Dysregulation of the circadian rhythm and sleep-wake may occur in various diseases, such as Parkinson’s disease (PD) [1]. As increasingly recognized, the functional incoordination of multiple parts of both central and peripheral systems and diversified neurotransmitters is affected for sleep disorders as non-motor symptoms in patients with PD [2]. PD is an extra-pyramidal disease with a slightly higher incidence in men than in women, affecting more than 1 in every 100 people aged over 60 [3]. The pathological hallmark of PD is dopaminergic neuronal death, which may affect 60% of total dopaminergic neurons [4]. A fundamental abnormality in PD is the accumulation of α-synuclein in the forms of Lewy bodies, which mediates the cell death [5]. The progressive loss of dopamine neurons makes the PD patients suffer from a large number of motor and non-motor features which can affect their health to a variable degree [4]. Motor symptoms of PD are characterized by quiescent tremor, slow movement, increased muscle tension and postural instability [4]. Additionally, non-motor symptoms are an integral component of PD, including sleep disorders, mood disturbances, cognitive impairments and apathy as the common ones [6].

Sleep disorders are among the most common non-motor manifestations in PD and have a significantly negative impact on quality of life [7]. There are different types of sleep disorders in PD, including rapid eye movement (REM), sleep behavior disorder (RBD), insomnia, sleep related breathing disorders (SBDs), excessive daytime sleepiness (EDS), restless legs syndrome (RLS) and periodic limb movements (PLM) among others [8].

Management of these sleep disorders often require complex therapeutic regimens, involving both pharmacological and non-pharmacological interventions [9]. For both health and wellbeing, comprehensive treatment of PD is quite essential; therefore that a great deal of clinical trials have been carried out to verify the efficacy of these interventions [10]. Nonetheless, these therapy methods often have a series of side effects, including excessive daytime sleeping, cognitive impairment, poor tolerance and so on; moreover, long-term use may also lead to drug dependence [11]. As one of the pharmacological interventions, melatonin (namely N-acetyl-5-methoxytryptamine), is well known for its natural synthesis within the pineal gland and reportedly used to treat sleep disorders, especially for RBD and insomnia in PD [12].

2. PD and Melatonin

Melatonin is a neurohormone with chronobiological effects that control circadian rhythms [13]. It was first described in 1958 by a dermatologist named Aaron Lerner [14], secreted mainly from the pineal gland situated at the center of the brain. It has a wide range of regulatory and protective effects, such as synchronizing circadian rhythm, protecting against oxidative stress, regulating energy metabolism, modulating the immune system, and postponing the ageing process [15]. The content of melatonin is quite little, as estimated between 10–80 mg per night in the body, the bottom-most values for a hormone secretion [13]. Its biosynthesis gradually declines with age, reduced by 10%~15% for every 10 years on average, especially after 35 [13]. Melatonin is released into the bloodstream exclusively at night following the circadian rhythm [16]. Alteration in circadian melatonin production has been reported in neurodegenerative diseases [17]. The secretion of melatonin is a key signal for sleep–wake cycle organization and has relevant neuroprotective activity in a number of experimental models [18]. Melatonin facilitates achieving better sleep for these patients by reducing the sleep-onset latency or by regulating sleep–wake times to coincide with the natural circulatory cycle, as well as reducing sleep episodes without muscle atonia [19]. In recent years, studies on its biological functions have shown that melatonin has many physiological functions, such as promoting sleep, regulating jet lag, anti-aging, regulating immunity and anti-tumor [20]. Furthermore, melatonin has preventive and therapeutic effects for many neurological disorders, including PD, Alzheimer’s disease, multiple sclerosis, etc. [21]. Melatonin exerts its function by binding to two main receptors, MT1 and MT2 [22]. Adi, N et al. determined the MT1 and MT2 receptors’ expressions in whole brain post-mortem tissue from the amygdala and substantia nigra (SN) of well-characterized PD and non-neurologic control subjects by the real-time polymerase chain reaction (PCR) [23]. They found that PD cases showed a statistically significant decrease in the MT1 receptor expression in both SN and the amygdala versus normal controls. The expression of the MT2 receptor was also decreased in both SN and the amygdala versus normal controls. The results demonstrated a down-regulation of melatonin receptors in regions affected by PD, indicating the relationship between melatonin and PD to some extent. Tamtaji, O.R et al. used the rotenone-induced PD male Wistar rat model to understand circadian dysfunction in PD, and then separated them into two groups: one is rotenone and melatonin; the other is a rotenone and melatonin vehicle [12]. The results showed that melatonin could stop the rotenone-induced phase alteration in rat Cry1 (rCry1) daily rhythm. Preclinical and clinical studies have shown that melatonin supplementation is an appropriate therapy for PD, especially for the sleep disorders [19]. Despite the multifactorial etiology, the pronounced decline in nocturnal melatonin synthesis is common in PD patients [21]. They exhibit not only reduced amounts of secreted melatonin, but also a higher degree of irregularities in melatonin production. Therefore, the melatonin rhythm has lost not only signal strength in clock resetting, but also its reliability as an internal synchronizing time cue [21]. Loss or damage of the neurons in the SN and other parts of the circadian timing system may account for the circadian rhythm abnormalities and sleep disorder seen in PD patients [24]. To inspect the potential of melatonin therapy in older patients with sleep disorders, Haimov, I and P. Lavie set a run-in period (where no treatment was administered) and four experimental periods [25]. They found that 1 week’s treatment of 2 mg of fast-release melatonin was as effective as 2 months’ treatment with 1 mg of sustained-release melatonin, on sleep initiation. The results convincingly demonstrated that melatonin could increase sleep efficiency in elderly insomniacs by decreasing nighttime activity. In addition to melatonin, melatonin analogues are also promising therapeutical approaches for PD [26]. Recently developed pharmacological agents, such as ramelteon, tasimelteon and agomelatine are melatonin receptor agonists which, compared with melatonin itself, have a longer half-life time and greater affinity for the melatonin receptors [26]. Consequently, they are thought to hold promise for treating a variety of sleep disorders. Ramelteon is a novel melatonin receptor agonist that has been shown to act on both MT1 and MT2 receptors, and has a longer duration of action than melatonin itself [27]. As the first commercially available melatonin receptor agonist in 2005, ramelteon could mimic the physiological effects of melatonin [28]. The participation of receptors MT1 and MT2 can affect the maintenance of the normal sleep–wake cycle [29]. It can be used for the treatment of patients with difficulty to fall asleep or with chronic and transient insomniacs, through reducing the sleep latency and improving the daytime sleep [29]. Tasimelteon, another MT1/MT2 agonist currently under evaluation, has also been shown effective for sleep re-synchronization [30]. Some authors, however, held a view that melatonin might play a deleterious role in impaired neurons with the process of dopamine degeneration, so that its antagonism might enhance recovery from PD conditions [31]. Dr. Willis proposed that ML-23 (N-[3,5-dinitrophenyl]-5-methoxytryptamine) and S-20928 (N-[2-(1-naphthyl) ethyl] cyclobutyl carboxamide) were used to antagonize the melatonin receptors and studied their pharmacological actions [31]. The mechanism involved in the repair effects observed with ML-23 could be mediated by ML-23’s ability to antagonize melatonin and to counteract the effect of melatonin on the cytoskeleton and impaired axoplasmic transport in dying neurons. Like the putative melatonin receptor antagonist ML-23, the antagonist S-20928 also seemed to possess anti-PD properties that enhanced the recovery in a chronic model of PD [31]. Moreover, it was thought that the combination of indole- and hydrazone-type compounds might provide new effective drugs against free radicals and give a new perspective to melatonin analogues [15].