Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties.

ABSTRACT

The amygdala-kindling model has been proposed as a model of sensitization processes with relevance to epilepsy as well as affective disorders. Levetiracetam is a novel anticonvulsant drug that delays the process of kindling, i.e., possesses antiepileptogenic properties. Preliminary reports also suggest a mood-stabilizing potential for levetiracetam. Brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) are central modulators of seizure activity, which undergo plastic changes during kindling epileptogenesis. Consequently, we investigated the regulation of BDNF and NPY mRNA and Y1-, Y2-, and Y5-like receptor binding in the hippocampus of vehicle-pretreated, partially and fully amygdala-kindled rats and corresponding levetiracetam-pretreated rats (40 mg/kg i.p.). The present data indicate that the process of kindling is associated with an upregulation of hippocampal BDNF and NPY mRNA levels and downregulation of Y1- and particularly Y5-like receptors. Pretreatment with levetiracetam markedly delays the progression of kindling and, in addition, exhibits a clear anticonvulsant effect. These effects are associated with abolition of the kindling-induced rise in BDNF and NPY mRNA and increasing levels of Y1- and particularly Y5-like receptors in all hippocampal subfields. Lastly, the present study reveals that an identical dose of levetiracetam reduced immobility in the rat forced swim test, the first experimental evidence indicative of an antidepressant and/or mood stabilizer-like profile of this drug. Considering that animal depression models display impairments in hippocampal NPY systems that become normalized following mood-stabilizing treatment, and that exogenous NPY exerts anticonvulsant as well as antidepressive-like activity in rodents, it is a heuristic possibility that increased hippocampal excitability and affective symptomatology may converge on an impaired hippocampal NPY function. Speculatively, the ability of levetiracetam to increase hippocampal Y1- and Y5-like receptor levels may have implications for the antiepileptic properties of levetiracetam, as well as its purported mood-stabilizing properties.