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Review Article Advances in the Preclinical Study of Some Flavonoids As Potential Antidepressant Agents

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Review Article Advances in the Preclinical Study of Some Flavonoids As Potential Antidepressant Agents Hindawi Scientifica Volume 2018, Article ID 2963565, 14 pages https://doi.org/10.1155/2018/2963565 Review Article Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents León Jesús German-Ponciano,1 Gilberto Uriel Rosas-Sánchez,1 Eduardo Rivadeneyra-Domínguez,2 and Juan Francisco Rodríguez-Landa 2,3 1 Programa de Doctorado en Neuroetolog´ıa, Instituto de Neuroetolog´ıa, Universidad Veracruzana, Xalapa, VER, Mexico 2Facultad de Qu´ımica Farmaceutica´ Biologica,´ Universidad Veracruzana, Xalapa, VER, Mexico 3Laboratorio de Neurofarmacolog´ıa, Instituto de Neuroetolog´ıa, Universidad Veracruzana, Xalapa, VER, Mexico Correspondence should be addressed to Juan Francisco Rodr´ıguez-Landa; [email protected] Received 25 August 2017; Revised 11 December 2017; Accepted 24 December 2017; Published 1 February 2018 Academic Editor: Marie-Aleth Lacaille-Dubois Copyright © 2018 Leon´ Jesus´ German-Ponciano et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Flavonoids are phenolic compounds found commonly in plants that protect them against the negative efects of environmental insults. Tese secondary metabolites have been widely studied in preclinical research because of their biological efects, particularly as antioxidant agents. Diverse favonoids have been studied to explore their potential therapeutic efects in the treatment of disorders of the central nervous system, including anxiety and depression. Te present review discusses advances in the study of some favonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical efects and the apparent mechanism of action of their preclinical antidepressant-like efects. Natural favonoids produce antidepressant-like efects in validated behavioral models of depression. Te mechanism of action of these efects includes the activation of serotonergic, dopaminergic, noradrenergic, and �-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant efects of some natural favonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans. 1. Introduction inhibitors (e.g., fluoxetine and fuvoxamine), selective dopam- ine reuptake inhibitors (e.g., amineptine and methylpheni- Depression is one of the most frequently diagnosed psy- date), selective norepinephrine reuptake inhibitors (e.g., chiatric disorders in the general population, the symptoms reboxetine and viloxazine), and dual antidepressant drugs ofwhichnegativelyimpacthealthandareassociatedwith (e.g., venlafaxine and duloxetine) [4, 5]. high fnancial costs [1]. According to the World Health Most antidepressant drugs have a delayed onset of ther- Organization, depression will become the primary cause of apeutic actions and many have side efects when taken in disability by 2030 [2]. the long term. Tis has led patients to search for alternatives, A wide variety of antidepressant drugs are available based on the use of plants with reputed antidepressant activity to treat the symptoms of depression. Such antidepressants [6]. An increasing number of studies have investigated natu- produce their therapeutic efects through actions on diverse ralchemicalcompoundswithpotentialantidepressantactiv- neurotransmitter systems, including the serotonergic, nora- ity [7], including bioactive metabolites, such as favonoids, drenergic, and dopaminergic systems [3]. Te principal anti- that exert multiple efects on the central nervous system [8]. depressant drugs are tricyclic antidepressants (e.g., clomi- Substantial preclinical evidence indicates that some fa- pramine and imipramine), monoamine oxidase inhibitors vonoids reduce behavioral endophenotypes of depression in (e.g., phenelzine and selegiline), selective serotonin reuptake animal models by increasing the concentrations of diferent 2 Scientifca 3 2 4 O B O 8 1 O 5 7 2 OH AC 6 6 3 O O 45 Flavones Flavonols Figure 1: Basic structure of favonoids and the system of numera- tion. A and B are phenyls, and C corresponds to pyrene. Numbers indicate the numeration system of the basic structure of favonoids. O O OH neurotransmitters and expression of neurotrophic factors in the brain [9, 10]. Te present review focuses on the results of Flavanones Flavan-3-ols preclinical research that indicate the potential antidepressant efects of some favonoids and describes the mechanisms O O of action that are involved in these efects. We propose future scientifc research in the area of pharmacotherapy to develop safe and efective antidepressant drugs based on OH O natural products to ameliorate the symptoms of depression O in humans. Flavanonol Isofavones 2. Background on Flavonoids Figure 2: General classifcation and basic structure of favonoids. Flavonoids are phenolic compounds that are widely dis- tributed in vascular plants. Many chemical compounds, both enzymethatfacilitatesthehydrolysisoffavonoidsiscytosolic in their free form and in the form of glycosides, have been �-glycosidase, which hydrolyzes a high number of glycosides evaluated to determine their biological activity [11]. More [68, 69]. Cytosolic �-glycosidase is located intracellularly than 5000 types of favonoids have been identifed, which are in erythrocytes; therefore, active transport is required to structurally diferent and possess a wide range of biological cross cellular membranes. It is produced by sodium-glucose activities. Flavonoids are chemical compounds with a low transport protein, which depends on sodium (SGLT-1) [69]. molecular weight whose base structure (Figure 1) comprises Hydrolyzed favonoids (aglycones) are conjugated a system of rings of diphenyl pyrene or phenyl benzopyrene through methylation, sulphatation, and glucuronidation. accompanied by two variable groups of hydroxyl phenolic Because of their high conjugation, hydrolyzed favonoids are radicals [12]. detected in low concentrations in plasma [70]. For example, According to the chemical structure of favonoids (Fig- hesperetin aglycone (the active form of the favonoid ure 2), they can be classifed as favonoids, favones, fa- hesperidin) is metabolized by the cytochrome isoforms P450 vanones, isofavones, and anthocyanidins [62]. Studies in CYP1A and CYP1B1. Tis frst-pass metabolism principally mammals and in vitro have shown that favonoids exert occurs through intestinal cells [71]. Te metabolites of antioxidant, antiallergic, hepatoprotective, antiviral, anticar- hesperidin/hesperetin are eliminated by renal route. Teir cinogenic, neuroprotective, antitoxic, anxiolytic, antiepilep- metabolites are found in urine but not feces, suggesting that tic, estrogenic, and antidepressant-like efects by inhibiting the high bacterial degradation of phenolic acids occurs at the some enzymes [63–66], which is dependent on the dose and level of the colon, allowing passage to the systemic circulation type of favonoid administered. [71]. Particularly, the elimination of the favonoid chrysin depends on the outfow, in which conjugated structures 3. Flavonoid Metabolism are hydrolyzed through sulphatases and glucuronidases in the intestine, suggesting that chrysin has low intestinal Te daily dietary intake of favonoids in humans is approx- absorption, in which it is detected in high concentrations in imately 1-2 g per day, principally depending on individual feces [72]. alimentary habits [67]. Most favonoids are found in plants in Some studies have shown that hydrolyzed favonoids and the �-glycoside form. Afer intake, the processes of hydrolysis their conjugated derivatives may cross the hematoencephalic occur, but since the union-� in these sugars is resistant barrier and exert actions on the central nervous system [73]. to the hydrolysis produced by pancreatic enzymes, this Tis may at least partially explain their multiple pharma- metabolic process occurs in the intestinal lumen through cological actions at the neuronal level that afect cognition actions of the lactase phlorizin hydrolase that is located and emotional and afective states. Numerous preclinical in the membrane of enterocytes. When phlorizin hydro- studies have shown that some favonoids reduce depressive- lase hydrolyzes favonoids, they become capable of crossing like behavior, and these efects are related to the activation of intestinal membranes through passive difusion. Another neurotransmitter systems and trophic factors in the brain. Scientifca 3 Table1:Plantswithantidepressant-likeefectsassociatedwiththeirtotalfavonoidscontent. Duration of Plant (family) Doses (animal) Behavioral test Reference treatment Alpinia oxyphylla Miq. 10 mg/kg, 14 days FST, SPT [13] (Zingiberaceae) p.o. (A) 400 mg/kg, Single dose TST [14] Hemerocallis citrina L. p.o. (B) (Xanthorrhoeaceae) 10, 20, and 40 mg/kg, 35 days SPT [15] p.o. (C) Apocynum venetum Linn. 0.35 mM/kg, Single dose FST, TST [16] (Apocynaceae) i.p. (B) Hibiscus esculentus L. 500 and 750 mg/kg, Single dose FST, TST [17] (Malvaceae) i.p. (D) Apocynum venetum L. 50 and 100 mg/kg, 10 days FST, TST [18] (Apocynaceae)
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