Analysis of Cortical Spread Depression in Rats Induced to Hyperprolactinemia and Treated with Melatonin

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Analysis of Cortical Spread Depression in Rats Induced to Hyperprolactinemia and Treated with Melatonin

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Introduction: Cortical spreading depression (CSD) is an electrophysiological phenomenon used experimentally to analyze the direct modulation of the electrical activity of cortical neurons, and the dissemination of this wave may be associated with several pathological factors. Hyperprolactinemia is a pathological condition related to high plasma levels of prolactin, which, at normal levels, influences brain functions. However, high levels of this hormone can act differently in the cerebral cortex. Melatonin is an influential hormone in the central and peripheral nervous system, playing a cerebrovascular, neuroendocrine, neuroimmune and neuroprotector regulatory role.

Objectives: The objective was to analyze CSD in rats induced to hyperprolactinemia and treated with melatonin.

Results: 64 rats were used, which were divided into two treatment periods (30 and 60 days), subdivided into 4 groups each: Control, Vehicle, Hiper (rats induced to hyperprolactinemia) and Hiper+mel (rats induced to hyperprolactinemia and treated with melatonin). After treatment, the animals were anesthetized for analysis of the CSD propagation velocity, which was calculated based on the distance between the two recording electrodes, and the time spent by the CSD to cover this distance. The recording was performed at the two parietal points of the right cerebral hemisphere, for a continuous period of 4 hours. The ANOVA results of the animals treated for 30 days showed that the control group had an average speed of 3.43 ± 0.11 mm/min and the vehicle 3.10 ± 0.04 mm/min. In the Hyper group, the mean speed was 3.38 ± 0.16 mm/min, while the Hyper+mel group had a speed of 2.21 ± 0.02 mm/min. As for the animals treated for 60 days, the control group obtained a speed of 3.21 ± 0.22 mm/min, while the vehicle 3.06 ± 0.17 mm/min.

The hyper group 4.65 ± 0.16 mm/min and the hyper+mel 2.34 ± 0.19 mm/min. There was a significant increase in the hyper group compared to the others, and a significant decrease in the hyper+mel group compared to the other groups.

Conclusions:It is concluded that hyperprolactinemia has a direct effect on increasing the speed of CSD, on the other hand, the neuroprotective effects of melatonin were sufficient to establish efficiency against hyperprolactinemia.

neurophysiology

prolactin

melatonin

cortex

Cortical spreading depression is an electrophysiological phenomenon that corresponds to a response to electrical, chemical or mechanical stimuli, which produces a reversible and propagable “wave” of reduction (depression) in brain electrical activity. (LEÃO, 1947). The direct modulation of the electrical activity of cortical neurons by the wave that spreads locally can lead to neurological symptoms such as, for example, the aura phase of migraine. (LEÃO, 1947).

Furthermore, several processes similar to the spread of spreading depression in animal cortex occur in various neuropathological conditions in humans. These conditions include head trauma, ischemia, migraine, epilepsy, hemorrhage, and transient global amnesia. (GORJI, 2001).

Melatonin (MEL) is a hormone produced mainly by the pineal gland, this hormone has been extensively studied, since it has numerous actions both in the central nervous system (CNS) and in peripheral organs, playing an important role in a variety of physiological functions, including the regulation of circadian rhythms associated with visual, reproductive, cerebrovascular, neuroendocrine, neuroimmune, and neuroprotective activities. In addition to acting on the cardiovascular system, energy metabolism, body weight and interacting with diabetes (LIMA; CABRAL; CAVALHEIRO, 2006; TENORIO et al., 2015; CIPOLLA-NETO; DO AMARAL, 2018).

The antioxidant capacity of MEL is the best known, studies have shown that this hormone acts in the cleaning of free radicals, stimulating the transcription and activities of antioxidant enzymes, binding to transition metals that inhibit the formation of hydroxyl radial (RODRIGUEZ et al., 2004). In addition, this substance protects lipids, proteins (participating in the ubiquitin-proteasome system) and DNA from oxidative damage, being found abundantly in mitochondria (JOU et al., 2002; RODRIGUEZ et al., 2004; CIPOLLA-NETO; DO AMARAL, 2018). Studies have demonstrated that MEL have the ability to prevent cytochrome C leakage and subsequent apoptosis (SUOFU et al., 2017).

In addition to MEL, prolactin (PRL) is a hormone that has been shown to influence a wide range of other brain functions. There have been few attempts to rationalize why a single hormone might exert a range of distinct and seemingly unrelated neuroendocrine functions (ALEEM, CHOUDHARI, PADWAL, BALASINOR, 2005). It is known that the neuroendocrine control of prolactin secretion is different from any other pituitary hormone. It is predominantly inhibited by the hypothalamus and, in the absence of a feedback regulatory hormone, acts directly on the brain to suppress its own secretion.

In experimental studies, the induction and maintenance of hyperprolactinemia is often performed through the use of drugs, which can act on the hypophysis, increasing plasma levels of prolactin. Domperidone is a medication commonly used for gastrointestinal motility disorders. However, this drug is an important inducer of hyperprolactinemia, since it is associated with the dopaminergic pathway, being primarily an antagonist of D2 receptors (OCHOA-AMAYA et al., 2010; OCHOA-AMAYA et al., 2015; FARMER; MATHEWS; HOVEY, 2019). This drug causes effects in regions of the central nervous system that do not have a blood-brain barrier, such as those that regulate emesis (chemoreceptor activation zone), temperature, etc. (POOVATHINGAL; BHAT; POOVATHINGAL, 2013).

This drug can cause adverse effects on the central nervous system such as: dizziness, palpitations, syncope and/or seizures, headache and irritability, being more frequent in patients who took doses above 30mg/day (JANTARASAENGARAM; SREEWAPA, 2012; KNOPPERT et al., 2013; SEWELL et al., 2017; WAN et al., 2008). Insomnia and anxiety were observed in a patient using 80mg/day (PAPASTERGIOU et al., 2013). Severe insomnia, severe anxiety, severe cognitive problems, rigors, severe psychomotor agitation, panic attacks and even depression have also been observed following the use of high doses of domperidone (SEEMAN, 2015; DOYLE; GROSSMAN, 2018).

It has already been elucidated, the knowledge that the firing of dopamine neurons are under cortical regulation (GARIANO; GROVES, 1988; MURASE et al., 1993). Blockade of this neurotransmitter promotes increased plasma levels of prolactin, leading the individual to the pathological state of hyperprolactinemia. Therefore, the analysis of cortical spreading depression may show possible changes in neuronal activity resulting from this pathological condition.

Bibliographic reports about the analysis of cortical spreading depression in hyperprolactinemic animals are still scarce in the literature. Aiming to bring important information about the causes of this pathological condition in the nervous system, as well as to understand the effects of melatonin used to treat these animals, the objective of this work was to analyze CSD in rats induced to hyperprolactinemia and treated with exogenous melatonin.

2.1 EXPERIMENTAL ANIMALS

This project was submitted to the ethics committee for the use of animals at the Federal University of Pernambuco under number nº. 23076/011943/2018-17. Sixty-four male albino Wistar rats (Rattus norvegicus albinus) from the vivarium of the Academic Center of Vitória, Federal University of Pernambuco, were used. These animals were kept in the experimental vivarium inside individual polypropylene cages, stored in rooms under standardized laboratory conditions, luminosity of 60 light and circadian cycle of 12 hours in light period and 12 hours in dark period, temperature (22°C ±1 °C), relative air humidity (45% ±5%) and exhaust system with air renewal. All animals were fed standard animal feed and water (Labina, Presence®, ad libitum).

The animals were randomly divided into two treatment period groups (30 and 60 days). Each treatment period group was subdivided into 4 categories, consisting of 8 animals each..

2.1.1 FORMATION OF EXPERIMENTAL GROUPS WITH 30 AND 60 DAYS OF TREATMENT:

Vehicle Group - placebo treatment;

Hyper Group – rats induced to hyperprolactinemia (domperidone);

Hyper+MEL Group - rats induced to hyperprolactinemia (domperidone) and treated with melatonin.

2.2 HYPERPROLACTINEMIA INDUCTION

The induction of hyperprolactinemia was obtained with the subcutaneous injection of domperidone (DOMP) at a daily dose of 4mg/kg of body weight, always at 11:00 am. DOMP was dissolved in 1mL of saline solution (0.9% NaCl). The animals in the placebo group received only saline solution in the same route and volume.

2.3 MELATONIN TREATMENT

Treatment with melatonin (Sigma, St. Louis, MO, USA) was performed according to the methodology proposed by Prata Lima, Baracat e Simões (2004). It was administered at a dose of 200μg of melatonin per 100g of the animal's body weight, through subcutaneous injections at the beginning of the night (18:00h). Melatonin was dissolved in a volume of ethanol (0.02 mL) and diluted in saline solution (0.9% NaCl). The animals in the vehicle group received, respectively, 0.9% NaCl solution and 0.02 mL of ethanol.

2.4 RECORD OF CORTICAL SPREADING DEPRESSION (CSD)

After 30 and 60 days, the animals were anesthetized with a solution of 10% urethane and 0.4% chloralose, at a dose of 10 ml/kg of body weight (1g/kg of urethane + 40 mg/kg of chloralose) intraperitoneally. Three holes were drilled on the right side of the skull, one frontal (2-3 mm in diameter) for application of the stimulus that triggered the CSD, and two parietal (3-4 mm in diameter) for placement of the two recording electrodes. The holes were aligned parallel to the midline.

The recording was made in the two parietal points of the right cerebral hemisphere, for a continuous period of 4 hours, in a digitizing system (EMG Systems) that allowed the visualization and storage of the data in a computer. The phenomenon was triggered every 20 minutes by chemical stimulation in the frontal region, using a cotton ball (1-2 mm in diameter) soaked in a 2% potassium chloride (KCl) solution (2 g of KCl dissolved in 100 ml of distilled water; approximately 270 mM), applied for 1 minute over the intact dura mater. During recording, the animal's rectal temperature was kept stable (37oC ± 1oC) using an electric heater. The propagation speed of the DAC was calculated based on the distance between the two recording electrodes, and the time taken by the DAC to travel this distance.

The stimulus carried out caused a wave of depolarization that spread throughout the entire cortex. First, it appeared in the area closest to the application site (electrode 1). Subsequently, the potential under the second electrode was also recorded by electrode 2. By measuring the time between the appearance of the depolarization wave on electrodes 1 and 2, the speed of the process was determined as the propagation speed of the CSD.

The ANOVA results of the animals treated for 30 days (Figure 2) demonstrated a significant increase in the mean speed of CSD in the Hyper group (3.38 ± 0.16 mm/min), when compared to the Vehicle group (3.10 ± 0.04 mm/min) and Hyper+mel (2.21 ± 0.02 mm/min). The latter had the lowest average speed, which is a significant difference when compared to the other groups in this treatment period. No significant difference was observed between the Hyper and Control groups (3.43 ± 0.11 mm/min) (Figure 2).

Based on the analysis of the results of the animals treated for 60 days (Figure 2), it was observed that the Hyper group (4.65 ± 0.16 mm/min) had a higher mean CSD speed when compared to the other groups in the same period of treatment. This result was significant when compared to the Control (3.21 ± 0.22 mm/min), Vehicle (3.06 ± 0.17 mm/min) groups and especially the Hyper+mel group (2.34 ± 0. 19mm/min). The latter was the group that significantly presented the lowest average speed of CSD when compared to the other groups in the treatment period. No significant differences were observed between the mean CSD speed of the control and vehicle groups (Figure 2).

In this study, it was demonstrated for the first time that hyperprolactinemia induced by the drug domperidone, in adult male rats, treated for 30 and 60 days, clearly accelerates the propagation of the CSD phenomenon, and the co-administration of melatonin, caused a reverse effect, decreasing this propagation speed.

The effects of domperidone result from suppression of acetylcholine release from myenteric motor neurons, antagonizing the inhibitory effect of dopamine on these neurons. And as it is involved in the dopaminergic pathway, it is an important inducer of hyperprolactinemia (FARMER; MATHEWS; HOVEY, 2019; OCHOA-AMAYA et al., 2010, 2015a; POOVATHINGAL; BHAT; POOVATHINGAL, 2013).

However, this drug does not easily cross the blood-brain barrier, however, it has been shown to cause effects in the central nervous system that also show the blood-brain barrier. Symptoms such as: dizziness, palpitations, syncope and/or convulsions in a patient with heart disease (JANTARASAENGARAM; SREEWAPA, 2012; KNOPPERT et al., 2013; SEWELL et al., 2017; WAN et al., 2008), insomnia and anxiety (PAPASTERGIOU et al., 2013), severe cognitive problems and even depression (SEEMAN, 2015), rigors, severe psychomotor agitation and panic attacks (DOYLE; GROSSMAN, 2018).

Second Montalvo et al. (2018) the increase in prolactin levels is directly related to the decrease in cognitive scores. This same study also showed that processing speed, working memory, visual learning and reasoning performance improved after a decrease in prolactin levels in patients with prolactinomas after treatment with cabergoline.

Reports about domperidone-induced hyperprolactinemia and its effects on the propagation of CSD are still unknown. However, the results observed in the present study suggest that the most plausible hypothesis of the relationship between hyperprolactinemia and the increase in the speed of CSD is the oxidative stress caused by the pathological condition. Second Sobrinho (1993), in mammals, prolactin is associated with an immune response, a decrease in body temperature, and an increase in the secretion of glucocorticoids, such as corticosterone. Glucocorticoids are known to be related to stress responses. And evidence suggests that treatment with glucocorticoids increases the production of reactive oxygen species (ROS) in cultured hippocampus and cerebral cortex (MCINTOSH; SAPOLSKY, 1996), and decreases the activity of brain antioxidant enzymes (MCINTOSH; HONG; SAPOLSKY, 1998). Factor that justifies the increase in CSD speed due to a possible pro-oxidant action of hyperprolactinemia, corroborating and justifying the observed results.

It is worth mentioning that in this study, it was observed that the hyper treated animals for 60 days (4.65 ± 0.16 mm/min), presented a higher speed of CSD propagation when compared to the same group treated for 30 days (3.38 ± 0.16 mm/min). Second Guedes, Amorim and Teodósio (1996) aging tends to hinder the speed of propagation of the phenomenon. In the case of this study, the opposite was observed. This result justifies even more that the increase was caused not by the age difference, but by the effects that the hyperprolactinemia induced by domperidone caused in the cerebral cortex of the animals.

In view of the result observed in the analysis of CSD in hyperprolactinemic animals treated with melatonin, it was observed what was expected, a reduction in the speed of propagation of CSD, since melatonin has antioxidant properties, among which, it causes a protective effect both in the nervous system and in in various other body systems (CARLONI et al., 2016; MARKUS et al., 2003; SLOMINSKI AT, KLESZCZYŃSKI K, SEMAK I, JANJETOVIC Z, ZMIJEWSKI MA, KIM TK, SLOMINSKI RM, REITER RJ, 2013; SLOMINSKI et al., 2013).

Melatonin has a direct relationship with serotonin, since both come from tryptophan (YU et al., 2017). Studies carried out by Guedes et al., (2017) showed the importance of serotonin in the propagation of the CSD phenomenon, considering that this neuromodulator reduced the average speed of this phenomenon. Pharmacological studies formed the first evidence that serotonergic activity can alter the propagation of CSD. Treatments using ferfluramine (CABRAL-FILHO; TRINDADE-FILHO; GUEDES, 1995), fluoxetine (GUEDES et al., 2002) caused a decrease in the speed of CSD. Other studies in adult and juvenile rats with antidepressants (Citalopram) also demonstrated a slower spread of CSD, suggesting that the effect is not significantly age-related. (GUEDES et al., 2002, 2017). In contrast, increased spread of CSD has been observed in several studies with animals fed a low-tryptophan diet during nursing and adulthood (FERNSTROM, 2013; SANCHEZ et al., 2015).

Given the proximity between melatonin and serotonin, and the performance of the common precursor (tryptophan) of these two neuromodulators, the evidence observed in this study leads to the conclusion that the action of exogenous melatonin tends to cause the effects observed in studies of serotonergic activity and tryptophan. This suggestion becomes even more valid given the enormous prophylactic activity of melatonin already described in the literature. Because, its very well-known antioxidant property, it acts in the cleaning of free radicals, stimulating the transcription and activities of antioxidant enzymes, binding to transition metals that inhibit the formation of hydroxyl radial (RODRIGUEZ et al., 2004). In addition, this substance protects lipids, proteins (participating in the ubiquitin-proteasome system) and DNA from oxidative damage, also protecting mitochondrial DNA against mutations and deletions. (JOU et al., 2002; RODRIGUEZ et al., 2004; CIPOLLA-NETO; DO AMARAL, 2018).

Studies have shown that melatonin is secreted in mouse brain mitochondria and acts through a mitochondrial outer membrane melatonin receptor 1 (MT1), with the ability to prevent cytochrome C leakage and subsequent apoptosis (SUOFU et al., 2017).

It is evident that the performance of domperidone and melatonin in the experimental conditions carried out in the cerebral cortex, presented themselves in an antagonistic way, however, a more in-depth investigation about the central mechanisms and the concomitant interaction of these substances in the nervous system is necessary.

In conclusion, the induction of hyperprolactinemia resulting from the treatment with domperidone caused a significant increase in the speed of propagation of CSD, a characteristic evidenced by the ability of the pathological condition to increase the synthesis of corticosteroids, which promotes a decrease in antioxidant activity in the nervous system. On the other hand, treatment with exogenous melatonin proved to be efficient in reversing, significantly decreasing the speed of CSD propagation, proven by its antioxidant and neuroprotective properties. However, there is still a need for a deeper understanding of the mechanisms of action of domperidone and consequent hyperprolactinemia, as well as of melatonin in electrical conduction in the cerebral cortex.

6.1 ETHICS COMMITTEE APPROVAL

This work registered under nº 23076/011943/2018-17 was approved by the ethics committee on animal use (CEUA) of the Federal University of Pernambuco (UFPE).

6.2 CONSENT FOR PUBLICATION

Not applicable.

6.3 AVAILABILITY OF DATA AND MATERIALS

Not applicable.

6.4 DECLARATION OF INTEREST

The authors report no declarations of interest.

6.5 FUNDING

This work was supported by the Anatomy Laboratory of the Academic Center of Vitória, Vitória de Santo Antão, Pernambuco, Brazil, and the Federal University of Pernambuco, Recife, Pernambuco, Brazil.

6.6 AUTHOR CONTRIBUTIONS

Performed the induction of hyperprolactinemia: Magalhães CP, Silva LH; Performed the animals' treatment with melatonin: Gomes JAS, Silva JV; Performed record of cortical spreading depression: Oliveira MLF; Noya AGAFC; Silva EFA; Performed the computer analysis: Tenorio BM, Tenorio FCA; Wrote this manuscript: Gomes JAS, Silva EFA.

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No competing interests reported.

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Analysis of Cortical Spread Depression in Rats Induced to Hyperprolactinemia and Treated with Melatonin

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1. INTRODUCTION

2. MATERIALS AND METHODS

3. RESULTS

4. DISCUSSION

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