P3-340: PLA2 enzyme: New target for memantine action

Memantine, an aminodamantane and uncompetitive NMDA receptor antagonist, which has been employed as a neuroprotective agent for the treatment of several dementias, particularly Alzheimer's disease. The NMDA receptor activation is required for induction of neural plasticity and memory formation. However the dysfunctional overactivation of NMDA receptors may lead to disturbances of plasticity. Unlike other Alzheimer's drugs, memantine blocks NMDAR channels in a dose, time and voltage-dependent manner. Additionally, previous results of our group evidenced a correlation of PLA2 inhibition activity and the severity of clinical aspects of Alzheimer's disease. Besides, in rat, the activity of PLA2 is required for memory retrieval and the inhibition of this activity in hippocampus was reported to impair memory acquisition. In mammalians, this important gene family is composed of >30 genes distributed in throughout the genome in almost every chromosome. These genes code for a large number of proteins that can be divided into five main enzymatic subgroups. After screening for PLA2 genes expressed in the brain, using in silico databases, we investigated if these genes were modulated by memantine. For this, three groups of Wistar rats (n=10 animals/group) was established. The two groups of treatment received memantine orally (by gavage) in two doses (10mg/kg/day and 20mg/kg/day) for a period of 30 days. After treatment the animals were sacrificed and samples of hippocampus and frontal cortex were used for quantification of PlA2 genes (by qRT-PCR) and enzymatic PLA2 subgroups activities (by radioenzymatic assay). The expression of specific PlA2 genes was significantly increased, which correlated with an increased of enzymatic activity of the investigated PLA2 subgroups. Our data does not prove that memantine has a direct effect over PLA2, however, we could demonstrate that PLA2 enzyme is activated after treatment with this drug. This information may be relevant to clarify its mechanism of action on both aspects: neuroprotection and reverse deficits in learning/memory.