Melatonin enhances L ‐ DOPA therapeutic effects, helps to reduce its dose, and protects dopaminergic neurons in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced parkinsonism in mice

L‐3,4‐dihydroxyphenylalanine (L‐DOPA) reduces symptoms of P arkinson's disease ( PD ), but suffers from serious side effects on long‐term use. Melatonin (10–30 mg/kg, 6 doses at 10 hr intervals) was investigated to potentiate L ‐ DOPA therapeutic effects in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine ( MPTP )‐induced parkinsonism in mice. Striatal tyrosine hydroxylase ( TH ) immunoreactivity, TH , and phosphorylated ser 40 TH (p‐ TH ) protein levels were assayed on 7th day. Nigral TH ‐positive neurons stereology was conducted on serial sections 2.8 mm from bregma rostrally to 3.74 mm caudally. MPTP caused 39% and 58% decrease, respectively, in striatal fibers and TH protein levels, but 2.5‐fold increase in p‐ TH levels. About 35% TH neurons were lost between 360 and 600  μ m from 940  μ m of the entire nigra analyzed, but no neurons were lost between 250  μ m rostrally and 220  μ m caudally. When L ‐ DOPA in small doses (5–8 mg/kg) failed to affect MPTP ‐induced akinesia or catalepsy, co‐administration of melatonin with L ‐ DOPA attenuated these behaviors. Melatonin administration significantly attenuated MPTP ‐induced loss in striatal TH fibers (82%), TH (62%) and p‐ TH protein (100%) levels, and nigral neurons (87–100%). Melatonin failed to attenuate MPTP ‐induced striatal dopamine depletion. L ‐ DOPA administration (5 mg/kg, once 40 min prior to sacrifice, p.o.) in MPTP ‐ and melatonin‐treated mice caused significant increase in striatal dopamine (31%), as compared to L ‐ DOPA and MPTP ‐treated mice. This was equivalent to 8 mg/kg L ‐ DOPA administration in parkinsonian mouse. Therefore, prolonged, effective use of L ‐ DOPA in PD with lesser side effects could be achieved by treating with 60% lower doses of L ‐ DOPA along with melatonin.