ANTIANXIETY PROPERTY OF TECOMA STANS LINN LEAVES EXTRACT IN EXPERIMENTAL ANIMALS - INTRODUCTION

1. introduction

 

            Experience of mental illness is as old as human existence, anxiety is one among them. Anxiety, fear and worry are all completely natural human feelings. If these feelings occur and endure for an extended period, it affects both physical and mental health. This leads to clinical anxiety disorders. Anxiety an exaggerated feeling of apprehension, uncertainty, and fear. It is an unpleasant state of tension with an anticipation of imminent danger¹. The disorder is associated with significant disability (including educational and occupational) which has a negative impact on the quality of life.²

             Anxiety disorders are one of the most prevalent and highly comorbid psychiatric conditions³.  Anxiety disorders are among the most prevalent disorders in the world that are characterized by symptoms of overriding apprehension or mental tension which could easily disrupt normal daily activity. Most anxiety disorders tend to run a long course and thus require long-term treatment.⁴

             Studies have reported that anxiety and depression may occur together with the association of sub threshold depressive symptoms^.5 Anxiety is a complex progressive behavioral and physiological alteration of the organism, which ultimately leads to wide variety of central nervous system (CNS) disorders, if remain untreated. In addition to individual genetic factors external influences, such as nutrition, smoking, alcohol, socioeconomic status, environmental conditions etc., can strongly contribute to its anticipated appearance.⁶      

             Anxiety disorder is increasingly recognized as a highly prevalent and chronic disorder with onset during the teenage years, with an incidence of 18.1% and a lifetime prevalence of 28.8% ⁷. Anxiety disorders affect 16.6% of population worldwide.⁸ Anxiety disorders are psychiatric disorders affecting nearly 25% of the adult population at some point in their life. The prevalence of anxiety disorders is 30.5% and 19.2% in women and men respectively. The prevalence of anxiety disorders is remarkably high in young people. Children aged 7 to 11 years reported a 15.4% prevalence rate of anxiety disorders. A survey has also stated that less than 14% of people with such psychiatric disorders receive treatment. ⁹

             Anxiety disorders are the most common class of neuropsychiatric disorders in USA ³ and many other countries¹⁰. The life time prevalence of panic attacks (a form of anxiety disorder) is around 7-9% in most countries and 1% alone in India with the prevalence of generalized anxiety disorder is very high i.e. 8.5% in the general population¹¹

             According to World Health report approximately 450 million people suffer from a mental or behavioral disorder, yet only a small minority of them receives even the most basic treatment ¹¹. This amounts to 12.3% of the global burden of disease and will rise to 15% by 2020 ¹². In the search for new therapeutic products for the treatment of neurological disorders, medicinal plant research worldwide has progressed constantly, demonstrating the pharmacological effectiveness of different plant species in a variety of animal models ¹³. Since the past decade, many herbal medicines have been used in people with anxiety disorders¹⁴.

             There are many types of anxiety such as General anxiety, Obsessive compulsive disorder, Panic disorder, Performance Anxiety, Post-traumatic stress disorder, Separation anxiety, Social anxiety, Specific phobias, State anxiety, and Trait anxiety ¹⁵

             Anxiety includes, mental, emotional, physical, behavioral and social symptoms.^16,17 Mental symptoms of anxiety such as confusion, hyper-reactivity, hyper-sensitivity, hyper-vigilance, poor concentration, poor judgment, and poor memory.¹⁸ There are many types of anxiety such as General anxiety, Obsessive compulsive disorder, Panic disorder, Performance Anxiety, Post-traumatic stress disorder, Separation anxiety, Social anxiety, Specific phobias, State anxiety, and Trait anxiety.¹⁵

             Anxiety includes, mental, emotional, physical, behavioral and social symptoms.^{16, 17} mental symptoms of anxiety such as confusion, hyper-reactivity, hyper-sensitivity, hyper-vigilance, poor concentration, poor judgment, and poor memory.¹⁸

                                    

Some of the emotional symptoms of anxiety include: Agitation, Anger, Confusion, Fear about specific things, health problems, spiders, memories general fears for self and loved ones, safety, health, and financial security.¹⁶

 

Some of the physical symptoms of anxiety include: Headaches, Heart palpitations, Joint pain, Muscle aches, Pain, Rapid breathing. Some of the physiological symptoms of anxiety include: Sweating ¹⁹

 

Some of the behavioral symptoms of anxiety include: As in the case of depression, people who suffer anxiety will tend to: Avoidance of performance, Avoidance of the feared thing, Drink excessively. Excessive attention to control or details in order to prevent mistakes, Indulge in promiscuity or reckless sex, other reckless behaviors such as excessive spending. Social avoidance, some people will avoid responsibility in order to decrease their anxiety ¹⁷

 

            Behavioral traits are passed from parents to child, anxiety disorders tend to run through family structures. Studies comparing the risk of psychiatric illness in identical twins (who share 100% of their DNA) have found that, if one identical twin has a psychiatric condition, the risk that the other twin will have the same condition is approximately 50%. It appears that non-genetic factors, including, environmental influences occurring throughout the life-span, must also contribute to the risk of developing an anxiety disorder. 

 

Neurotransmitters involved in anxiety:

            Neurotransmitters are chemicals located and released in the brain to allow an impulse from one nerve cell to pass to another nerve cell. There are approximately 50 neurotransmitters identified.  Some common neurotransmitters are acetylcholine, norepinephrine, dopamine, serotonin, and gamma aminobutyric acid (GABA). Acetylcholine and norepinephrine are excitatory neurotransmitters while dopamine, serotonin, and GABA are inhibitory. Each neurotransmitter can directly or indirectly influence neurons in a specific portion of the brain, thereby affecting behavior.^{20, 21}

 

Some of the receptors in the brain responsible for anxiety/ anti‑anxiety:

1. Benzodiazepine receptors ²²
2. Serotonin receptors (5‑hydroxytriptamine):
1. 5-hydroxytryptamine1A (5 HT1A) ²³
2. 5-HT3 receptor: 5-HT3 receptor antagonism contributes the anxiolytic effect ²⁴
3. Selective 5-HT reuptake inhibitors.
3. y-aminobutyric acid receptor (GABA) ^25,26,27
4. GABAA-benzodiazepine receptor
5. Histamine receptor (H-receptor).

      H‑receptor plays an important role in anxiety and other CNS disorders with          reference to H1, H2, H3 receptors ²⁸

6. Opoid receptors ²⁹
7. AdenosineA1receptors ³⁰
8. Dopaminergic receptor: (D2) receptors ³¹
9. Somodendritic auto receptors ^{32, 33}
10. Adrenergic receptors ³¹

Physiology of Anxiety

            Anxiety is recognised as one of the most important emotional processes with firm neurobiological roots. The neurochemistry of anxiety although not well understood has emerged to be a major area of research leading to new approaches in the treatment of anxiety. Anxiety is caused due to too many or too few neurotransmitters in the brain. Brain synthesizes several neurotransmitters such as acetylcholine, adrenaline, dopamine, endorphins, serotonin, gamma amino butyric acid, glutamate etc. Most information has come from studying the action of anxiety-reducing or anxiolytic drugs. The evidences suggest anxiety to be caused by dysfunction of one or more neurotransmitters and their receptors. The major thrusts of current work dealing with anxiety disorders have centered on the gamma amino butyric acid mechanisms, the serotonergic system, noradrenergic mechanisms and neuropeptides²². New evidences suggest a role for adenosine and cholecystokinin in the development of anxiety; drugs interactions with these neurotransmitters also may have anxiolytic effects

            The human brain is the centre of human nervous system and is a highly complex organ. The part of the brain that triggers a response to danger is the Locus ceruleus and the area of the brain responsible for the acquisition and expression of fear conditioning is the Amygdala³⁴.  Once the neurotransmitters pick up over activity/hyperactivity in the locus ceruleus, the amygdala senses danger and instructs us to run from danger. Hence, once the amygdala gets activated it sends an alarm to the heart to beat faster, breathing to become rapid and in turn activates all the biological components of fight/flight response.

 

            Pharmacotherapeutic approaches for the management of anxiety disorders include psychotropic drugs, but these agents are limited by their side-effect profile, the need for dietary precautions, and drug interactions.³⁵ Regular use of benzodiazepines causes deterioration of cognitive functioning, addiction, psychomotor impairment, confusion, aggression,  excitement, anterograde amnesia, physical dependence, and tolerance.³⁶ These are some of the factors that caused interest in many researchers to evaluate new compounds from plant origin in the hope to identifying other anxiolytic drugs with fewer unwanted side effects.

 

            In recent years, anxiolytic drugs have been among the frontrunners in terms of the number of prescription written in medical practice. This may be due to the tense life-style imposed on man by the current competitive atmosphere. Patients facing a life-threatening illness commonly experience anxiety over their fears and uncertainties about their future. Currently available drugs used for treatment of psychological disorders are not totally devoid of side effects.

            At present, the etiological factors responsible for these disorders are not expected to decrease; there is a need for new drugs with less adverse reactions. In the search for new therapeutic products for the treatment of neurological disorders, medicinal plant research, worldwide, has progressed constantly, demonstrating the pharmacological effectiveness of different plant species in a variety of animal models.¹³

 

            In present era, a sudden holocaust of mental disorders, and recognition of severe side effects and addiction liabilities associated with long term administration of widely prescribed synthetic drugs have aroused the attention of researchers towards natural resources India has an ancient heritage of traditional medicine. The material medica provides a great deal of information on the folklore practices and traditional aspects of therapeutically important natural products. Indian traditional medicine is based on various systems including Ayurveda, Siddha, Unani and Homoeopathy. The evaluation of all these drugs is based on phytochemical and pharmacological approaches which lead to drug discovery often is reffered to as “natural product screening ³⁷. Any part of the plant may contain active components like bark, leaves, flowers, roots, fruits, seeds, etc ³⁸. The beneficial medicinal effects of plant materials typically result from the combinations of secondary products present in the plant.

 

            Nature is the best combinatorial chemist and possibly has answers to all diseases of mankind.  Herbal treatment is a natural form of healing or alternative therapy where herbs and plants are used in the form of extracts, pills, syrup or powder to cure ailments or diseases of human beings and in some cases animals too. Today herbal remedies are back into prominence. The efficacy of many conventional medicines which once had near universal effectiveness against serious infections is on the wane.

            In Ayurveda-drug discovery uses “Reverse pharmacology”, in which drug candidates are first identified, based on large scale use in the population and validated

in clinical trials. Till now, natural product compounds discovered from medicinal plants (and their analogues also) have provided numerous clinically useful drugs. Four

billion people or about 80% of the world’s population uses herbal medicine as part of health care. In India itself, there are more than 1100 medicinal plants grown all over the wild forests. Of these, some 60 genuses are used immensely in medicinal preparations ^{39, 40, 41}

 

            Various types of herbal medicines have been used as anxiolytic agents in different part of the world, such as Citrusaurantium from Brazil-Indians, Afro-Brazilians and Caboclos⁴², roots of kava plant from the topical pacific region, and the saponin-containing fraction of leaves of Albizia lebbeck  from India, Some of the medicinal plants that are used as sedative or anxiolytic are Matricaria recutita⁴³, Salvia guaranitica⁴⁴ Valeriana officinalis⁴⁵ , Passiflora caerulea⁴⁶ and Stachys lavandulifolia⁴⁷  are all known to have anxiolytic effects ⁴⁸

 

            The literature survey reveals that the genus Tecoma stans possesses various bioactive compounds such as saponins, flavonoids, alkaloids, phenols, steroids, anthraquinones, tannins, terpenes, phytosterols, triterpenes, hydrocarbons, resins, volatile oil and glycosides^{49, 50}. Recent studies found that Tecoma genus possess various bioactive compounds that are reported to exhibit various pharmacological activities such as antioxidant, antimicrobial and antifungal activities.^{49, 51, 52}

 

            Despite a long tradition of use, no systematic phytochemical and pharmacological work for anxiolytic activity has been carried out on this potential plant.  The purpose of this study was to characterize the putative anxiolytic-like activity of an ethanolic extract prepared from the leaves ofTecoma stan linn using the elevated plus maze (EPM) and light–dark exploration test in mice