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Melatonin Pretreatment Effect in a Parkinson Disease Experimental Model Induced by the Inhalation of Manganese in Mice

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Maria Rosa Avila-Costa, Mariana Stephania Rodríguez-Alcántara, Ana Luisa Gutierréz-Valdez, José Luis Ordoñez-Librado, Vianey Rodríguez-Lara, Leonardo Reynoso-Erazo, Claudia Dorado-Martínez, Cesar Alfonso Garcia Caballero, Enrique Montiel-Flores, Javier Sanchez-Betancourt, Rocío Tron-Alvarez, Patricia Aley-Medina and Jesús Espinosa-Villanueva

Submitted: 19 June 2022 Reviewed: 21 June 2022 Published: 20 July 2022

DOI: 10.5772/intechopen.106001

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Melatonin Recent Updates Edited by Volkan Gelen

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Melatonin - Recent Updates

Edited by Volkan Gelen, Emin Şengül and Abdulsamed Kükürt

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Abstract

Parkinson disease (PD) is characterized by dopaminergic neuron loss of the substantia nigra compacta (SNc) and motor alterations. Here, we used the experimental model of inhalation of the mixture of manganese chloride (MnCl2) and manganese acetate Mn (OAc)3 for inducing PD. This model causes bilateral and progressive degeneration of the SNc dopaminergic neurons. Melatonin has antioxidant properties and it has been suggested that it contributes to the protective effect in neurodegenerative diseases. Therefore, we aimed to determine whether melatonin pretreatment protects against the Mn-induced alterations. Before Mn inhalation, three groups were trained for motor performance (1. control group, 2. Mn mixture exposed without pretreatment, and 3. melatonin-pretreated/Mn-exposed groups) for motor tests. The motor coordination was evaluated through the single-pellet reaching task and the beam-walking test. After five months, all the animals were sacrificed. Dendritic spines were counted in the striatum medium-sized spiny neurons and the number of TH-immunoreactive neurons in the SNc. Our findings show that the melatonin-pretreated animals had better motor coordination and less dendritic spines and TH immunoreactive neuron loss than the Mn-inhalation-only group. Therefore, melatonin pretreatment has a neuroprotective effect and could be considered an alternative treatment before the more severe PD symptoms appear.

Keywords

  • melatonin pretreatment
  • Parkinson disease
  • manganese inhalation
  • motor performance
  • dendritic spines
  • TH immunohistochemistry

1. Introduction

Parkinson disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s [1, 2, 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, 10, 11, 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:

  • Environmental factors: Various epidemiological studies suggest the relationship between industrialization and the use of agrochemicals as factors in the incidence of PD, such as paraquat and rotenone [9, 13, 14].

  • Genetic factors: Recently, several genes related to susceptibility and risk loci associated with PD have been identified. Research has focused on mutations in the SNCA genes (PARK 1/PARK 4), which is the first dominant autonomic transmission gene identified in PD [12], and the mutation in the GBA gene, which is the most significant genetic risk factor for developing PD [15]. The LRRK2 gene (PARK 8) is the most frequent form, representing 4% of hereditary PD [16]. Three genes are associated with PD and involved in Lewy body formation: PARK 1, PARK 2, and PARK [17].

  • Oxidative stress: The oxygen oxidative properties play an essential role in biological phenomena and can cause damage within cells, mainly through the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), hydroxyl radicals (OH•), and superoxide (O2−) [18]. In PD, it has been reported that oxidative stress is the leading cause of SNc dopaminergic neurons deterioration [19]; neuronal death in the SNc can be caused by: (a) increased DA turnover resulting in excess H2O2 formation; (b) glutathione peroxidase deficiency, which consequently decreases the ability to clean H2O2, and (c) increase in reactive iron, which promotes the OH• formation. In PD, the SNc cells appear to be in a high oxidative stress state, which is assumed by the increase in lipid, protein, 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, 21, 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].

ModelCharacteristicsDisadvantages
6-OHDAaThe first established model. The neuronal degeneration is in 24 h. Enters via dopamine transporter (DAT) and inhibits the mitochondrial respiratory chain.Unilateral injection, acute model.
Unilateral damage, measurable by ipsi or contralateral rotations.
MPTPbHumans and monkeys have the same symptoms/histopathology and response to L-DOPA.
It is transformed to MPP+ in the glia and enters through the DAT		Lower susceptibility in rodents, the administration is acute or subacute.
In rodents, there is recovery.
RotenoneDamage to the SNc and cytoplasmic inclusions, similar to Lewi bodies.
Inhibition of mitochondrial respiratory chain.		Neuronal selectivity, not all animals are affected.

Table 1.

Some PD experimental models.

6-hydroxydopamine.


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


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+) 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 of Mn mixture inhalation, striatal dopamine was reduced by 71%, and SNc showed a significant decrease in the number of TH+ 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 dopamine-producing 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, 52, 53, 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.

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2. Methods

Male CD1 mice (n = 15) with an initial weight of 33 ± 3 g were used; the mice were maintained in 12:12 light/dark cycles, with free access to water and food (except on the days of motor test evaluation). Mice were divided into three groups (see Table 2).

GroupInhalationTreatment
Control n = 5Deionized water—
Mn-exposed (n = 5)MnCl2/Mn(OAc)3—
Melatonin pretreated (n = 5)MnCl2/Mn(OAc)3Melatonin (10 mg/kg 30 days before Mn inhalation)

Table 2.

Group distribution.

2.1 Melatonin pretreatment

The pretreated group was administered, melatonin 10 mg/kg mixed with Nestlé® Cerelac in 0.3 ml water orally in the afternoon (2:30 p.m.); the animals received the dose for 30 days before the MnCl2/Mn(OAc)3 inhalation.

2.2 Motor evaluation

On day 23 of melatonin administration, the animals of the three groups were trained in the beam walking test and the reaching task.

2.2.1 Beam walking test

This test evaluates the mice’s ability to cross a narrow beam (3 mm wide) to reach an enclosed safety platform [64]. A wooden device with two pedestals was used, to which a 1 m long wooden beam with a 15° inclination and 3 mm width was attached (Figure 1), where the animals had to walk from the bottom of the device until they reached their home box. During training, animals were placed at the beam start with no inclination and trained over 4r days (four trials per day). Once the animals crossed the beam in a ~20 s interval, they received two more consecutive trials with the inclined beam. The time it took for the animals to cross the beam (total time) [27] was recorded with a stopwatch; a maximum time of 16 s was expected, and if at the end of this time the mouse did not cross, the activity was terminated. The parameters evaluated by this test are motor impairment in slowness, balance, and muscle stiffness, in addition to the alternate use of the limbs [28].

Figure 1.

The beam walking test dimensions. The home box is located at one end of the beam.

2.2.2 Single pellet reaching task

Besides the beam-walking training, the mice were taught the single pellet reaching task. Each mouse was placed inside an acrylic box 19.5 cm long, 8 cm wide, and 20 cm high, with a 1-cm wide vertical slit in the front of the box. A 0.2 cm thick plastic shelf (8.3 cm long and 3.8 cm wide) through which the animal had to reach a pellet with its preferred forelimb and eat it (Figure 2). A total of 20-milligram food pellets were placed in indentation spaced 1 cm away from the slit and centered on its edges. Before training and testing, the mice were food-deprived for 24 h. Afterward, they received a restricted diet of ~10 g/kg body weight-adjusted to keep their weight constant. Each animal reached 20 pellets each day during the testing period. Every time the animal took the pellet and brought it to its mouth, it was scored as a success, and when it could not hold it or fell off, the reach was scored as a miss [65]; each animal was given 20 opportunities. The qualitative evaluation comprised the “reaching performance” analysis, the postural shift, impairments in limb extension, aim, supination-pronation of the paw during grasping, and the pellet release into the mouth. The following sequence of movements of the forelimbs was considered [27]: 1. The mouse is placed facing the box slit; 2. Raises the forelimb adjusting its posture to project the limb toward the food pellet, and 3. Holds the pellet, returns its forelimb to the mouth, and introduces it.

Figure 2.

The single pellet reaching apparatus. The figure shows the dimensions of the reaching box.

This test helps determine the motor deterioration in terms of slowness in the sequence of movements, tremors, and a decrease in strength and precision [28]. The evaluations of both tests were carried out once a week for 5 months.

The inclusion/exclusion criteria of the mice trained to continue with the experiment were those animals that took less than 17 s to perform the test in the case of the beam test. Only those mice that obtained 16 or more successful executions were used for the single pellet reaching task.

2.3 Manganese inhalation

Mn inhalation was performed as described previously by our group [66]. Ten mice were placed in an acrylic compartment inhaling the mixture of 0.04 M MnCl2 and 0.02 M Mn(OAc)3 (Sigma Aldrich Co., Mexico), 1 h twice a week for 5 months. Five control mice inhaled deionized water for the same time. Inhalations were performed in closed acrylic boxes (35 cm wide × 44 cm long and 20 cm high) connected to an ultra-nebulizer (Ultra Neb DeVilbiss, IL, USA) with 10 l/min continuous flux. The ultra-nebulizer produces drops in a 0.5–5 μ range. A vapor trap was placed on the opposing side with a sodium bicarbonate solution to precipitate the residual Mn. During inhalation, mice were constantly monitored for respiration rate, depth, and regularity. The exposure system’s temperature, oxygen level, and Mn concentration were continuously examined.

After 40 inhalations, when significant motor alterations were observed, mice were anesthetized and sacrificed using a lethal dose of sodium pentobarbital. The animals were perfused via aorta with phosphate buffer saline (0.1 M pH 7.4) containing 2% glutaraldehyde and 2% paraformaldehyde. The brain was removed and placed in a fixative solution for 2 h and processed for tyrosine hydroxylase (TH) immunocytochemistry and Golgi impregnation method.

2.4 Golgi method

Blocks from the striatum were processed for the rapid Golgi method and cut into 90 μm-thick sections [67]. The histological analysis consisted in counting the number of dendritic spines in a 10 μm-long area from five secondary dendrites to 10 medium-sized spiny neurons (MSN) per group on both hemispheres [66].

2.5 TH immunocytochemistry

For immunocytochemistry, coronal sections (50 μm) were obtained on a vibrating microtome through the mesencephalon. Tyrosine hydroxylase (Chemicon International, Inc. CA, USA, 1:1000) immunostaining with the ABC detection method (Vector Lab MI, USA) was performed for light microscope analysis. The analysis was conducted with a computer-assisted system (Image-Pro Plus, Media Cybernetics, L. P. del Mar, CA, USA) connected by a CCD camera to Optiphot 2 microscope (Nikon, Japan). The number of TH+- positive neurons was counted in 1500 μm2 from seven SNc sections of each mouse [66].

2.6 Statistical analysis

Two-way ANOVA was used to analyze behavioral and cellular data. Group differences were considered statistically significant at P < 0.05. When appropriate, posthoc comparisons were made with the Tukey test. All analyses were conducted with GraphPad Prism 9 Software for Mac.

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3. Results

After 5 months of Mn inhalation, neither clinical alterations nor significant weight changes were detected in the exposed animals compared with controls.

The motor impairment induced by inhaling MnCl2/Mn(OAc)3 mixture was bilateral and progressive. Melatonin pretreatment showed significant results regarding protection against motor alterations and neuronal degeneration.

3.1 Motor behavior

When evaluating the motor deficit that appeared in the beam-walking test and the single pellet reaching task after 5 months, we observed that the melatonin-pretreated/Mn-exposed group obtained better coordination performance in both cases while the exposed group progressively decreased their motor skills (Figures 3 and 4). Figure 3 depicts the beam-walking test results. The average time taken to cross it was determined; after 14 inhalations, the mice in the Mn mixture-exposed group showed an increase in the time to perform the test, and the melatonin-pretreated/Mn-exposed and control groups remained constant. We found significant differences between melatonin-pretreated/Mn-exposed and Mn-exposed/no treatment groups since the latter had greater difficulty crossing the beam.

Figure 3.

Mean of the time traveled on the beam ± SE (* Mn-exposed groups vs. control group, P < 0.05; # = melatonin-pretreatment vs. Mn-no treatment exposed group; two-way ANOVA followed by Tukey’s posthoc test).

Figure 4.

Reaching success (number of pellets obtained out of 20; mean ± S.E.) by control, melatonin-pretreated/Mn-exposed, and Mn-exposed/no treatment mice in the single-pellet reaching task. Note that the Mn-exposed/no treatment group is impaired after four inhalations (* P < 0.001 vs. control group; # P < 0.001 between melatonin-pretreated/Mn-exposed and Mn-exposed/no treatment groups. ANOVA with post hoc test).

Regarding the single pellet reaching task, in Figure 4 we can observe that during the 5 months, the control group maintained an average of 16 correct answers, while in the Mn-exposed/no treatment group, after the fourth inhalation, the number of successes decreased and dropped to an average of 5; however, the melatonin-pretreated/Mn-exposed group had significant differences compared to the Mn-exposed/no treatment group; it was clear that the motor coordination on melatonin-pretreated mice was not so affected.

Motor qualitative assessment after Mn mixture inhalation/no treatment resulted in tremor and bradykinesia, postural shifts and limb extension impairments (resulting in evident shortened reaches), paw aim, and supination-pronation during grasping and pellet release into the snout (Figure 5 sequence B). Mn-exposed/no treatment mice exhibited abnormal movements when recollecting the pellet after Mn-exposure. The paw is often fully pronated and moves either, laterally over the pellet, or the mouse slaps at the pellet from above. These mice repeatedly could not accurately close their fingers around the pellet and took it to the slot without lifting the paw. Mice also failed to supinate the paw entirely and placed their snout into the slot to retrieve the pellet with the tongue. When the paw was pulled out through the slot, Mn-exposed mice frequently twisted their bodies and “chased” the pellet with the mouth instead of opening the fingers and placing it into the snout. However, when observing the control and the melatonin-pretreated/Mn-exposed groups, those animals advanced their forelimb through the slot and extended their fingers, supinated their paw to present the food to the mouth, and extended their digits to release the food into the snout (see Figure 5 sequences A, C).

Figure 5.

Representative still frames of the three groups. The control (sequence A) and the melatonin-pretreated/Mn-exposed (sequence C) animals advanced their forelimb through the slot and extended their digits, and also supinated their paw to present the food to the mouth and extended their fingers to release the food into the mouth. In contrast, the Mn mixture-exposed/no treatment mice (sequence B) showed impairments using extreme postural adjustments advancing the limb diagonally through the slot, making many short attempts rather than aligning the limb with the midline of the body. The fingers are concurrently adducted. The paw comes in from the side or slaps laterally, and digits do not contact the food pellet.

3.2 Dendritic spines

When analyzing the number of dendritic spines of the striatal MSN with the Golgi impregnation technique, it was observed (Figures 6 and 7) that the number of dendritic spines significantly decreased in the Mn-exposed/no treatment group and in the melatonin-pretreated/Mn-exposed group compared to control; however, it is also shown that the melatonin-pretreated/Mn-exposed group is statistically different from the Mn-only exposed group, in other words, despite having a significant loss of dendritic spines, they lost fewer spines than the group that did not receive treatment.

Figure 6.

Golgi-stain analysis. Striatal MSN dendritic spines density of the control, melatonin-pretreated/Mn-exposed, and Mn-no treatment groups (* = versus control group, P < 0.05; # = melatonin-pretreatment vs. Mn-no treatment exposed group; two-way ANOVA followed by Tukey’s posthoc test).

Figure 7.

Dendritic spine density. Photomicrographs of representative Golgi-stained MSN of the striatum from control (A, a), melatonin-pretreated/Mn-exposed (B, b), and Mn mixture-exposed/no treatment groups (C, c). Both Mn-exposed groups had a significant decrease in the total number of spines. However, melatonin-pretreated/Mn-exposed group showed less dendritic spine loss and an almost a well-preserved dendritic spines density (magnifications: A, B, C 10×; a, b, c 100×).

3.3 TH+ immunocytochemistry

Regarding the number of SNc dopaminergic neurons (TH+) (Figures 8 and 9), it was observed that the Mn-mixture-exposed/no treatment group presented a significant loss of neurons compared to the melatonin-pretreated/Mn exposed group; both groups had significant differences compared to the control group.

Figure 8.

SNc TH+ cell count. The data are presented as mean ± SEM. It is observed that both Mn-exposed groups showed a drastic decrease in cells. It is important to note that animals receiving melatonin pretreatment before Mn inhalation lose fewer neurons than Mn-exposed/no treatment group. (* = P < 0.05 versus control group; # = P < 0.05 melatonin-pretreated/Mn exposed group vs. Mn-exposed/no treatment group, ANOVA test followed by Tukey’s posthoc test).

Figure 9.

Representative TH-immunostained from coronal sections containing the SNc of A. Control group; B. Melatonin-pretreated/Mn exposed group, and C. Mn-exposed/no treatment group. Note the great cell loss in the Mn-exposed/no treatment group; although there was a neuronal loss in the pretreated group, it was less drastic than in the untreated-Mn exposed group (magnification 10×).

However, it is observed that, although the melatonin-pretreated/Mn exposed group had a significant loss of TH+ neurons, this loss was less than the group that only inhaled Mn, with significant differences between the two groups.

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4. Discussion

PD is a degenerative disorder, determined clinically from movement alterations, and it is reported that the motor symptoms appear relatively late when 80−90% of SNc dopaminergic neurons have been lost [4, 5, 9, 68]. Progressive cell loss leads to increased physical disability, followed by a cognitive decline [1]. Ordoñez-Librado and collaborators [27] indicate that the MnCl2/Mn(OAc)3 inhalation model is an alternative that allows us to carry out evaluations in the different stages of evolution of the disease since it produces progressive and bilateral degeneration of the SNc dopaminergic neurons in exposed mice, as well as motor alterations, for which it is the model most closely related to what happens in humans [28].

4.1 Motor behavior

Our results showed that in both motor tests, the mice pretreated with melatonin did not have such a drastic decrease in motor coordination as observed in the animals exposed to Mn with no treatment. In previous works from our group, Sánchez-Betancourt et al. [28] and Ordoñez-Librado et al. [26] reported that animals exposed to the mixture of Mn compounds present motor alterations as the number of inhalations increases. Motor alterations are closely related to basal ganglia, which have a fundamental role in the initiation and execution of continuous movement; in other words, they participate in the planning of complex movements [69], for example, in the automatic control of movements such as gait primarily through its interaction with cortical motor areas. However, disruption of this system can lead to gait disturbances as in PD [70]; gait disturbances are common symptoms of parkinsonism [71, 72]; PD patients have a shortened stride length with a shuffling step and reduced speed (festinant) [73]. Our results also agreed with Fernagut et al. [74], who observed that MPTP-lesioned mice presented alterations in the extremities’ coordination. In the beam walking test results, the mice exposed to Mn/no treatment did not coordinate their limbs correctly and had great difficulty climbing the beam. This group also manifested akinesia. It is well known that akinesia rapidly becomes intolerable when PD patients are not LD-treated [30]. This symptom was not present in the melatonin-pretreated/Mn exposed animals. According to this, melatonin bioavailability in the brain is observed from the first 30 min after oral administration. It continues to exert its antioxidant properties through its metabolites for extended periods [75, 76], thus facilitating the reduction of abnormal motor behavior.

On the other hand, in the single pellet reaching task, which consists of a series of motor subcomponents [77], since reaching movements are shortened and limb pronation and supination are impaired due to the decrease in dopamine [78] in Mn-exposed mice [27], in humans, we can observe that manual dexterity worsens as PD progresses [79]; Farr and Whishaw [65] mention that rodents reaching movements are very similar to those of humans and, due to this, homology between them is suggested. Whishaw et al. [78] indicated that using this test is helpful in studies of PD subjects to assess movement efficacy and evaluate dopamine denervation. Conversely, regarding the melatonin-pretreated/Mn exposed group, we observed less deterioration even though they inhaled the mixture of Mn compounds. The motor behavior of these animals was very similar to those of the control group. It has been reported that melatonin systemic administration protects SNc dopaminergic neurons against 6-OHDA neurotoxicity in the rat [52, 80]. The effect is accompanied by a significant motor behavior recovery. In this regard, Singh et al. [52] have reported that melatonin pretreated animals and subsequently 6-OHDA-lesioned and treated with melatonin for seven more days showed a diminution in the number of apomorphine-induced rotations, improved posture, and slowness of movement compared to 6-OHDA-lesioned treated with vehicle solution group.

It has also been reported that elevated ROS participate in Mn-neurotoxicity [81, 82, 83, 84]; this has been evidenced by the reduction in brain GSH levels and the loss of SOD activity [83]. Melatonin stimulates antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GRd) [76, 85]. These results demonstrate that melatonin might have beneficial effects on PD treatment.

4.2 Dendritic spines

We found a significant dendritic spine loss in both Mn-exposed groups, being more drastic in the Mn-exposed/no treatment group. Our findings agreed with what was reported previously by our group [26, 28]. We found a decrease in the density of dendritic spines after Mn mixture exposure. Also, it has been reported that striatal MSN of postmortem PD brains and the brains of PD animal models in rodents and primates show severe spine loss [86, 87, 88]. In this regard, Archibald and Tyree [89] suggested that Mn interacts with dopaminergic catechol groups causing dopamine depletion and damage to these neurons; such loss of striatal dopamine is therefore associated with the reduction of MSN dendritic spines as a compensatory mechanism [90] since by reducing the number of dendritic spines, it also decreases the possibility of glutamatergic synaptic contacts [91, 92, 93], avoiding death due to excitotoxicity [92, 93] because cortex excitatory innervation [94].

However, we observed that melatonin pretreatment has a protective effect on the nigrostriatal dopaminergic pathway since, as mentioned, the pretreated animals showed better stability and coordination in the motor tests. We can also observe that in the group pretreated with melatonin, the mice had a significant loss of dendritic spines compared to the exposed group. This agrees with what was reported by Anaya-Martinez et al. [80], where they showed that the animals treated with melatonin that were lesioned with 6-OHDA showed improvement at 28 days after the lesion, as well as the administration of melatonin prevented the loss of MSN dendritic spines, suggesting that melatonin can activate some signaling pathways to increase the defense against ROS. Melatonin stimulates the system of antioxidant enzymes [76], such as SOD, GPx, GRd, and catalase [95], preventing lipid peroxidation in the striatum, and preserving a greater number of dopaminergic neurons in the SNc; this can be explained by the free radical scavenging effect of melatonin and some of its metabolites [76]. Therefore, it is likely that due to these properties, melatonin prevents dopaminergic neurons from degenerating, which is evidenced by the preservation of dendritic spines, since by avoiding the loss of TH+ neurons, dopaminergic transmission to the striatum is maintained, as well as the dendritic spines integrity [96].

4.3 TH+ immunocytochemistry

We observed an intense decrease of TH+ cells after Mn inhalation in both exposed groups. Our results coincide with Damier et al. [97], who found that PD patients displayed a dopaminergic neurons decrease of up to 95% depending on the time of clinical evolution. Likewise, it has been demonstrated that the medial forebrain bundle unilateral 6-OHDA lesion reduces 98% of the SNc ipsilateral number of TH- immunoreactive neurons [98, 99]. Some studies have found that Mn exposure causes a decrease in the number of SNc dopaminergic neurons since the Mn enters them through the dopamine transporter (DAT) [27, 28, 100, 101], and intracellularly Mn accumulates in the mitochondria via the 𝐶𝑎2+ uniport channel [102], inhibiting respiratory chain complex I and thus, promoting the ROS formation [83], leading neurons to oxidative stress and therefore dead. It is known that melatonin increases complex I and IV mitochondrial activity by raising mitochondrial DNA expression [103]. In addition, melatonin’s free radical scavenger property neutralizes radicals such as OH• and O2•− [58]. Our findings showed that melatonin pretreatment partially prevents SNc dopaminergic cell death produced by Mn mixture inhalation. Among the Mn-inhalation consequences are ROS production [81, 82, 83] and the complexes I and IV inhibiting the mitochondria electron transport chain [104]. Inhibition of these complexes has also been described in PD patients SNc. This inhibition triggers energy depletion and increases mitochondria free radical concentration [105].

In the present work, for melatonin pretreated/Mn-exposed group, although the TH+ cell percentage decreases (compared to the control group), the loss was less severe than that observed in the Mn-exposed/no treated group. Melatonin antioxidant effects and its protective characteristic against the uncoupling of the electron transport chain of several toxins in the mitochondria are summarized by Acuña-Castroviejo et al. [106]. These data give rise to further analyses based on this hypothesis. In vivo melatonin pretreatment studies in experimental PD models are scarce. These authors also reported that melatonin prevented lipid peroxidation increase and the decrease in striatal TH+ terminals after MPTP single dose, concluding that melatonin was able to prevent the damage caused by this drug in the striatal dopaminergic axons. In this way, Ortiz et al. [107] found apoptosis of the SNc dopaminergic neurons with an MPTP-unique dose; melatonin prevented cell death. Moreover, melatonin was able to avoid the reduction in striatal TH+ immunoreactivity and the mitochondrial complex I alteration induced by 6-OHDA-lesion [108].

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5. Conclusion

The results obtained in the present work provide evidence that melatonin pretreatment performs as a dopamine regulator protecting partially the striatal MSN dopaminergic denervation by preserving the dendritic spines and preventing the SNc TH+ cell death, causing motor behavior recovery, as melatonin-pretreated mice displayed better motor performance and no parkinsonian symptoms, compared to Mn-exposed/no treatment mice.

It is likely that in the MnCl2/Mn(OAc)3 inhalation PD model, we are recreating an initial stage of the disease since the Mn-exposed mice lost ~70% of the dopaminergic cells, so we believe that it would be helpful to give melatonin to patients who start with the disease, in order to delay the symptoms and dopaminergic cell death and, above all, the start of L-DOPA treatment since it produces very disabling side effects for the patient.

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Acknowledgments

This work was supported by COMECyT FICDTEM-2021-066 and PAPIIT-DGAPA IN216821 grants. We are very grateful to Veronica Rodriguez Mata for her excellent photographic and technical assistance.

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Conflict of interest

Authors have declared that no competing interests exist.

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Written By

Maria Rosa Avila-Costa, Mariana Stephania Rodríguez-Alcántara, Ana Luisa Gutierréz-Valdez, José Luis Ordoñez-Librado, Vianey Rodríguez-Lara, Leonardo Reynoso-Erazo, Claudia Dorado-Martínez, Cesar Alfonso Garcia Caballero, Enrique Montiel-Flores, Javier Sanchez-Betancourt, Rocío Tron-Alvarez, Patricia Aley-Medina and Jesús Espinosa-Villanueva

Submitted: 19 June 2022 Reviewed: 21 June 2022 Published: 20 July 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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