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Year : 2012  |  Volume : 2  |  Issue : 3  |  Page : 266-271

Chronotherapeutic effect of morin in experimental chronic hyperammonemic rats

Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India

Date of Web Publication8-Aug-2012

Correspondence Address:
Perumal Subramanian
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar - 608 002, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0738.99483

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Aim: Ammonia is a neurotoxin that has been strongly implicated in the pathogenesis of hepatic encephalopathy and a major pathogenic factor associated with inborn errors of urea cycle. In this present work we aimed to evaluate the chronotherapeutic effect of morin (3,5,7,2',4'-pentahydroxyflavone), a plant component, on ammonium chloride (AC) (100 mg/kg; intraperitoneal)-induced hyperammonemia in Wistar rats (180-200 g). Materials, Methods and Results: Morin (30 mg/kg body weight) was administered to rats at 06:00, 12:00, 18:00, and 24:00 hours in hyperammonemia. The influence of morin on AC-induced hyperammonemia at different time points (06:00, 12:00, 18:00, and 24:00 hours) was evaluated by analyzing the circulatory levels of ammonia; urea; thiobarbituric acid reactive substances (TBARS); hydroperoxides (HP); liver markers [alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP)]; glutathione peroxidase (GPx); superoxide dismutase (SOD); catalase (CAT); reduced glutathione (GSH); and vitamins A, C, and E. The levels of these components were significantly elevated in AC-treated rats but were decreased significantly after treatment with morin. Administration of morin at 24:00 h caused significantly greater reduction in these parameters than administration at other time points (P<0.05; Duncan's multiple range test). Conclusion: The chronotherapeutic effect of morin in hyperammonemic rats may be due to various factors, including (i) temporal variations of metabolic enzymes involved in the degradation of morin; (ii) temporal variations of lipid peroxidation and of antioxidants, urea cycle enzymes etc.; and (iii) temporal variation in bioavailability of morin. However, the exact underlying mechanism(s) is/are still unclear and further investigations are needed.

Keywords: Ammonia, antioxidants, chronotherapy, liver markers, urea

How to cite this article:
Subash S, Subramanian P. Chronotherapeutic effect of morin in experimental chronic hyperammonemic rats. Int J Nutr Pharmacol Neurol Dis 2012;2:266-71

How to cite this URL:
Subash S, Subramanian P. Chronotherapeutic effect of morin in experimental chronic hyperammonemic rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2022 Nov 29];2:266-71. Available from:

   Introduction Top

Hyperammonemia is defined as elevated ammonia concentration in blood, resulting from inadequate ammonia detoxification due to impairment in liver function. In living organisms, ammonia is an important nitrogen substrate in several reactions and plays an important role in nitrogen homeostasis of cells. Moreover, ammonia is a product as well as precursor of various important nitrogen-containing metabolites such as amino acids, the smallest subunits of proteins. [1] Ammonia is neurotoxic when it accumulates in excess. Hyperammonemia is mainly responsible for the neurological alterations-including impaired intellectual function-found in the hepatic encephalopathy seen in patients with liver disease. Antiepileptic drugs such as valproate and salicylate also cause hyperammonemia and urea cycle disorders (UCDs). Ammonia toxicity results in free radical generation that leads to oxidative stress-mediated tissue damage, [2],[3],[4] and elevated ammonia concentration in the brain exerts toxic effects on neural cells. [5]

Chronotherapy is a new strategy of drugs administration based on circadian rhythms. [6] The hypothalamic biological clock (suprachiasmatic nuclei) modulates the rhythms of cellular metabolism and proliferation in normal tissues. [7] Normal cell physiology is characterized by predictable changes over a 24-hour timescale, which is coordinated by the suprachiasmatic nucleus. These circadian rhythms can be utilized to reduce cytotoxic treatment insults by making temporal adjustments to the administration schedule of drugs (chronotherapy). [8] Drugs that target the regulation of cell-cycle events or angiogenesis are examples of drugs that are more effective if administered at specific times. With chronotherapy, such drugs may fully achieve in vivo the pharmacodynamic effects they display in vitro.

Preclinical and clinical evidence support investigations of the chronotherapy hypothesis in cancer patients. The recognition of the importance of diurnal patterns led to the development of the innovative technique of chronotherapy, which is the delivery of medications in synchrony with endogenous biological rhythms of the pathophysiology of disease states, so as to optimize treatment outcomes. [9] Recently, this strategy of chronotherapy has been successfully implemented in the therapy of allergic rhinitis and asthma, [9] hypertension and ischemic heart disease, [10] and cancer. [11]

The greatest disadvantage of the presently available potent conventional or synthetic antihyperammonemic agents/therapies lies in their toxicity and the tendency for reappearance of symptoms after discontinuation of treatment. These drugs or therapies are sometimes inadequately effective and have serious adverse effects. [12] Therefore screening and development of drugs for antihyperammonemic activity is still in progress and there is a worldwide trend to go back to traditional medicinal plants and natural products. There is a need to find effective natural protective agents against hyperammonemia. This can be achieved by research focusing on the active principles of plants, and there are many indications that natural products may be better than currently used drugs. Polyphenols/flavonoids occur ubiquitously in foods of plant origin [13] and have received much attention because of their broad-spectrum pharmacological activities and extensive biological effects. [14],[15] The basic structure of flavonoids is usually characterized by two aromatic rings, ring A and ring B, joined by a three-carbon-linked c-pyrone ring (ring C), forming a C 6 -C 3 -C 6 skeleton unity where polar groups-usually hydroxyl, methoxyl, or glycosyl-are appended at various positions. [16] Flavonols vary from one another on the basis of the number and position of hydroxyl groups and their pharmacological actions. Each flavonol has its own specific biological function and activity. [17]

Morin (3, 5, 7, 2',4'-pentahydroxyflavone) is a kind of flavonoid belonging to the group of flavonols found in old fustic (Chlorophora tinctoria), osage orange (Maclura pomifera), [18] almonds (P. guajava L.), [19] mill (Prunus dulcis), fig (Chlorophora tinctoria), [20] onion and apple, [21] and other Moraceae, which are all part of the normal diet and/or are taken as herbal medicine. [22] Morin has been shown to have potent antioxidant and metal ion-chelating capacities; it has various biological and biochemical effects, including antioxidative, anti-mutagenesis, anti-inflammatory, [23],[24],[25] antineoplastic, cardioprotective, [26],[27] and anticancer [28] activities; and it is also an xanthine oxidase inhibitor, [29] protein kinase C inhibitor, [30] and cell proliferation inhibitor. [31] In addition to inhibiting P-gp, morin can modulate the activities of the metabolic enzymes, including cytochrome P450 (CYPs). [32] Furthermore, morin exerts an antitumor effect by significantly inhibiting the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen activation and TPA-induced skin tumor promotion. [33],[34] Morin has also been shown to act as a chemopreventive agent against oral carcinogenesis in vitro and in vivo.[28],[35]

Although various traditional medicinal values have been attributed to morin, no biochemical studies have been carried out to shed light on the chronotherapeutic effect of morin on circulatory liver markers and redox status in experimental hyperammonemia. Therefore, the present study was designed to analyze the chronotherapeutic effect of morin on circulatory (i) ammonia, urea, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP); (ii) thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP); and (iii) enzymatic and nonenzymatic antioxidants such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and vitamins A, C, and E in hyperammonemic rats.

   Materials and Methods Top

Experimental animals

Adult male albino Wistar rats (180-200 g), bred in the Central Animal House of Rajah Muthiah Medical College, Annamalai University, were used in this study. The animals were housed in polycarbonate cages in a room with a 12-hour/12-hour day-night cycle, in temperatures of 22±2°C and humidity of 45%-64%. The animals were fed with a standard pellet diet (Hindustan Lever Ltd, Mumbai, India) and provided water ad libitum. Studies were carried out in accordance with Indian national laws on animal care and use, and ethical clearance was obtained from the Committee for the Purpose of Control and Supervision of Experiments on Animals of Rajah Muthiah Medical College and Hospital (Reg. No: 160/1999/CPCSEA), Annamalai University, Annamalainagar.

Drugs and chemicals

Morin was purchased from Sigma Chemical Co. (St. Louis, MO, USA). Ammonium chloride was purchased from Sisco Research Laboratories, Mumbai, India. All other chemicals used in the study were of analytical grade.

Preparation of morin

Morin was freshly dissolved in a small amount of ethanol and then diluted with physiological saline. [36]

Induction of experimental hyperammonemia

Hyperammonemia was induced in Wistar rats by intraperitoneal (ip) injections of ammonium chloride at a dose of 100 mg/kg body weight, thrice a week, for 8 consecutive weeks. [37]

Experimental design

A total of 32 rats were used in the experiment. The rats were divided into four groups of eight rats each. Group I rats received physiological saline and formed the control group; group II rats were administered morin (30 mg/kg body weight) using an intragastric tube; [38] group III rats were treated with ammonium chloride (AC; 100 mg/kg body weight, ip); [37] and groups IV-VII (at 06:00, 12:00, 18:00, and 24:00) rats treated with AC (100 mg/kg) + morin (30 mg/kg) thrice in a week for 8 weeks. At the end of 8 weeks the rats were fasted overnight and sacrificed by cervical dislocation after anesthesia with intramuscular injection of ketamine hydrochloride (30 mg/kg body weight).

Biochemical analysis

After the experimental period, blood samples were collected from the animals for biochemical estimations (groups I-IV) at (06:00, 12:00, 18:00 and 24:00). Ammonia [39] , urea [40] , AST and ALT, [41] ALP, [42] TBARS, [43] HP, [44] SOD, [45] CAT, [46] GPx, [47] vitamin A, [48] α-tocopherol,[49] vitamin C, [50] and GSH [51] levels were estimated.

Statistical analysis

Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Duncan's multiple range test (DMRT) using SPSS® software v 9.05. Results were expressed as the mean value (±SD) of the eight rats in each group. P<.05 was considered as significant.

   Results Top

[Table 1] shows the levels of blood ammonia, plasma urea, HP, TBARS, and serum AST, ALT, and ALP in control and experimental rats. The levels of circulatory ammonia, urea, liver markers, HP, and TBARS were significantly higher in AC-treated rats when compared with control. Hyperammonemic rats treated with morin at 24:00 hours showed significant normalization of the levels of ammonia, urea, liver markers, and lipid peroxidation products as compared with control rats.
Table 1: Chronotherapeutic effect of morin on blood ammonia, plasma urea, TBARS, HP, and serum AST, ALP, and ALT of normal and experimental rats

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The levels of circulatory antioxidants in control and experimental groups are given in [Table 2]. The levels of vitamins A, C, and E; GSH; GPx; SOD; and CAT were significantly lower in AC-treated rats and these levels were significantly normalized in hyperammonemic rats treated with morin at 24:00 hours.
Table 2: Chronotherapeutic effect of morin on changes in the enzymatic and non-enzymatic antioxidants of normal and experimental rats

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   Discussion Top

Ammonia is present in all living organisms as a product of degradation of proteins and other nitrogenous compounds. However, at high levels, ammonia is toxic and can cause functional disturbances in the central nervous system (CNS) that could lead to coma and death. To avoid the deleterious effects of ammonia, ureotelic animals detoxify ammonia by incorporating it into urea, which is then eliminated in urine. However, when the liver fails or when blood is shunted past the liver, blood ammonia levels are elevated and brain function deteriorates. [52] In the liver, ammonia is removed either in the form of urea in periportal hepatocytes and/or as glutamine in perivenous hepatocytes. [52] Increased levels of circulatory ammonia and urea indicates a hyperammonemic condition in rats treated with AC, [37] which may be due to liver damage caused by ammonia intoxication. Administration of morin at 24:00 hours to AC-induced hyperammonemic rats significantly decreased the levels of blood ammonia and urea as compared with administration of morin at other time points. The reduction in the levels of ammonia and urea during morin treatment shows the potent anti-hyperammonemic effect of morin. [38],[53],[54]

In our study, the elevated levels of circulatory liver markers and lipid peroxidation products in AC-treated rats might be due to the liver damage caused by ammonia-induced free radical generation. Reports have shown that excess ammonia intoxication leads to excessive activation of NMDA receptors, leading to neuronal degeneration and death. [55],[56] The mechanisms by which excessive activation of NMDA receptors leads to neuronal degeneration and death include increased Ca 2+ concentration in the postsynaptic neuron. [57],[58] Ca 2+ binds to calmodulin and activates nitric oxide synthase, increasing the formation of nitric oxide (NO), which contributes to the neurotoxic process. Activation of NMDA receptors also leads to increased production of superoxide radical, which has also been proposed to play a role under in vivo conditions. [59],[60] Superoxide and NO have the ability to generate hydroxyl radicals. [61] This leads to oxidative stress, which causes tissue damage. [62] Decreased levels of circulatory liver markers and lipid peroxidation products in morin-administered rats may be due to its free radical scavenging property. [63],[64] Previous studies show that morin offers neuroprotection by inhibiting excess activation of NMDA receptors and NMDA receptor-mediated neurotoxicity. The potent neuroprotective activity of morin could be of value in the treatment of acute neuronal damage and adisability. [65]

Evidence shows that the oxidative stress and free radical production could be involved in the mechanism of ammonia intoxication, [66] which might have been responsible for the decrease in the levels of enzymatic (GPx, SOD, and CAT) and nonenzymatic (GSH and vitamins A, C, and E) antioxidants in AC-treated rats. Administration of morin significantly restored the levels of enzymatic and nonenzymatic antioxidants; this may be due to its potent antioxidant property by offering possible role in reducing the oxidative stress by inducing cellular antioxidant enzymes. [64] It has been reported that flavonoids such as morin, quercetin, and kaempferol are potent free radical scavengers and antioxidants. [67] For instance, phenolic phytochemicals, due to their phenolic ring and hydroxyl substituents, can function as effective antioxidants by virtue of their ability to quench free radicals. It is therefore believed that dietary phenolic antioxidants can scavenge harmful free radicals and thus inhibit their oxidative reactions with vital biological molecules, [68] thereby preventing the development of many pathophysiological conditions. The possible mechanisms by which morin modulates liver marker levels and redox status during experimental hyperammonemia might be via removal of excess ammonia, inhibition of NMDA receptor-mediated neurotoxicity, and antioxidant activity. [69],[70]

Chronobiological studies provide the capability of therapeutic intervention at a time when this intervention is useful and best tolerated and avoidance when it is not. [71] The chronobiologic approach to treatment, by exploring the rhythmic nature of oxidants and antioxidants, is especially critical and meaningful when potentially damaging or toxic agents have to be used. But beyond this, the time factor has to be introduced in just about all aspects of clinical pharmacology and many time-honored customs like 'three times a day' medications will have to be replaced by more meaningful, and often more effective and less toxic, chronobiologic treatment schedules. [72] The choice of the 'right time' will require chronobiologic knowledge, interpretation and experience since treatment at the 'wrong time' can be potentially harmful. [71],[73]

   Conclusion Top

The chronotherapeutic effect of morin (administered at 24:00 hours) in hyperammonemic rats may be due to various factors, including (i) significant variations in the pharmacokinetics of morin over the 24-hour day ; (ii) temporal variations of metabolic enzymes involved in the degradation of morin; (iii) temporal variations of liver marker enzymes, lipid peroxidation products, antioxidants, urea cycle enzymes, etc.; and (iv) temporal variation in the bioavailability of morin. However, to elucidate the underlying mechanism(s) further investigations are desirable.

   Acknowlegment Top

Financial assistance from the University Grants Commission, New Delhi, is gratefully acknowledged.

   References Top

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  [Table 1], [Table 2]

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