The effects of neurolipins and their synthetic analogues on normal and transformed glial cells

In this work, we studied the effects of endogenous and synthetic derivatives of polyunsaturated fatty acids (neurolipins) on the viability of cells of rat C6 glioma and human U251 glioma cells. We synthesized 46 analogues of endogenous substances, amides and esters of fatty acids, with different modifications of the carboxyl group. We studied the four following groups of substances: analogues of 2-arachidonoyl glycerol and N-arachidonoylethanolamine, N-acyl amino acids, and N-acyl dopamines. Among all substances studied, N-acyl dopamines, in particular N-arachidonoyl dopamine (AA-DA) and N-docosahexaenoyl dopamine (DHA-DA) had the highest activities at concentrations below 10 μM. Our studies on the mechanisms of toxicity of AA-DA and DHA-DA showed that suppression of viability did not involve intracellular cascades that include mitogen-activated kinases, protein kinases C and A, and calmodulin-dependent kinases. We showed that toxic effects are developed through the caspase-dependent pathway, which includes activation of caspases 3 and 9. Note that AA-DA and DHA-DA at the same concentrations did not suppress the viability of normal glial cells and neurons of rats, which suggests that this group of substances may be used as a basis for the development of pharmacological agents for treatment of gliomas.