Eswar Kumar A. et al / IJPPDR / 3(2), 2013, 56-62.

e-ISSN: 2249-7625 Print ISSN: 2249-7633 International Journal of Pharmacy Practice & Drug Research www.ijppdr.com ROLE OF FLAVONOIDS IN STRESS DISORDERS

*1Eswar Kumar A, 2T. Karunakar, 1K.Naresh, 1Rohan, 3N.Sriram

*1Palamuru University, Mahabubnagar, Andhra Pradesh, India. 2Dhanvanthri College of Pharmaceutical Sciences, Mahabubnagar, Andhra Pradesh, India. 3Smt.Sarojini Rammulamma College of Pharmacy, Mahabubnagar, Andhra Pradesh, India.

ABSTRACT Stress is a fact of everyday life. When people reach out for help, they are often dealing with circumstances, situations, and stressors in their lives that leave them feeling emotionally and physically overwhelmed. Stress is the body‟s reaction to a change that requires a physical, mental or emotional adjustment or response. Flavonoids: Common plant pigment compounds that acts as antioxidants, enhance the effects of vitmin C, and strengthen connective tissue around capillaries. Mechanism of flavonoids as antioxidants: Flavonoids are powerful antioxidants against free radicals and are described as free-radical scavengers. Oxidative stress is involved in diverse pathologies, including the spectrums of inflammatory, cardiovascular and neurodegenerative disease. Green and black tea drinking (rich in a class of flavonoids named catechins) may help protect the aging brain and reduce the incidence of dementia like Alzheimer´s disease (AD) and Parkinson´s disease (PD). Flavonoids in treatment of CVS Studies ensure that long-term administration of flavonoids can decrease, or tend to decrease the incidence of cardiovascular diseases and their consequences. Flavonoids in treatment of memory cognition: Historically, the biological actions of flavonoids to their ability to exert antioxidant actions. Thus Flavonoids are the beneficiary aspect in our life and plays a major key role in stress and stress disorders.

Keywords: Flavonoids, Catechins, Antioxidants, Cardiovascular system.

INTRODUCTION situations differently and has different coping skills. For Stress is a fact of everyday life. When people this reason, no two people will respond exactly the same reach out for help, they are often dealing with way to a given situation. Stress is caused by an existing circumstances, situations, and stressors in their lives that stress causing factor or stressor. Dealing with a serious leave them feeling emotionally and physically illness or caring for someone who is can cause a great deal overwhelmed. Many people feel that they have very little of stress. resources or skills to deal with the high levels of stress they are experiencing stress, it often isn‟t clear what stress is Stress really about. Many people consider stress to be something Stress is the body‟s reaction to a change that requires a that happens to them, an event such as an injury or a job physical, mental or emotional adjustment or response [2]. loss. Others think that stress is what happens to our body, Sources of Stress mind, and behaviour in response to an event (E.g. heart We can experience stress from four basic sources: pounding, anxiety, or nail biting). While stress does involve events and our response to then, these are not the most The Environment – the environment can bombard you important factors. Our thoughts about the situations in with intense and competing demands to adjust. Examples of which we find ourselves are the critical factor [1]. environmental stressors include weather, noise, crowding, Stress can come from any situation or thought that pollution, traffic, unsafe and substandard housing, and makes you feel frustrated, angry, or anxious. Everyone sees crime [1].

Corresponding Author:- Eswar Kumar Email : [email protected]

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Eswar Kumar A. et al / IJPPDR / 3(2), 2013, 56-62.

Social Stressors Examples of negative personal stressors can include: We can experience multiple stressors arising • The death of a partner from the demands of the different social roles we occupy, • Filing for divorce such as parent, spouse, caregiver, and employee. Some • Losing contact with loved ones examples of social stressors include deadlines, financial • The death of a family member problems, job interviews, presentations, disagreements, • Hospitalization (oneself or a family member) demands for your time and attention, loss of a loved one, • Injury or illness (oneself or a family member) divorce, and co-parenting. • Being abused or neglected Physiological Situations and circumstances • Separation from a spouse or committed relationship affecting our body can be experienced as Physiological partner stressors. Examples of physiological stressors include • Conflict in interpersonal relationships rapid growth of adolescence, menopause, illness, aging, • Bankruptcy/money problems giving birth, accidents, lack of exercise, poor nutrition, • Unemployment and sleep disturbances. • Sleep problems • Children‟s problems at school Thoughts • Legal problems Your brain interprets and perceives situations as • Inadequate or substandard housing stressful, difficult, painful, or pleasant. Some situations in • Excessive job demands life are stress provoking, but it is our thoughts that • Job insecurity determine whether they are a problem for us. • Conflicts with team mates and supervisors • Lack of training necessary to do a job Types of Stressors • Making presentations in front of colleagues or clients Situations that are considered stress provoking • Unproductive and time-consuming meetings are known as stressors. Stress is not always a bad thing. • Commuting and travel schedules Stress is simply the body‟s response to changes that create Examples of positive personal stressors might include: taxing demands. Many professionals suggest that there is a • Receiving a promotion at work difference between what we perceive as positive stress, • Starting a new job and distress, which refers to negative stress. In daily life, • Marriage or commitment ceremony we often use the term “stress” to describe negative • Buying a home situations. This leads many people to believe that all stress • Having a child is bad for you, which is not true [1]. • Moving • Taking or planning a vacation Positive stress has the following characteristics: • Holiday seasons • Motivates, focuses energy • Retiring • Is short-term • Taking educational classes or learning a new hobby • Is perceived as within our coping abilities • Feels exciting Stress Warning Signs and Symptoms • Improves performance Cognitive Symptoms • Memory problems In contrast, negative stress has the following • Indecisiveness characteristics: • Inability to concentrate • Causes anxiety or concern • Trouble thinking clearly • Can be short or long-term • Poor judgment • Is perceived as outside of our coping abilities • Seeing only the negative • Feels unpleasant • Anxious or racing thoughts • Decreases performance • Constant worrying • Can lead to mental and physical problems • Loss of objectivity • Fearful anticipation [2] Stress Management It is somewhat hard to categorize stressors into Physical Symptoms objective lists of those that cause positive stress and those • Headaches or backaches that cause negative stress, because different people will • Muscle tension and stiffness have different perceptions and reactions to particular • Diarrhea or constipation situations. However, by generalizing, we can compile a • Nausea, dizziness list of stressors that are typically experienced as negative • Insomnia or positive to most people, most of the time [1]. • Chest pain, rapid heartbeat

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• Weight gain or loss Clinically signifcant trauma re-experiencing, • Skin breakouts (hives, eczema) situation avoidance, and increased arousal symptoms for > • Loss of sex drive 1 month after exposure [4]. • Frequent colds - Acute: Symptoms > 1 month, < 3 months Emotional Symptoms - Chronic: Symptoms ≥ 3 months • Moodiness - Delayed Onset: Onset ≥ 6 months • Agitation • Restlessness Post Traumatic Stress Disorder (PTSD) • Short temper Risk Factors • Irritability, impatience  Severe trauma • Inability to relax  Type of trauma (interpersonal traumas such as torture, • Feeling tense and “on edge” rape or assault increase the risk of (PTSD) • Feeling overwhelmed  High perceived threat to life • Sense of loneliness and isolation  Age at trauma (school age youth, 40-60 years old) • Depression or general unhappiness  Community (mass) trauma  Other peri-traumatic factors including: history of Behavioural Symptoms peritraumatic dissociation and interpersonal trauma • Eating more or less • Sleeping too much or too little Pre-Traumatic Factors • Isolating yourself from others  Ongoing life stress or demographics • Procrastination, neglecting responsibilities  Lack of social support • Using alcohol, cigarettes, or drugs to relax  Young age at time of trauma • Nervous habits (e.g., nail biting, pacing) • Teeth grinding or jaw clenching  Pre-existing psychiatric disorder • Overdoing activities (e.g., exercising, shopping)  Other pre-traumatic factors including: female gender, • Overreacting to unexpected problems low socioeconomic status, lower level of education, lower • Picking fights with others level of intelligence, race (African-American, American Indian, Pacific Islander), prior trauma exposure (reported Acute stress disorder (ASD) abuse in childhood, report of other previous Acute stress disorder (ASD) is an anxiety traumatization, report of other adverse childhood factors), disorder characterized by a cluster of dissociative and family history of psychiatric anxiety symptoms occurring within one month of a traumatic event. (Dissociation is a psychological reaction Post-Traumatic to trauma in which the mind tries to cope by "sealing off"  Ongoing life stress some features of the trauma from conscious awareness)  Lack of social support [3].  Bereavement  Major loss of resources Causes and symptoms  Other post-traumatic factors including: children at Acute stress disorder is caused by exposure to home and female with distressed spouse trauma, which is defined as a stressor that causes intense fear and, usually, involves threats to life or serious injury Signs and symptoms of post-traumatic stress disorder to oneself or others. Examples are rape, mugging, combat, (PTSD) natural disasters, etc. The symptoms of post-traumatic stress disorder The symptoms of stress disorder include a (PTSD) can arise suddenly, gradually, or come and go combining of one or more dissociative and anxiety over time. Sometimes symptoms appear seemingly out of symptoms with the avoidance of reminders of the the blue. At other times, they are triggered by something traumatic event. Dissociative symptoms include emotional that reminds you of the original traumatic event, such as a detachment, temporary loss of memory, depersonalization, noise, an image, certain words, or a smell. While everyone and derealization. Anxiety symptoms connected with experiences PTSD differently, there are three main types acute stress disorder include irritability, physical of symptoms: restlessness, sleep problems, inability to concentrate, and being easily startled. 1. Re-experiencing the traumatic event 2. Avoiding reminders of the trauma Post Traumatic Stress Disorder (PTSD) 3. Increased anxiety and emotional arousal

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Symptoms of PTSD: Re-experiencing the traumatic Post-traumatic stress disorder (PTSD) causes and risk event factors  Intrusive, upsetting memories of the event Previous traumatic experiences, History of depression, anxiety, or  Flashbacks (acting or feeling like the event is especially in early life another mental illness Family history of PTSD or High level of stress in everyday life happening again) depression Lack of support after the trauma  Nightmares (either of the event or of other frightening History of physical or sexual abuse Lack of coping skills things) History of substance abuse  Feelings of intense distress when reminded of the trauma Role of flavonoids in stress:  Intense physical reactions to reminders of the event Flavonoids are natural products widely (e.g. pounding heart, rapid breathing, nausea, muscle distributed in plant kingdom and currently consumed in tension, sweating) large amounts in the daily diet. These are categorised according to their molecular structures into flavonols, Symptoms of PTSD: Avoidance and numbing flavones, flavanones, isoflavone, Catechin, anthocyanidin  Avoiding activities, places, thoughts, or feelings that and chalcones. remind you of the trauma Flavonoids are capable of modulating the activity of enzymes and affect the behaviour of many cell systems  Inability to remember important aspects of the trauma and exerting beneficial effects on body. This property of  Loss of interest in activities and life in general flavonoids has aroused considerable interest. This review  Feeling detached from others and emotionally numb has presented the recent research advancements of  Sense of a limited future (you don‟t expect to live a chemistry and pharmacological properties of flavonoids normal life span, get married, have a career) [5]. Flavonoids are low molecular weight [6,7] Symptoms of PTSD: Increased anxiety and emotional bioactive polyphenols [8] which play a vital role in arousal photosynthesising cells [9]. The original “flavonoid”  Difficulty falling or staying asleep research apparently began in 1936, when Hungarain  Irritability or outbursts of anger scientist Albert Szent-Gyorgi was uncovering a synergy  Difficulty concentrating between pure vitamin C and as yet unidentified co-factors  Hypervigilance (on constant “red alert”) from the peels of lemons, which the first called “citrin”,  Feeling jumpy and easily startled and, later, “vitamin P”[10]. Flavonoids are secondary metabolites Other common symptoms of post-traumatic stress characterised by flavan nucleus [7] and C6-C8-C6 carbon- disorder (PTSD) skeleton [11,12]. These are group of structurally related Anger and irritability Depression and hopelessness compounds with a chromane-type skelton having phenyl Guilt, shame, or self-blame Suicidal thoughts and feelings substituent in C -C position [13]. The basic structural Substance abuse Feeling alienated and alone 2 3 Feelings of mistrust and betrayal Physical aches and pains feature of flavonoid is 2-phenyl-Y-pyrane nucleus consisting of two benzene rings (A and B) linked through Symptoms of PTSD in children and adolescents a heterocyclic pyran ring (C). In children—especially those who are very young—the Flavonoids constitute one of the most symptoms of PTSD can be different than the symptoms in characteristic classes of compounds in higher plants. Many adults. Symptoms in children include: flavonoids are easily recognised as flower pigments in  Fear of being separated from parent most angiosperm families (flowering plants). However,  Losing previously-acquired skills (such as toilet their occurence is not restricted to flowers but include all training) parts of the plant. In a few cases, the six-membered heterocyclic  Sleep problems and nightmares without recognizable content ring C occurs in an isomeric open form or is replaced by a five - membered ring [14]  Somber, compulsive play in which themes or aspects . of the trauma are repeated Flavonoids  New phobias and anxieties that seem unrelated to the Common plant pigment compounds that acts as trauma (such as a fear of monsters) antioxidants, enhance the effects of vitmin C, and  Acting out the trauma through play, stories, or strengthen connective tissue around capillaries [15]. Any drawings of a compounds containing a characteristic aromatic  Aches and pains with no apparent cause nucleus and widely distributed in higher plants, often as a  Irritability and aggression pigment; a subgroup with biological activity in mammals is the bioflavonoids. Any of a large group of phyto

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nutrients that are water-soluble pigments, considered to hydroxyl radicals. They terminate chain radical reaction have antioxidant and anti-inflammatory properties. Also by donating hydrogen atom to a peroxy radical, thus, called bioflavonoids. Bioflavonoid nutrition any forming flavonoids radical, which, further reacts with free biologically active polyphenol found in fruits, especially radicals thus terminating propagating chain [21,22]. in the pulp, vegetables, tea, redwine, which are potent antioxidants and platelet inhibitors [16]. Oxidative Stress Oxidative stress is involved in diverse Flavonols: 3-hydroxyflavone, azaleatin, fisetin, galangin, pathologies, including the spectrums of inflammatory, gossypetin, kaempferidin, kaempferol, isorhamnetin, cardiovascular and neurodegenerative disease. Oxidative morin, myricetin, natsudaidain, pachypodol, quercetin, stress in the vasculature occurs when the finely tuned rhamnazin, rhamnetin [16]. interplay of these oxidants as intra and inter-cellular signalling molecules is disturbed, and oxidants, Flavonols Glycosides: Astragalin Azalein, Hyperoside, particularly the ROS, are overproduced. In general, this Isoqueercetin, kaempferitin, myricitin, quercitin, robinin, can occur when endogenous antioxidant defence rutin, spiraeoside, zanthorhamin, amurensin, icarin and mechanisms, such as superoxide dismutase, glutathione troxerutin [16]. peroxidase, chain terminators (vitamin A and C) hemaglobin, and catalase are unable to balance oxidant Flavonoids-containing food: Apple, strawberries, stress. At the cellular level, ROS-mediated injury occurs blacktea or blackberries, green tea, onion, basil, lettuce, through oxidant of macromolecules, including cranberry, spinach, asparagus, soy, lime bean, cayenne, peroxidation of lipids, and oxidative modification of coriendar, peppermint, chamomile, anise, leaves of proteins and nucleic acid [23-25]. caryacolhayensis, cherries, pears, tea etc.[16] Effect of flavonoids on memory Applications of Flavonoids Flavonoids in treatment of memory cognition:  Flavonoids contained in the blue berries may help to Historically, the biological actions of flavonoids to their improve memory in elderly people. ability to exert antioxidant actions. However, it has been  Flavonoids contained in the blue berries may have a speculated that this classical hydrogen-donating positive effect and protect against Parkinson‟s disease. antioxidant activity cannot account for the bioactivity of  Responsible for the colour of the fruit and vegetables flavonoids in the brain as they are present in very low rich in flavonoids. concentrations. Instead, it has been postulated that their  Quercetin possessing anti-infimmatory, antiallergic effects in the brain is mediated by an ability to protect and antioxidant properties. vulnerable neurons, enhance existing neuronal function,  Anti-agening. stimulate neuronal regeneration and induce neurogenesis.  Cancer preventive agent (skin cancer, skin disorders) Indeed, it has become evident that flavonoids are able to exert neuroprotective actions even at low concentration  Able to decrease capillary fragility via their interactions with critical neuronal intracellular  Flavanols- Vasodilatory effect. signalling pathways pivotal in controlling neuronal  Flavanols- Treatment for dementia and strokes. survival and differentiation, long-term potentiation and  Chalcones- Antifungal, antitumour and anti- memory. Early indications regarding the ability of inflammatory properties [17]. flavonoids to impact upon brain function were reported in the 1950s, with flavones reported to act as novel brain- Flavonoids as antioxidants stem stimulants [26]. Studies suggest that flavonoids, in Mechanism of flavonoids as antioxidants: Flavonoids particular isoflavones such as genistein might be are powerful antioxidants against free radicals and are detrimental to memory processes in the brain due to their described as free-radical scavengers [18]. This activity is ability to act as tyrosine kinase inhibitors. Researches attributed to their hydrogen-donating ability. Indeed, the revealed that isoflavones results in positive effects on phenolic groups of flavonoids serve as a source of a neuro-cognitive functions which is apparent in post- readily available „„H” atoms such that the subsequent menoupausal women. Activation of both synaptic radicals produced can be delocalized over the flavonoid plasticity and new neural growth may act together to structure [19]. enhance memory and cognition as shown in fig [27]. Free radical scavenging capacity is primarily It has been found that flavonoids subclasses attributed to high reactivities of hydroxyl substituents that flavonols, flavanols, flavanones, flavones and participate in the reaction [20] anthocyanins do not exert oestrogen like effects and thus F-OH + R. F-O. + RH cannot influence memory and cognition via similar Flavonoids inhibit lipid peroxidation in vitro at an early mechanism. stage by acting as scavengers of superoxide anion and

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Flavonoids in treatment of depression Flavonoids have found to be ligands for GABAA flavonoid glycosides, the following decreasing order of receptors in the central nervous system and it led to action results: hypothesis that they act as benzodiazepine-like molecules. 2S-hesperidin>linarin>rutin>diosmin\cong2S- Many flavone derivatives were found to be ligands for the neohesperidin> gossypin>2S-naringin. GABAA receptors in the CNS; and thus they bind to the benzodiazepine binding site with resulting depressant Flavonoids in treatment of CVS actions in mice [6]. These were also found to possess Studies ensure that long-term administration of sedative action, tranquilizers, anticonvulsant. Considering flavonoids can decrease, or tend to decrease the incidence the sedative, the spontaneous locomotor activity and of cardiovascular diseases and their consequences [28]. thiopental-induce sleeping time effects obtained with the

Table 1. Flavonoids in treatment of CVS S.No. Cardiovascular diseases Influence of flavonoids Decrease in LDL oxidation by LOX inhibition and attenuation of 1. Atherosclerosis oxidative stress, inhibition of leucocyte leucocyte adhesion, myeloperoxidase, decreased expression of iNOS and COX-2 2. Acute myocardial infarction Decrease in ROS burst, inhibition of platelet aggregation Decrease in oxidative stress (direct ROS scavenging) inhibition of 3. Heart Failure metalloproteinase 4. Arrhythmia Decrease in oxidative stress Vasodilatory properties, inhibition of NADPH oxidase, recovery of NO 5. Hypertension due to inhibition of superoxide production

Flavonoid consumption prevents many brain and reduce the incidence of dementia like cardiovascular diseases including hypertension and Alzheimer´s disease (AD) and Parkinson´s disease (PD). atherosclerosis. Quercetin protects LDL against oxidative Neuroprotective/neuroregenerative effects of green tea modifications effect. 7-monohydroxyethylrutoside and 7‟, catechins were found to act not only as antioxidant metal 3‟, 4‟-trihydroxyethylrutoside are reported to be cardio chelators but also as modulators of intracellular neuronal protective. signalling and metabolism, of cell survival/death genes, and mitochondrial function. Thus, these dietary Green tea flavonoids and brain dementia compounds are receiving significant attention as Green and black tea drinking (rich in a class of therapeutic multifunctional cytoprotective agents that flavonoids named catechins) may help protect the aging simultaneously manipulate various brain targets [29].

Figure 1. Overview of functions of flavonoids on memory system [27]

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