Chronic inhibition of brain phospholipase A2 in rats as a model to investigate Alzheimer-related alterations: a preliminary study

Altered membrane-associated phospholipase A2 (PLA2) activities have been correlated with several forms of chronic brain injury, in particular Alzheimer's disease (AD). Several studies suggest that persistent inhibition of PLA2 (particularly cPLA2 and iPLA2 isoforms) may play a central role in memory deficits as well as β-amyloid production in AD, thus participating in the neurodegenerative process. In order to validate a reversible animal model which is suitable for the study of Alzheimer-related alterations and treatments, we investigated in rats the effect of chronic intracerebroventricular infusion (using 3-days mini-osmotic pumps) of the dual cPLA2 and iPLA2 inhibitors PACOCF3 (reversible) and MAFP (irreversible), or minimal DMSO (vehicle), on the activity of the enzyme in the dorsal hippocampus and pre-frontal cortex. Both 500µM and 5 mM PACOCF3 did not cause any inhibition of PLA2 in relation to vehicle (n=3/group). 1 mM MAFP showed a trend towards inhibition of PLA2 in both hippocampus and cortex when compared to vehicle (n=4/group). Finally, 3 mM MAFP did significantly inhibit PLA2 (p<0.05; t-test) by 21% in hippocampus and 26% in cortex when compared to vehicle (n=3/group). The findings of lack of inhibition by PACOCF3 and greater inhibition power of MAFP, even at lower concentrations than PACOCF3, point to the viability of using the irreversible inhibitor MAFP to study the effects of chronic inhibition of cerebral PLA2 in vivo.

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)