**1. Introduction**

Parkinson disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's [1–3]. This disorder usually occurs in middle/advanced ages with gradual progression and prolonged evolution. It is also disabling and incurable. The estimated prevalence of PD is 0.3% in the general population and 3% in those older than 60. James Parkinson described PD in 1817 where he refers to the "shaking palsy" syndrome as "involuntary trembling movements with decreased muscle strength, in areas that are not in activity and even when helped; propensity to lean the trunk forward and transition from walking to running, while the senses and intellect remain unchanged" [4]. The first PD symptoms are evident after 80% dopamine depletion [5].

PD is a neurodegenerative disorder in which neuronal loss and reactive gliosis are observed in dopamine-synthesizing neurons in the substantia nigra compacta (SNc), along with alpha-synuclein inclusions called Lewy bodies [4]. Biochemical studies show a decrease in dopamine concentration in the striatum, which is why it is considered a disease of the nigrostriatal dopaminergic system [1, 4]. This loss is probably caused by the overexpression and misfolding of proteins such as α-synuclein, which generates structural malformations that lead to mitochondrial respiratory chain dysfunction and Lewy body formation [6, 7].

The dopaminergic neuron degeneration begins some years before PD is symptomatic and makes it difficult to establish the cause of the development of the disease [8]. Some genetic and environmental factors have been related to the etiology of the disease [4, 9]. Although it is known that in 10% of cases, the origin is genetic of Mendelian transmission [9–12], the vast majority (90%) are classified as sporadic PD, defined as polygenic and multifactorial [4, 10]. For this reason, different hypotheses have been established about its origin, some of which include:


*Melatonin Pretreatment Effect in a Parkinson Disease Experimental Model Induced… DOI: http://dx.doi.org/10.5772/intechopen.106001*

and DNA oxidation products; in the SNc of parkinsonian patients, it is possible to detect oxidative alterations using different markers such as malondialdehyde, which is up to 10 times higher than its average value [19].

• Mitochondrial dysfunction: Currently, it has been proposed that the mechanism of action of a large number of the toxic agents used as PD models involves the inhibition of mitochondrial complexes I and IV and ROS generation so that the role of the mitochondria during the development of PD is fundamental [20–22]. The first evidence was reported in MPTP-induced Parkinson's that produces complex I deficiency and oxidative damage only in the SNc, conferring toxicity and neuronal death [23].

#### **1.1 Parkinson disease experimental models**

Although PD etiology is still not fully understood, animal models have provided essential information. Based on clinical and experimental discoveries, PD was the first neurodegenerative disease to be modeled and, later, to be treated by neurotransmitter replacement therapy [13]. The typical PD models (**Table 1**) are designed to induce nigrostriatal dopaminergic neuronal loss, commonly with 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, or rotenone [11, 13, 14, 24].

Most of these models induce mitochondrial dysfunction and produce ROS, but none of them completely replicates PD pathology and symptoms observed in humans [11]. MPTP and 6-OHDA are neurotoxins that promptly and selectively destroy dopaminergic neurons (1–3 days), whereas PD pathogenesis gradually develops throughout decades [13, 25].

Recently, we developed a novel PD experimental model in mice [26, 27] and rats [28] by the inhalation of the mixture of two manganese (Mn) compounds, manganese chloride (MnCl2) and manganese acetate (Mn(OAc)3). After 5 months (mice) or 6 months (rats) of Mn mixture inhalation, the animals presented a significant loss of SNc tyrosine hydroxylase-positive (TH<sup>+</sup> ) neurons; the loss of these neurons was 67.58% [27] and 71% [28]. Further on, we confirmed that the alterations were of dopaminergic origin since the motor alterations improved at the level of the controls with Levodopa (L-DOPA) treatment [28, 29]. In short, after 5 or 6 months


*b 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.*

#### **Table 1.**

*Some PD experimental models.*

of Mn mixture inhalation, striatal dopamine was reduced by 71%, and SNc showed a significant decrease in the number of TH<sup>+</sup> neurons. The animals developed akinesia, postural instability, and tremor, providing evidence that MnCl2/Mn(OAc)3 mixture inhalation produces comparable morphological, neurochemical, and behavioral alterations to those observed in PD, suggesting a useful experimental model for the study of this neurodegenerative disease. Additionally, Mn inhalation is progressive and bilateral, making it more reliable.

#### **1.2 Parkinson disease treatments**

Current treatments include pharmacological and surgical approaches, but despite advances, none of these manages to modify the clinical course of the disease [30]. The most common therapeutic approaches are mentioned below:

#### *1.2.1 Cell therapy and neurotrophic factors*

The main objective of this treatment is to replace the altered cells with others that can replace their function. Usually, these neurons implanted in the SNc are dopamineproducing cells, and, ideally, they restore the functional connectivity of the nigrostriatal pathway [31, 32]. However, the most frequent drawbacks of cell therapy are infections or rejections [33].

Neurotrophic factors also regulate the proliferation, survival, migration, and differentiation of all cell types of the nervous system; in addition to regulating the establishment of adequate connections, both in embryonic and adult development phases, including the glial cell-derived neurotrophic factor (GDNF), which is the most appropriate for PD treatment, since it is the most powerful neurotrophic factor described to date [34] exerting a powerful trophic action on dopaminergic neurons [35].

#### *1.2.2 Dopaminergic agonists*

Bromocriptine was the first proposed dopaminergic agonist. It is used for the initial stages of PD because it delays the motor complications induced by long-term L-DOPA administration [36, 37]. Avila-Costa et al. [38] reported that the treatment with bromocriptine in the 6-OHDA-induced PD model attenuated the neurotoxic effect. However, it induces side effects such as nausea, vomiting, confusion, and hallucinations [39, 40]. Apomorphine is another dopaminergic agonist, which can be administered subcutaneously, sublingually, and rectally, but intermittent administration of apomorphine has been reported to cause adverse problems such as skin inflammation, crusting, and nasal obstruction [40, 41].

Another commonly used dopaminergic agonist is pramipexole, which stimulates D3 receptors and, to a lesser extent, D2 and D4 receptors [42], which has been evaluated against placebo, with the demonstration of absolute efficacy in symptom control [43]. Compared to L-DOPA, pramipexole has a lower incidence of dyskinesias and motor fluctuations; however, undesirable effects have been described with this drug, such as alterations in short-term verbal memory, executive functions, and verbal fluency in comparison with patients treated with L-DOPA [44].

The most common PD treatment is with the dopamine precursor L-DOPA. The precursor is used due to the inability of DA to cross the blood−brain barrier [45, 46]; however, L-DOPA loses its efficacy after a few years because

neuronal death continues, and therefore the dosage has to be increased, and in most patients, chronic administration of L-DOPA causes dyskinesias [30, 47, 48], which affect the patients to the degree of incapacitating them to continue with their activities [49].

### *1.2.3 Antioxidants*

The proposal to use therapeutic strategies based on drugs with antioxidant properties is because antioxidant enzymes play a significant role in protecting against oxidative stress, which plays a substantial role in PD neurodegeneration [22, 23, 50], some of these, such as vitamin E, coenzyme Q, and melatonin, have been widely proposed as therapeutic strategies [22, 51–54], but they usually are used in combination with some dopaminergic agonists [55].

### *1.2.4 Melatonin*

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone, synthesized mainly in the pineal gland from the amino acid tryptophan, which is converted to 5-hydroxytryptamine by the enzymes tryptophan hydrolase and 5-hydroxytryptophan decarboxylase [56]. From this moment on, 5-hydroxytryptamine is transformed into N-acetylserotonin by the action of N-acetyl transferase, the rate-limiting enzyme in melatonin synthesis. Finally, N-acetylserotonin is converted into melatonin by O-methylation through hydroxy indole-O-methyltransferase [57]. Melatonin is involved in multiple biological processes; it mainly regulates circadian rhythms due to its effect on the hypothalamus and the suprachiasmatic nucleus during the dark phase of the photoperiod. However, their functions are much broader in terms of the sites of biosynthesis and action [56, 58]. This molecule has been extensively studied since important antioxidant properties have been attributed to it [59, 60]. It has been reported that it is twice more efficient than vitamin E and four times more efficient than glutathione peroxidase and ascorbic acid [61]. Melatonin acts through two G protein-coupled membrane receptors: MT1 and MT2 [62]. Melatonin also shows an affinity for another binding site, MT3 receptors, which represent a quinone enzyme reductase 2, which may participate in antioxidant protection by removing prooxidant quinones [63].

In 2012, Gutiérrez-Valdez et al. [55] compared the effect of the chronic administration of L-DOPA and melatonin in unilaterally 6-OHDA-lesioned rats where they found that melatonin treatment is capable of protecting the alterations produced by the lesion, suggesting that melatonin may be a possible candidate for the treatment of PD.

As mentioned above, PD is the second most prevalent neurodegenerative disease worldwide, and unfortunately, with the standard treatments, unfavorable side effects have been described that can become very frequent and hinder the patient more. One of the most accepted hypotheses regarding PD etiology is that dopaminergic cell damage is caused by oxidative stress. Therapeutic alternatives have been sought to reduce the secondary damage caused by the treatments, and it has been found that melatonin has important antioxidant properties that could prevent cytological damage and not cause adverse effects, improving the patient's quality of life. Thus, this work investigates the possible protective effect (avoiding or delaying neuronal damage) of melatonin pretreatment through the Mn mixture inhalation as a PD experimental model.
