USO DA MELATONINA NA PREVENÇÃO E
TRATAMENTO DA PANCREATITE

 

 

 

Int J Inflam. 2012; 2012: 173675.Published online 2012 April 23. doi:  10.1155/2012/173675 PMCID: PMC3347751

Protective Effect of Melatonin on Acute Pancreatitis

Jolanta Jaworek, * Joanna Szklarczyk, Andrzej K. Jaworek, Katarzyna Nawrot-Porąbka, Anna Leja-Szpak, Joanna Bonior, and Michalina Kot

 

A SEGUIR ALGUMAS PARTES DO TEXTO ORIGINAL (COM OS HIGHLIGHTS DESTACADOS ANTES, PARA FACILITAR A LEITURA) - referências no final:

 

 

MELATONINA ENDÓGENA

• Produzida pela mucosa do digestório, provavelmente também pelo pâncreas, além da pineal.

• No digestório produzida pós ingestão de alimento.

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Although melatonin has been recognized as the pineal hormone, subsequent studies have shown that melatonin could be synthesized in many tissues and that the gastrointestinal tract appears to be the main source of this substance [5–7]. Two main enzymes involved in the control of melatonin production, arylalkylamino-N-acetyl-serotonin-transferase (AA-NAT) and hydroxyindolo-O-methyl-transferase (HIOMT), have been detected in the gastrointestinal system [8, 9]. In addition, the estimated level of melatonin in the gastrointestinal tract was 400 times higher than that in the pineal gland [10]. In the gut, this indoleamine is produced mainly in the enteroendocrine (EE) cells; however, high concentration of melatonin has also been found in the bile [11–14]. Melatonin is released from the gastrointestinal mucosa in response to ingested food and this process is independent from the light/dark cycle and from the pineal gland [7, 15].

 

• Produção pelo pâncreas:

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Previous studies have suggested that melatonin could be produced in the pancreas; the mRNA signal for AA-NAT, an enzyme involved in the synthesis of melatonin from L-tryptophan, has been detected in the isolated rat pancreatic acinar cells [16], and gene expression for HIOMT, another enzyme controlling the above reaction has been, discovered in the human pancreas [17]. Recent studies revealed that melatonin and its receptors are present in the pancreatic gland [18]. Even though melatonin production in the pancreas is independent from the pineal gland, the content of melatonin in the pancreatic tissue undergoes rhythmic diurnal/nocturnal fluctuations [19].

 

• Secretagogo pancreático

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Melatonin has also been recognized as a potent pancreatic secretagogue. Administration of melatonin or its amino acid precursor, L-tryptophan, to the animals resulted in the spectacular enhancement of pancreatic enzyme secretion accompanied by a significant increase of CCK plasma level [25]. Stimulatory effects of melatonin or L-tryptophan were much stronger following intraduodenal than intraperitoneal administration of investigated substances. The results of experimental studies suggest that melatonin activates cholinergic enteropancreatic reflex to increase pancreatic enzyme secretion [26]. It is very likely that melatonin produced in the gut lumen in response to food ingestion is implicated in the physiological regulation of pancreatic exocrine function.

 

 

EFEITOS ANTI-INFLAMATÓRIOS DA MELATONINA

 

 

• potente efeito anti-inflamatório, através de propriedades anti-oxidantes e imunomoduladoras

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Melatonin is best known as the scavenger of radical oxygen (ROS) and nitrogen (RNS) species and activator of antioxidant enzymes [29, 42–47]. ROS and RNS are products of mitochondrial metabolism, and, under normal conditions, they are immediately neutralized by natural nonenzymatic scavengers and antioxidant enzymes. Melatonin together with reduced glutathione, vitamins C and E, uric acid, selenium, and creatinine belong to nonenzymatic scavengers [44, 48, 49]. Antioxidant enzymes such as; superoxide dismutase (SOD), catalase (CAT), glutathione peroxydase (GPx), or glutathione reductase (GR) are another line of defense against the noxious effect of ROS and RNS [17, 29, 43–45]. 

 

• Efeito anti-inflamatório na pancreatite

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Oxidative stress in acute pancreatitis resulted in excessive production of ROS and RNS leading to the impaired ability of tissue to detoxify above intermediates. ROS and RNS are accumulated in the tissue leading to its damage [50–52]. The harmful effects of ROS and RNS in acute pancreatitis have been confirmed in previous studies [53, 54]. Melatonin, which is a highly lipophilic substance, penetrates inside the cells to maintain antioxidant enzymes activities, to keep the mitochondria from oxidative injury, and to prevent lipid membranes from peroxidation [55].

Recently melatonin has been shown to trigger signal transduction pathways leading to the activation of antioxidant enzymes and to the reduction of inflammatory mediators in the pancreas [56]. In acute pancreatitis, melatonin was demonstrated to inhibit nuclear binding of NF-κB, the transcription factor, which controls the expression of genes involved in immunity and inflammation, production of prostaglandins, cytokines, cell adhesion molecules, nitric oxide (NO), and inhibitors of apoptosis [57,58]. Melatonin has been demonstrated to reduce gene expression and synthesis of proinflammatory cytokine; tumor necrosis factor α (TNFα), proinflammatory interleukins; IL-1β, IL-6, IL-8, and prostaglandins [56, 59, 60]. In addition, melatonin was also reported to modulate the processes of apoptosis and necrosis, to stimulate the production of vascular endothelial growth factor (VEGF), and to activate the process of angiogenesis [32, 61, 62]. All of the above effects could be related to the inhibition of NF-κB by melatonin [56].

 

 

EFEITOS BENÉFICOS DA MELATONINA NO TRATAMENTO E PREVENÇÃO DA PANCREATITE

 

 

• Atenua o desenvolvimento da pancreatite aguda e protege o tecido pancreático contra os danos da inflamação aguda

Experimental studies have shown that application of melatonin significantly attenuated the development of acute pancreatitis and protected pancreatic tissue against the damage caused by acute inflammation [16, 17, 59–61, 68–75]. In the rats pretreated with melatonin prior to the induction of acute pancreatitis, the morphological signs of inflammation such as edema, leukocyte infiltration, and cell vacuolization were dramatically reduced [16, 60, 70–73]. Also other parameters of acute pancreatitis severity such as blood levels of amylase or lipase were significantly diminished in the animals pretreated with melatonin, as compared to the rats with acute pancreatitis alone [16, 17, 59, 68,70–75]. The beneficial effect of this indoleamine on acute pancreatitis was also manifested by the dose-dependent reduction of proinflammatory cytokine TNFα blood level, accompanied by a marked rise of anti-inflammatory interleukin 10 (IL-10) in the animals subjected to acute pancreatitis and pretreated with melatonin [16, 69, 70] (Figure 1).

 

• Reduz a formação de ROS no tecido pancreático

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Melatonin is able to diminish the generation of ROS in the pancreatic tissue, as was demonstrated by the reduced amount of lipid peroxidation products: MDA + 4HNE in the pancreas of animals with acute pancreatitis pretreated with this indoleamine [16, 17, 68, 70–73, 75]. In addition, the application of the mentioned protective substance resulted in the significant and dose-dependent increase of antioxidant enzyme (SOD) activity in the pancreatic tissue taken from the rats with acute pancreatitis [17, 61,72–74] (Figure 2).

 

• Ação protetora em modelos animais de pancreatite (inclusive por ligadura dos ductos pancreáticos)

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The protective action of melatonin on acute pancreatitis was confirmed in several studies, using different models of experimental pancreatitis. Melatonin attenuated acute pancreatitis severity and diminished harmful effects of acute inflammation induced by L-arginine [72], ischemia/reperfusion, or caerulein overstimulation [16, 59, 61, 68, 70, 74, 76]. Melatonin protected the pancreas against acute pancreatitis caused by taurocholic acid [60] or by obstruction of pancreatic duct [75]. However, in the model of necrotizing pancreatitis induced by glycodeoxycholic acid melatonin appears less effective, because increased serum amylase level and high mortality rate of experimental animals was unaffected by this indoleamine [77].

Studies on melatonin revealed that not only melatonin but also its amino acid precursor, L-tryptophan, is able to attenuate pancreatic tissue damage caused by acute inflammation and to reduce lipid peroxidation in two models of acute pancreatitis: caerulein-induced and ischemia/reperfusion pancreatitis [16]. It is likely that the protective effect of L-tryptophan on acute pancreatitis was dependent on the conversion of this amino acid into melatonin, because intraduodenal administration of L-tryptophan resulted in the significant and dose-dependent increase of plasma melatonin level (Figure 3). These results lead to the conclusion that endogenous melatonin, which is produced from L-tryptophan effectively protects the pancreas from the damage caused by acute inflammation [16]

 

• Regeneração pancreática

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It is worth remembering that this substance was also found to promote the regeneration of pancreatic tissue following the damage caused by acute pancreatitis. Treatment with melatonin improves the rate of DNA synthesis, as well as pancreatic enzyme content in the rats with arginine-induced pancreatitis [76].

 

• Em animais em que a pineal foi retirada, ou que receberam antagonistas de receptors de melatonina, a pancreatite induzida se revelou muito mais grave

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This observation indicates that endogenous melatonin could be one of the physiological protectors of the pancreas. This notion is supported by the study showing that blockade of the melatonin receptor aggravated pancreatic damage caused by caerulein overstimulation. In the rats subjected to acute pancreatitis and pretreated with melatonin MT1/2 receptor antagonist, luzindole, the histological and biochemical manifestations of pancreatitis were significantly higher than in the group with acute pancreatitis alone [70].

A recent study on rats with removed pineal glands give further evidence for this hypothesis. As we have observed, acute pancreatitis was much more severe in pinealectomized animals, than in those with intact pineal glands. This was manifested by significant decrease of an antioxidant enzyme GPx in the pancreas of pinealectomized rats subjected to acute pancreatitis, as compared to the animals with intact pineal glands (Figure 4). Application of melatonin to the rats deprived of the pineal gland and subjected to acute pancreatitis significantly reduced pancreatic tissue lesions and attenuated the course of acute inflammation [75].

 

• Formas brandas de pancreatite em humanos se correlaciona com níveis elevados de melatonina, enquanto indivíduos com formas severas apresentam níveis mais baixos

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Recent observation from humans with acute pancreatitis supported and reinforced this hypothesis. It was observed that melatonin serum level, measured in the first 24 hours after the onset of acute pancreatitis, negatively correlated with the severity of this illness. In the patients with mild pancreatitis, serum level of melatonin was markedly higher than in these with severe form of this disease [78]. This study presents additional evidence that melatonin could be one of the natural pancreatic protectors and that high blood level of this indoleamine has a protective value against acute pancreatic inflammation.

 

 

MODOS DE AÇÃO PROPOSTOS:

 

 Antioxidative Mechanism
 

Melatonin as an effective scavenger of free radicals is able to neutralize above toxic products directly [16,17, 68, 70–73]. In addition, this indoleamine could activate the antioxidant enzymes such as SOD, CAT, GPx, and GSH and protects them from inactivation by reactive intermediates. Thus, melatonin could improve the oxidative status of the pancreatic tissue indirectly [16, 61, 70, 71, 73–75].

 

Modulation of the Immune System
 

Melatonin is able to affect the immune system and to strengthen the immune defense. This substance has been demonstrated to inhibit neutrophile infiltration [16, 70–74], to decrease myeloperoxidase (MPO) activity [56], and to diminish the prostaglandin generation [59] in the inflamed pancreas. Recently, melatonin has been shown to reduce mRNA expression of many proinflammatory cytokines such as IL-1 β, IL-6, IL-8, and TNFα in the pancreatic tissue subjected to acute inflammation [56]. The inhibitory effect of melatonin on proinflammatory cytokine production has been confirmed by marked reduction of the blood level of TNFα in the rats with acute pancreatitis pretreated with this indoleamine [16, 69, 70]. On the contrary; anti-inflammatory IL-10 was increased in these animals [16]. Melatonin enhanced the expression of nuclear factor erythroid 2-related factor (Nrf2) and diminished the nuclear binding of NF-κB, and it is likely that above effects could be involved in the curtailing of acute pancreatitis by melatonin [56].

 

Improvement of Pancreatic Blood Flow
 

Melatonin has been demonstrated to increase the blood flow and to remove the toxic substances from pancreatic tissue [16, 69, 70, 76, 79].
 

Effect on Apoptosis

 

Melatonin is able to reduce processes of apoptosis and necrosis in the pancreas [61]. However in the tumor cells, this substance promotes apoptosis maintaining the viability of normal pancreatic units [80].

 

Stimulation of Heat Shock Protein (HSP)
 

HSPs are known to protect the cell compartment against the damage. Production of these proteins is augmented in response to high temperature, oxidative stress, or inflammation [81]. Melatonin has been reported to increase mRNA signal for HSP60 in pancreatic acinar cell line AR42J [82]. It could be expected that melatonin works to save acinar cells from acute damage through the stimulation of HSP production. As was observed, melatonin prevented these cells from mitochondrial and nuclear damage caused by acute pancreatitis, reduced the dilatation of endoplasmatic reticulum and Golgi apparatus, and diminish formation of autophagosomes [72].

3.6. Promotion of Pancreatic Regeneration

It should be emphasized that administration of melatonin following the induction of acute pancreatitis not only reduced the severity of inflammation, but also promotes the spontaneous regeneration process of the pancreatic tissue. This was manifested by an increased rate of DNA and protein synthesis and supported by histological examination [77].

The results of previous experimental studies and clinical test indicate that melatonin should be employed in clinical trials as a supportive agent for the treatment of patients with acute pancreatitis. Melatonin has been used previously as part of composed therapy in patients with tumors and neurological diseases [82–84]. In patients with cancer melatonin significantly decreased thrombocytopenia, asthenia, neuro- and cardiotoxicity induced by chemotherapeutic treatment [82]. It is important to emphasize that the use of this indoleamine is safe, it has been reported that melatonin given at doses of 20

 

 

mg/day for several weeks in patients with dyskinesia or with sleep disturbance did not produce any side effects [84,85]. It was suggested that melatonin at doses as high as 50–100

 

 

mg/day could be applied for treatment of insomnia and depression [85]. Regarding the beneficial effects and safety of melatonin use, this substance could also be introduced as a component of early jejunal feeding in patients with acute pancreatitis.

 

 

 

 

 

 

Outro paper:

 

Eur J Pharmacol. 2010 Feb 25;628(1-3):282-9. doi: 10.1016/j.ejphar.2009.11.058. Epub 2009 Dec 1.
Melatonin treatment is beneficial in pancreatic repair process after experimental acute pancreatitis.

Sidhu S, Pandhi P, Malhotra S, Vaiphei K, Khanduja KL.

Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. sidhushabir@rediffmail.com

Abstract

Current treatment options for acute pancreatitis are supportive and symptomatic. Due to lack of agents targeting the underlying pathophysiology a large amount of experimental work is going on to identify novel therapeutic agents. The present study was carried out to explore if melatonin can modulate the spontaneous regeneration process of the pancreas after experimentally induced acute pancreatitis. Rats were given two i.p. injections of l-arginine in a dose of 200mg/100g at an interval of 1h for induction of pancreatitis. After this rats were randomly divided into three groups i.e. saline, CCK-8 and melatonin. Drug treatment was started 2h after the last l-arginine injection and continued till the day of sacrifice. An additional only saline treated control group was included for comparison. Animals in each group were sacrificed at 24h, days 3, 14 and 28 after pancreatitis induction for determination of biochemical parameters (serum amylase, lipase and IL-10 and pancreatic amylase, total proteins and nucleic acid content) and histological examination. For rate of DNA synthesis and immunohistochemical studies animals were sacrificed at day 3 and day 7. Melatonintreatment was found to be beneficial in acute pancreatitis. Severity of acute pancreatitis was significantly reduced in melatonin group. Nucleic acid content, rate of DNA synthesis, pancreatic proteins and pancreatic amylase content were significantly improved. Histopathological examination showed significantly lower total scores in melatonin group. Results of melatonin group were comparable to that of positive control, CCK-8 group. Thusmelatonin treatment was found to promote the spontaneous regeneration process of pancreatic tissue.

PMID:19958759[PubMed - indexed for MEDLINE]