A Novel Melatonin Agonist Neu-240 Improves Motor Abnormality In MPTP And 6-OHDA-induced Rodent Models Of Parkinson’s Disease

Parkinson’s disease(PD) is a common neuro-degenerative disease of elder population. The exact etiology of PD remains to be verified, and there w a s n o r a d i c a l c u r e f o r t h e s e P D p a t i e n t s. T h e r e f o r e, t o e x p l o r e neuropathological mechanisms of PD and seeking novel agents are becoming clinically important. A large amount of researches revealed that the activities of oxidative stress, cellular apoptosis and inflammation response play a critical role in the development of PD. Melatonin is a natural hormone secreted by the pineal gland of mammals, and it exhibits anti-oxidant, anti-apoptotic and anti-inflammatory properties against various injuries; however, the deficiencies of melatonin itself restrict its clinical application. Neu-240, a novel melatonin-receptor agonist, is confirmed to exert anti-oxidant, anti-apoptotic and anti-inflammatory effect, the similar biological effects of melatonin. [Objective] To investigate the effect of Neu-240 on motor abnormality in rat/mice models of PD, and to discover the possible underlying mechanism involved. [Methods] MPTP-induced PD model in C57BL/6 mice: Mice received daily injections of saline or MPTP(1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 30 mg/kg/day) for five consecutive days to induce Parkinsonism. Vehicle or Neu-240(0.1 or 3 mg/kg/day) was administered(i.p.) once per day for 17 days, starting on the first day of MPTP injections. Open field test, pole test, forepaw stride length test and traction test were conducted on day 14, 15, 16 and 17 after the first injections of MPTP, respectively. The contents of corpus striatum dopamine, dihydroxy phenyl acetic acid(DOPAC) and homovanillic acid(HVA) were measured by the method of high performance liquid chromatography(HPLC).6-OHDA-induced PD model in SD rats: Rats received microinjection of 6-OHDA into the medial forebrain bundle on one side of the brain to induce Parkinsonism. Neu-240(0.1 or 3 mg/kg/day) was administered(i.p.) once per day for 3 weeks. Head position and apomorphine rotation tests were conducted.[Results] MPTP-induced PD model in mice: Neu-240 at 3 mg/kg improved behavioral impairment induced by MPTP in the open field test, forepaw stride length test and traction test but not in the pole test. Neu-240 at 0.1 mg/kg was effective only in the open field test. Neu-240 also ameliorated the MPTP-induced reduction of dopamine but not DOPAC and HVA levels in the striatum.6-OHDA-induced PD model in rats: Neu-240 at 0.1 but not 3 mg/kg improved 6-OHDA-induced ipsilateral head position bias and contralateral rotation rates. [Conclusion] The results suggested that Neu-240 improved motor abnormality in MPTP and 6-OHDA induced rodent models of PD.