al., 2007). As early as 1957, Bonnycastle et al. (1957) suggested that there may also be a link between 5-HT levels and epilepsy. Experimental data indicate that 5-HT has anticonvulsant properties both in experimental models of epilepsy and in humans (Bagdy et al., 2007). Likewise, a reduction in brain 5-HT concentrations leads to an increase in seizure susceptibility in animal models of epilepsy (Browning et al. 1997; Statnick et al. 1996) and, possibly, in humans (Maynert et al., 1975). Based on this background, we aimed to evaluate the potential anticonvulsant/antiepileptogenic activity of alpha-lactalbumin (ALAC), a whey protein rich in tryptophan (TRP) relative to other large neutral amino acids (LNAAs), in rodent models of seizures and epilepsy. We have previously demonstrated that ALAC possess some antiepileptic effects in preclinical model of epilepsy/seizures (Citraro et al., 2011). The effects of ALAC administered per os were evaluated by standard protocols against spontaneous chronic seizures in mice exposed to pilocarpine-induced status epilepticus (SE), and absence seizures in WAG/Rij rats both evaluating the antiepileptic and antiepileptogenic effects.
Single doses of ALAC up to 500 or 6000 mg/kg were devoid of anticonvulsant activity in all models tested.Conversely, similarly to CBZ, ALAC (125-500 mg/kg/day for 15 days) was effective against spontaneous seizures in the post-pilocarpine SE model. Absence seizures in WAG/Rij rats were not significantly affected by ALAC (15 days) whereas, an early long-term treatment protocol (Russo et al., 2011) was able to reduce absence seizures development showing antiepileptogenic effects. Similarly, when ALAC was administered during the silent phase of post-pilocarpine SE model a smaller number of spontaneous seizures was observed.
In conclusion, ALAC exerts significant protective activity against seizures in some animal models, the effect being especially prominent against spontaneous seizures in mice exposed to pilocarpine induced SE. A certain antiepileptogenic effects has also been observed suggesting a protective role of this drug against neuroadaptation during epileptogenesis. These action are likely to be mediated by increased availability of TRP in the brain, with a consequent increase in 5-HT mediated transmission.
Bagdy et al. (2007). J Neurochem. 100, 857-873.
Barnes and Sharp (1999). Neuropharmacology. 38, 1083-1152.
Bonnycastle et al. (1957). Br. J. Pharmacol. 12, 228-231.
Browning et al. (1997). Eur. J. Pharmacol. 336, 1–6.
Citraro et al. (2011). Epilepsy Res. In press.
Maynert et al. (1975). Adv Neurol. 13,79-147.
Russo et al. (2011). Epilepsia. In press.
Statnick et al. (1996).Life Sci. 59, 1763-1771.
Single doses of ALAC up to 500 or 6000 mg/kg were devoid of anticonvulsant activity in all models tested.Conversely, similarly to CBZ, ALAC (125-500 mg/kg/day for 15 days) was effective against spontaneous seizures in the post-pilocarpine SE model. Absence seizures in WAG/Rij rats were not significantly affected by ALAC (15 days) whereas, an early long-term treatment protocol (Russo et al., 2011) was able to reduce absence seizures development showing antiepileptogenic effects. Similarly, when ALAC was administered during the silent phase of post-pilocarpine SE model a smaller number of spontaneous seizures was observed.
In conclusion, ALAC exerts significant protective activity against seizures in some animal models, the effect being especially prominent against spontaneous seizures in mice exposed to pilocarpine induced SE. A certain antiepileptogenic effects has also been observed suggesting a protective role of this drug against neuroadaptation during epileptogenesis. These action are likely to be mediated by increased availability of TRP in the brain, with a consequent increase in 5-HT mediated transmission.
Bagdy et al. (2007). J Neurochem. 100, 857-873.
Barnes and Sharp (1999). Neuropharmacology. 38, 1083-1152.
Bonnycastle et al. (1957). Br. J. Pharmacol. 12, 228-231.
Browning et al. (1997). Eur. J. Pharmacol. 336, 1–6.
Citraro et al. (2011). Epilepsy Res. In press.
Maynert et al. (1975). Adv Neurol. 13,79-147.
Russo et al. (2011). Epilepsia. In press.
Statnick et al. (1996).Life Sci. 59, 1763-1771.