Therapeutic potential of melatonin and its analogs in Parkinson's disease: focus on sleep and neuroprotection

Abstract

Sleep disorders constitute major nonmotor features of Parkinson's disease (PD) that have a substantial effect on patients' quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT(1) and MT(2) receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed.

Keywords: Parkinson’s disease; REM sleep behavior disorder; agomelatine; insomnia; light therapy; melatonin; oxidative stress; ramelteon; tasimelteon.

Figure 1.

Upper part: Schematic representation (modified from Saper et al. [2005]) of key components of the ‘ascending reticular arousal system’ mediating wakefulness (left) and the inhibitory control on these components during slow-wave sleep (SWS) by GABAergic neurons of the ventrolateral preoptic nucleus (VLPO), located at the bottom of the anterior hypothalamus (right). During wakefulness the histaminergic neurons in the ventral tuberomammillary nucleus (TMN) at the bottom of the posterior hypothalamus provide a strong inhibitory influence to the VLPO. The components of the ascending reticular activating system further include the dorsal raphe nuclei (DRN, 5HT neurons), the locus coeruleus (LC, noradrenergic neurons), the pedunculopontine and laterodorsal tegmenti [PPT/LDT, acetylcholine (Ach)-containing neurons], DA-containing neurons in the substantia nigra (SN) and the ventral tegmental area (VTA), and the basal forebrain (BF, cholinergic neurons). Orexin–melanocyte concentrating hormone (MCH) neurons on the lateral hypothalamus (LH) provide stimulatory input to the wakefulness-promoting areas. The LC-α and magnocellular nuclei (MN), participating in REM-induced atonia (see Figure 2) are also depicted. Red labels denote activation, while blue labels denote inhibition. In PD several of these monoaminergic areas promoting wakefulness degenerate (see the text) which is a feasible explanation for the increased somnolence found. Lower part: the SCN, projecting through the hypothalamic ventral subparaventricular zone (sPVZ), promotes wakefulness principally by augmenting the activity of orexinergic/MCH-containing neurons in LH. Melatonin inhibits via MT₁ and MT₂ receptors, SCN activity and promotes sleep. In PD a decrease of MT₁ and MT₂ receptors are found in SN and amygdala [Adi et al. 2010], which could explain the impoverishing of sleep.

Figure 2.

A schematic drawing of nuclei and neural structures involved in the regulation of REM sleep. Pontogeniculooccipital (PGO) activity is typical of REM sleep and can be recorded in animals with the pons isolated from the rest of the brain. The PGO system can be activated by drugs or lesions that lead to a suppression of 5HT secretion in the Raphe nuclei. PGO generators use acetylcholine (Ach) as a transmitter. During REM, the increasing loss of activity in the locus coeruleus leads to disinhibition of locus coeruleus-α which in turn activates the magnocellular nucleus via glutamatergic (Glu) projections. Glycine (Gly)-mediated inhibition of motor neurons in spinal cord is activated and atonia ensues. The Locus coeruleus-α begins to be active, a few minutes before the actual onset of REM. In PD, loss of REM sleep atonia and/or increased locomotor drive have been suggested as likely mechanisms for the clinical expression of REM-associated sleep behavior disorder (RBD) [Boeve et al. 2007b]. LGN: lateral geniculate nucleus. PPT/LDT: pedunculopontine and laterodorsal tegmenti.