THE NEUROPROTECTIVE AND NEURONAL RESCUE EFFECTS OF (-)-DEPRENYL

The pharmacological effects of (-)-deprenyl is multi-fold in its natur e (dopamine sparing activity, neuroprotective and neuronal rescue effe cts), which cannot be explained solely by the irreversible MAO-B inhib itory action of the substance. Deprenyl slightly inhibits the re-uptak e of noradrenaline and dopamine, but methylamphetamine, the metabolite of the inhibitor, by one order of magnitude is more potent in this re spect, than the parent compound. Neither the metabolite nor (-)-depren yl acts on the uptake of serotonin. The inhibitor has an intensive fir st pass metabolism after oral treatment. The in vivo pharmacokinetic s tudies with (-)-deprenyl, using the double labelled radioisotope techn ique (1.5 mg/kg; orally) in rats revealed that the molar concentration of methylamphetamine can reach the level suitable to induce a signifi cant inhibition of amine uptake. Deprenyl, but especially methylamphet amine pre-treatment can prevent the noradrenaline release induced by t he noradrenergic neurotoxin DSP-4. The uptake inhibitory effect of (-) -deprenyl and the metabolites is reversible. After repeated administra tion of (-)-deprenyl (1.5 mg/kg daily, for 8 days) sustained concentra tion of its metabolites was detected, compared to that of the acute st udies. This can at least partly explain why (-)deprenyl should be admi nistered daily to evoke therapeutic effects in Parkinson's disease. Ad ministration of (-)deprenyl in a low dose, following the toxic insult, can rescue the damaged neurones. The neuronal rescue effect of the dr ug was studied on M-l human melanoma cells in tissue culture. The inhi bitor reduced the apoptosis of serum-deprived M-l cells, but the (+)-i somer failed to exert this effect. The (+/-)-desmethyl-deprenyl almost lacks the property to inhibit apoptosis. For neuroprotection and neur onal rescue an optimal dose of (-)-deprenyl should be administered, be cause to reach a well balanced concentration of the metabolites in tis sues is critical.