Recovery from experimental Parkinson's disease in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride treated marmoset with the melatonin analogue ML-23

Abstract

A new mechanism has been recently proposed, whereby melatonin may participate in the ongoing process of neuronal degeneration in models of neurodegenerative disorders, such as Parkinson's disease (PD). Antagonism of the melatonin receptor in rats using constant light or pinealectomy induced recovery and reduced the mortality typically associated with dopamine (DA) degeneration. In additional studies, employing ML-23 in the 6-OHDA-treated rat, remission from experimental PD was achieved using this drug in a post 6-OHDA treatment regime. To permit the further assessment of ML-23 as a potential clinical candidate for the treatment of PD, the present study was undertaken to determine the efficacy of ML-23 in the 1-methyl-4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP) model in the common marmoset. ML-23 was administered orally in a dose of 3 mg/kg twice daily to half of the animals, while the other half received vehicle only, in a blinded protocol, for 56 days. The effects of the treatment on positive and negative features of MPTP-induced PD were assessed, including horizontal and vertical movement, head checking, general behaviour and Parkinsonian condition, raisin board performance, the ability to remove a foot label, palatable and dry food intake, water consumption, bradykinaesia, and the positive symptoms of tremor, obstinate progression, and agitation. On all parameters, ML-23 produced a significant remission from MPTP-induced Parkinsonism, and this effect did not abate when ML-23 treatment was withdrawn. In a further pilot study involving a crossover of two animals, one animal treated previously with MPTP plus vehicle showed some remission of negative and positive features, although ML-23 treatment was not commenced until 8 weeks post-MPTP. Conversely, a recurrence of Parkinsonian signs was not observed when ML-23 treatment was withdrawn and substituted with oral vehicle. Dopamine transporter was severely impaired in all marmosets treated with ML-23 or vehicle for the duration of the study. These results suggest that a novel mechanism involving melatonin is involved in the primary aetiology of the chronic aspects of PD, and such a mechanism is not related to the antioxidative function of this hormone. From these preliminary results, it is concluded that ML-23 and other melatonin analogues have an important role to play in the treatment and clinical management of Parkinson's disease.