Botanicals for mood disorders with a focus on epilepsy

YEBEH-04516; No of Pages 10 Epilepsy & Behavior xxx (2015) xxx–xxx

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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh

Review

Botanicals for mood disorders with a focus on epilepsy Germain Jean Magloire Ketcha Wanda a,⁎, Steve Guemnang Ngitedem b, Dieudonné Njamen b a b

Department of Psychology, Faculty of Arts, Letters and Social Sciences, University of Yaounde I, P.O. Box. 755, Yaounde, Cameroon Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon

a r t i c l e

i n f o

Article history: Revised 13 August 2015 Accepted 14 August 2015 Available online xxxx Keywords: Mood disorders Epilepsy Animal models Botanicals

a b s t r a c t Mood disorders are among the major health problems that exist worldwide. They are highly prevalent in the general population and cause significant disturbance of life quality and social functioning of the affected persons. The two major classes of mood disorders are bipolar disorders and depression. The latter is assumed to be the most frequent psychiatric comorbidity in epilepsy. Studies published during the second half of the 20th century recognized that certain patients with epilepsy present a depressed mood. Synthesized pharmaceuticals have been in use for decades to treat both mood disorders and epilepsy, but despite their efficiency, their use is limited by numerous side effects. On the other hand, animal models have been developed to deeply study potential botanicals which have an effect on mood disorders. Studies to investigate the potential effects of medicinal plants acting on the nervous system and used to treat seizures and anxiety are increasingly growing. However, these studies discuss the two conditions separately without association. In this review, we present animal models of depression and investigative models (methods of assessing depression) of depression and anxiety in animals. Other classical test models for prediction of clinical antidepressant activity are presented. Finally, this review also highlights antidepressant activities of herbals focusing specially on depression-like behaviors associated with epilepsy. The pharmacological properties and active principles of cited medicinal plants are emphasized. This review, therefore, provides an overview of the work done on botanicals for mood disorders, potential mechanisms of action of botanicals, and the major compounds. This article is part of a Special Issue entitled “Botanicals for Epilepsy”. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Mood disorders are treatable medical conditions in which the emotional symptoms are intense, long-lasting, or recurrent and decrease the ability to function. Some of the major symptoms include low mood, reduced interest or pleasure in all activities, appetite changes, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy, worthlessness or excessive guilt, and reduced ability to concentrate [1]. Mood disorders are among the major health problems in the world for two reasons: they are highly prevalent in the general population, and they cause significant disturbance of life quality and social functioning of the affected persons. They are generally classified into two groups, which are bipolar disorders and depression.

⁎ Corresponding author. Tel.: +237 675947772. E-mail address: [email protected] (G.J.M. Ketcha Wanda).

Bipolar disorder has traditionally been thought to have a lifetime prevalence of about 1% of the world populace. The term “depression” is suggestive of a single entity; it denotes a very heterogeneous psychiatric disorder with several clinical manifestations, some of which are particular to patients with epilepsy. Depression in epilepsy has been considered, for a long time, as a complication of the underlying seizure disorder. Psychosocial aspects of being diagnosed with epilepsy may contribute to depression associated with epilepsy. Some clinical and experimental evidence suggests that the imbalances in such neurotransmitters as GABA, glutamate, norepinephrine, and serotonin, which are presumed to occur in patients with epilepsy, may concurrently contribute to the development of depression. Major depression and dysthymia are the most common mood disorders experienced by people with epilepsy, and the incidence of depressive disorders in epilepsy ranges between 20% and 80% [2,3]. Indeed, the relationship between mood disorders and epilepsy has been observed for over 2400 years, and studies published during the second half of the XX century also recognized that certain patients with epilepsy present depressed mood [4]. Depression is the most

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Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

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frequent psychiatric comorbidity in epilepsy, affecting one out of three patients with epilepsy in population-based studies. It is lower in community-based samples with epilepsy (20–30%) and higher in specialist epilepsy clinics (20–55%). This large variation in epidemiological data is due to the diversity of methodologies across the studies and to the differences in definitions of mood disorder [5]. Yet, despite its high prevalence, depression remains unrecognized and undertreated in patients with epilepsy [6]. Depression as a common comorbidity of temporal lobe epilepsy (TLE) is poorly understood [7,8]. In general, evidence for treatment strategies of mood disorders in epilepsy is lacking, and development of management approaches tends to rely on clinical experience rather than evidence-based trials favoring one treatment over another [9]. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition and preclinical development of effective therapies. For instance, the pharmacological mechanisms of many antidepressant drugs have been well documented. However, there is a notable paucity of data on the effectiveness of antidepressants in epilepsy-associated depression. Increasingly, researchers are developing animal models of the comorbidity between depression and epilepsy and to evaluate the effects of herbals on depression in animals with chronic epilepsy induced by status epilepticus. This review presents the major experimental models that are in use to test drugs and botanicals for use in mood disorders and an overview of the work done on botanicals for mood disorders, potential mechanisms of action of botanicals, and the major compounds. This review will also focus on animal models for depression associated with epilepsy and on studies that examine whether a commonly used animal model of TLE is characterized by behavioral and biochemical alterations involved in depression. Then, we will look at studies based on the potential of botanicals used as possible treatment modality for epilepsy-associated depression. 2. Integrative description of experimental models used to test drugs and botanicals 2.1. Tests of depression and anxiety based on behavioral changes or environmental challenges 2.1.1. Tests to assess depression in animals Depression is diagnosed on the basis of a cluster of highly variable symptoms [1]. In addition to depressed or irritable mood, depression includes cognitive symptoms (guilt, ruminations, and suicidality), emotional symptoms (anhedonia), homeostatic or ‘neurovegetative’ symptoms (for example, abnormalities in sleep, appetite, weight, and energy), and psychomotor agitation or retardation. Only a subset (homeostatic symptoms, anhedonia, and psychomotor behavior) can be measured objectively in rodents. Studies that attempted to develop valuable animal models of comorbidity between epilepsy and depression focused on behavioral alterations in animal models of epilepsy classically linked to depression. Most animal models of depression are based either on environmental challenges or on manipulation of sensory and integrative functions of the brain [10]. Two of the major symptoms in depression are despair and anhedonia [4]. In rodents, the behavioral equivalents to these emotional states are accessed by the forced swim test, the saccharin or sucrose taste preference test, and the tail suspension test, based on the observation that animals exposed to uncontrolled or unpredictable aversive events for a sufficient period of time will develop long-lasting deficits in escape performance [11]. The forced swim test (FST) is a well-characterized model used to screen the effectiveness of antidepressant drugs in rodents. The FST assesses the adaptive behavior of rodents when confronted to a

stressful situation. The swim test involves the scoring of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape [12]. There are two versions that are used, namely, the traditional and modified FSTs, which differ in their experimental setup. For both versions, a pretest of 15 min (although a number of laboratories have used a 10-min pretest with success) is included, as this accentuates the different behaviors in the 5-min swim test following drug treatment. Immobility period is regarded as the time spent by the rats to float in water with no struggle and making only those movements necessary to keep their head above the water. Reduction in passive behavior (duration of immobility) is interpreted as an antidepressant-like effect of the manipulation, provided that it does not increase general locomotor activity, which could provide a false positive result in the FST [13]. In the sucrose taste preference test, when given access to tap water and sweet solution, rodents naturally and strongly prefer the latter. However, animals submitted to experimental stress show a decrease in consumption of the sweet solution. Some studies have demonstrated that rats in which seizures have been induced by kainite, lithium–pilocarpine, or electrical kindling spent a significantly longer time immobile in the forced swim test and exhibited loss of preference for saccharin solution when compared with nonepileptic animals [4]. In the tail suspension test (TST) [14], which relies on similar assumptions and interpretations as the FST, the mice are individually hung upside down by their tails on the edge of a table, 50 cm above the floor by using adhesive tape placed approximately 1 cm from the tip of their tails. The total period of immobility is recorded manually for 6 min. An animal is considered to be immobile when it does not show any body movement, hangs passively, and is completely motionless. The time spent immobile is evaluated. Other classical test models for prediction of clinical antidepressant activity are as follows: apomorphine antagonism and reserpineinduced hypothermia. Apomorphine (in higher doses) and reserpine induce syndromes like hypothermia, the reversal of which is used as a reliable initial method to detect antidepressant activity. In fact, imipramine-like tricyclic antidepressants antagonize hypothermia induced by apomorphine in mice [15]. 5-Hydroxytryptophan (5-HTP) potentiation of head twitches in mice is one test model used to assess therapeutic action of antidepressant drugs, which in part reduce functional activity of some central 5-HT systems. The 5-HT precursor produces typical behavioral responses in rodents. The effect in rats designated “wet dog shakes”, comprising intermittent body movements including a shaking of the head, whereas, in mice, predominantly rapid and intermittent head twitches are the effect. Jobe et al. [16] and Kondziella et al. [17] have shown that serotonin (5-HT) deficiency is not only a mechanism of depression but also a defining approach in the treatment of the disease through the use of selective serotonin reuptake inhibitors (SSRIs). On the other hand, dysfunction of serotonergic transmission has been reported under conditions of TLE [18]. It was suggested that impairments in serotonergic transmission represent a pathophysiological link between epilepsy and depression [16,19]. The action of a given substance in apomorphine, reserpine-induced hypothermia, and 5-HTP potentiation of head twitch models can, therefore, show that this substance might have effect on serotonin reuptake inhibition to exert its antidepressant activity. 2.1.2. Tests to assess anxiety in animals Anxiety, which has also been reported as a psychological disorder common in people with epilepsy, has been described as an unpleasant emotional state for which the cause is either not readily identified or perceived to be uncontrollable or unavoidable [20].

Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

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The development of anxiety and mood disorders has been associated with seizure disorders involving limbic structures, such as seizures of temporal and frontal lobe origin. In fact, ictal fear can be identified in seizures originating in the amygdala, hippocampus, and cingulate gyrus. Yet, anxiety symptoms can also be identified in primary generalized epilepsy. The common pathogenic mechanisms that may be operant in the development of anxiety disorder and epilepsy include neurotransmitter abnormalities and structural and functional abnormalities in common neuroanatomic structures, particularly the amygdala, hippocampus, and cingulate gyrus [21]. Given the comorbidity of anxiety and epilepsy, experimental tests have been developed to quantify anxiety level in rats. Open field and elevated plus maze are two experimental tests used to induce stress (anxiety) in animals. As the previous tests, they are based on the fact that mice not only display high levels of exploration of a novel environment but also have an innate aversion to enter exposed and well-lit areas [22]. The elevated plus maze (EPM) presents the mouse with the choice of spending time exploring the open areas of a plus-shaped runway or spending time exploring the enclosed sections [23]. The maze consists of two opposite open (30 cm × 5 cm × 0.2 cm) and two opposite closed (30 cm × 5 cm × 15 cm) arms, extending from a central platform (5 cm × 5 cm) and elevated to a height of 45 cm above the floor. The entire maze is made of clear Plexiglass. Mice are individually placed on the center of the maze facing an open arm, and the number of entries and the time spent in the closed and open arms are recorded during a 5-min observation period. Arm entries are defined as the placement of all four paws into an arm [24]. Another exploration-based test, founded on similar conflicting tendencies to approach or avoid a potentially dangerous area, is the open-field (OF) test where the aversive area is represented by the central zone of a brightly lit open field. An ‘open-field apparatus’ suitable for a mouse is made of a floor space of 40 cm × 40 cm with 30-cm high walls. The floor is colored black, and the floor area is divided into 9 equal squares by white lines. A mouse is placed at the center of the field and is left for 2 min for acclimatization with the apparatus. Thereafter, for the next 5 min, the time spent in the central square, the number of squares crossed, and the number of rearings (no. of times the animal stands on the rear paws) are noted. 2.1.3. Antidepressant activity focusing specifically on depression-like behaviors associated with epilepsy Although the mechanisms of depression in patients with epilepsy are poorly understood, for both understanding the mechanisms of the condition and preclinical development of effective chemical or herbal therapies, animal models of the comorbidity between epilepsy and depression have been established. Mazarati et al. [19] have examined whether a commonly used animal model of TLE is characterized by behavioral and biochemical alterations involved in depression. For that purpose, male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epilepsy was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited an increase in immobility time under conditions of the FST which was indicative of a despair-like state and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Depression has been described in WAG/Rij inbred rats, which exhibit spontaneous absence seizures [25], and in genetic absence epilepsy rats from Strasbourg (GAERS) [26]. However, reports on depression-like disorders associated with experimental TLE are scarce and controversial. Thus, Mortazavi et al. [27] reported increased behavioral despair under conditions of forced swim test (FST) in pentylenetetrazole-kindled rats. Mazarati et al. [28] have

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described anhedonia and despair in animals that had been subjected to rapid kindling at a young age. However, Ma and Leung [29] found no changes in forced swimming behavior after amygdala kindling. Adamec et al. [30] and Wintink et al. [31] found no changes in taste preference in animals which had been subjected to kindling. Koh et al. [32] reported changes in FST in juvenile rats following kainic acid induced status epilepticus (SE). In contrast, Groticke et al. [33] found an improved performance of mice under conditions of FST in postpilocarpine SE model of epilepsy compared with nonepileptic controls. Clearly, more efforts are required in the pursuit of validation of available models of the comorbidity of epilepsy and depression. For example, Mortazavi et al. [23] reported increased behavioral despair under conditions of FST in pentylenetetrazolekindled rats. 2.2. Animal models of depression and anxiety Animal models of depression and anxiety are mostly based on functional modules corresponding to specific neural circuits, hormonal systems, and behavioral/psychophysiological responses which are found both in humans and in animals. As regards the genetic bases of vulnerability to anxiety disorders and depression, many different approaches are being used including selected rodent lines. 2.2.1. Lesion model A bulbectomized rat or mouse has been considered as a model of agitated depression [34,35] because ablation of the olfactory bulb in mice not only induces typical loss of smell but also disrupts the limbic–hypothalamic axis with the consequence of behavioral, neurochemical, neuroendocrine, and neuroimmune alterations, all of which may resemble changes in patients with depression [36,37]. The behavioral outcome of olfactory bulbectomy is largely thought to result from compensatory mechanisms of neuronal reorganization. Underlying changes are thought to involve alterations in synaptic strength and/or loss of spine density in various limbic regions including the amygdala and hippocampus resulting in changes to major neurotransmitter systems [38]. 2.2.2. Genetic models The currently available animal models of anxiety are based on studying the etiology and underlying neurobiological mechanisms of anxiety disorders, in particular for psychiatric genetic research. Trait anxiety (the “anxious temperament”), supposed to be a major risk factor for anxiety disorders [39], is found in a number of individuals in a normal rat or mouse population but is easier to study in lines obtained by (psycho)genetic selection, where expression of this trait is enhanced. A number of rat lines have been proposed as models of trait anxiety: the HAB rats [40], selected on the basis of their behavior in the EPM; the Syracuse rats [41]; the Maudsley reactive/nonreactive strains [42]; the Tsukuba [43] and Floripa [44] 86 lines; and two lines selected on the basis of pups' ultrasonic vocalizations [45]. The Roman low-avoidance (RLA) rats, selected on the basis of poor acquisition of a two-way avoidance response in the shuttle box, can also be considered as a model of high trait anxiety-emotionality [46–49]. Other genetic models include targeted manipulation of candidate genes (e.g., generation of knockout or transgenic animals), siRNA and viral transfection, quantitative trait loci (QTL) analysis, and the use of gene expression arrays, among others [50]. A relatively new field in animal models of anxiety disorders is the study of structural brain plasticity and adaptive neurogenesis, which appears to be involved in anxiety-related behaviors [51]. There are transgenic mice that have additional copies of certain genes in their genome, which results in a gain-of-function generally by the knock-in techniques or in a loss-of-function by the

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knockout technique [52,53]. The last technique consists in the precise disruption of a gene resulting in the complete ablation of protein and/or mRNA production within every cell [54]. The monoamine hypothesis postulates that depression is caused by an impairment of serotonergic, noradrenergic, or dopaminergic neurotransmission due to a decrease of synthesis or early degradation of neurotransmitters, alteration of expression or function of neurotransmitter receptors, and impairment of signal transduction systems [55]. A less explored approach with high translational value is the introduction in mice of genes having natural human mutations associated with vulnerability or pathologies. A most relevant case is that of the val66met polymorphism of the brain-derived neurotrophic factor (BDNF) neurotrophin, which impairs activitydependent BDNF secretion [56] and results in enhanced stressinduced anxiety [57] and impaired fear extinction learning in both mice and humans [58]. Originally, the neurotrophic theory was based on findings in rodents, demonstrating that acute or chronic stress decreases BDNF expression in the hippocampus and that diverse classes of antidepressants produce the opposite effect and can prevent the actions of stress [55]. 2.3. Advantages and disadvantages of the various tests to assess anxiety and depression Measuring depression and anxiety in animals is not simple because the classifications of psychiatric pathology (either with the DSM-IV or ICD-10 systems) remain essentially syndromic and are regularly revised; on the other hand, there is a great variability in the population concerning (epi) genetic factors and other predisposition factors, neurobiological mechanisms, and comorbidities. In addition, certain aspects of human pathologies will probably never be accessible in animal models. However, some symptoms observed in anxiety disorders and depression can be accurately modeled in rats and mice [50]. The FST is one of the most commonly used animal models for assessing antidepressant-like behavior. The classical procedure of the FST involves a preexposure (pretest) to the water tank for 15 min, and the time spent immobile during the test was the critical measure. By introducing measurement of three different behaviors (struggling or climbing, mild swim, and immobility), Armario and Nadal [59] have demonstrated that a pretest was not needed to detect antidepressant activity in rats, although the efficacy of antidepressants was better after previous experience with the situation. The TST, another test based on the same principle as the FST, is reported to be less stressful and has higher pharmacological sensitivity than FST. Unfortunately, this test can only be applied to mice [14]. One major advantage of the TST is that it is not confounded by stressful hypothermia as is the case in the FST. However, the TST is restricted to strains that do not tend to climb with their tail, which otherwise confuses the interpretation of behavioral measures [11]. In either test, the underlying principles measuring the lack of active coping behavior are the same. However, whether immobility should be interpreted as passive stress coping, behavioral despair or even depression-like behavior remains controversial. The different anxiety tests for rodents found in the literature are classified in two main categories: unconditioned response tests (which require no training and usually have a high eco/ethological validity) and conditioned response tests (which often require extensive training and may show interference with mnemonic and motivational processes) [60]. One of the issues raised by the use of animal models is whether the test measures something related to anxiety in humans. The second is whether any individual behavioral test or particular measure

within a test is capturing the essence of anxiety. Given the complex theoretical construct of anxiety, like other traits, it is unwise to think that we can catch the essence of the trait with only one single test or one single measure. In fact, psychometric tests in humans assuming such a complexity very often contain subscales measuring different components of anxiety [59]. Reports classifying animals in groups with putatively different levels of anxiety (or any other behavioral trait) are based on a single test and a single measure within a particular test (i.e., time spent in the open arms of the EPM), and this constitutes a strong limitation of these types of studies. Although measurements can be done using a single test, it is better to use a battery of these tests (for instance, the open field, the EPM, and a dark–light transition test) to assess each individual's behavioral phenotype, since these tests measure anxiety under different conditions [61]. Some of these tests are timeconsuming and, therefore, not always appropriate for large screening studies. The approach based on the use of genetically segregated lines/ strains also raises in part the problem of the validity of studies with animals because of different conceptualization of animal and human models. There is another possible reason for discrepancies among the tests other than the fact that they measured different aspects of anxiety. Performance in a particular test may be influenced by factors (genes) other than anxiety that can perturb the actual relationship between the variable measured and the anxiety trait. The perturbing effects of those factors may be markedly different among lines/strains because of the random selection of genes related to these interfering factors [59]. More classical approaches have been to utilize genetically driven silencing or overexpression of a particular gene. Again, approaches strongly differ in humans and animals, thereby making it more difficult to translate results from bench to clinic. Exploring how gene–environment interactions (and associated epigenetic and psychophysiological/behavioral mechanisms) determine each individual's capacity to cope with fear, threat, and stressful situations appears to be a major goal of animal models in the years to come. 3. Botanicals for mood disorders The history of plants being used for medicinal purpose is probably as old as the history of mankind. It is estimated that about 67% of the current drugs have a natural origin [62]. Plants have gained an increasing popularity as an alternative treatment for their low toxicity and therapeutic effects. The effects of crude extract and alcoholic extract of many plants on the rodent central nervous system are been investigated worldwide. Table 1 summarizes findings observed in models of epilepsy and other animal models. Some studies investigating the potential effects of medicinal plants acting on the nervous system are also summarized in Table 1. Plant nomenclature, traditional uses, and geographical distribution are also mentioned. A variety of active plant-derived substances such as flavonoids, isoflavonoids, polyphenols, saponins, and tannins are included in Table 1. Antidepressant effects in animal models of epilepsy-associated depression are presented as well as plants with anticonvulsant and antidepressant effects. The clinical effects on the two conditions have been associated where addressed in the literature like in the case of Gladiolus dalenii. 4. Common pathogenic mechanisms between depression and epilepsy and mechanisms of action of the botanicals for mood disorders While psychosocial aspects of having epilepsy may contribute to depression associated with epilepsy, there is a growing consensus that this condition has neurobiological bases [104]. For example, both clinical evidence and experimental evidence suggest that the

Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

Names

Families

Common or vernacular names

Distribution

Models tested and effects

Models of epilepsy

Gladiolus dalenii Van Geel

Iridaceae

“Mantsap Letoupuh” (wild onion) in the Babadjou language (local language in the western region of Cameroon), Khahla-e-kholo, Phende-phende (South Africa), Karungu, Kegenege (Congo), Sakavirondamba (Madagascar)

Grasslands, savannas and woodlands of sub-Saharan and Southern Africa, Eastern Africa, and western Arabia

Significantly greater immobility times than the control animals Forced swim test Decrease in locomotor activity in the open field Assessment of hypothalamic–pituitary–adrenal (HPA) axis activity Determination of BDNF

Induction of temporal lobe epilepsy (TLE) Antidepressant-like properties similar to fluoxetine in epilepsy-associated depressive states

Acosmium subelegans (Mohlenbr) Yakovl

Leguminaceae

“Perobinha-do-campo”

Securidaca longepedunculata (Fresen.)

Polygalaceae

Violet tree (English)

Savanna woodland from Senegal to Northern and Southern Nigeria and is generally widespread in tropical Africa

Cissus sicyoides (CS)

Vitaceae

“Insulinas, cipo-puca, bejuco de porra, bejuco caro, puci, and anil trepador”

Tropics, mainly in Brazil and the Caribbean

Alpha-tocopherol protects against pentylenetetrazoland methylmalonate-induced convulsions and prevents the occurrence of epileptic foci in a rat model of posttraumatic epilepsy.

Passiflora edulis Sims

Passifloraceae

Argentina, Brazil, Paraguay, Peru, Sleep-inducing properties and Cameroon Potentiated the total sleeping time induced by diazepam. STR-induced seizures and NMDA-induced turning behavior Decreases spontaneous motor activity and exploratory behavior in mice, increases pentobarbital-induced sleep time in rats, and attenuates the intensity of apomorphine-induced stereotypies in mice As N. latifolia is used to treat diseases of the nervous system such as anxiety and anxiolytic and sedative properties in mice Spontaneous motor activity and exploratory behavior in mice increase pentobarbital-induced sleep in rats, and attenuate the intensity of apomorphine that induces stereotypies in mice.

Presence of anticonvulsant properties

Nauclea latifolia Smith Rubiaceae

Depressant effect upon the central nervous system (CNS) of rats and mice, Potentiation of barbiturate sleep, a reduction of the spontaneous and the amphetamine-induced locomotor activity Anxiolytic Strychnine-induced seizure test in mice Anxiolytic activity Elevated plus maze test Sedative activity Hexobarbitone-induced sleep tests

Proposed active compounds

Picrotoxin-induced seizure test in mice Anticonvulsant

Significant anticonvulsant properties

α-Tocoferol, coumarin, flavonoids, two steroids, phenolic compounds Anthocyanins and saponins

Other traditional uses or potential health effects

Authors

Treatment of headache, epilepsy, convulsions, and intestinal spasms; antidote for venomous stings and bites, arthritis, rheumatism, and nasopharyngeal affections; and laxative. The bulbs of G. dalenii Van Geel traditionally used for the treatment of epilepsy and schizophrenia in Cameroon. Digestive problems, muscle and joint aches, and mood disorders Used in the Brazilian folk medicine as sedative or “tranquilizer”, in epilepsy treatment and in hysteria, nervous breakdown, and chorea

[63] [64] [65]

Used in traditional medicine for the management of pain, inflammation, epilepsy, and other ailments

[67] [68]

[66]

Used in popular medicine as a diuretic, anti-inflammatory, and antidiabetic. In Brazil, CS was evaluated for its anticonvulsant property, where it is used against epilepsy and cytotoxic activity

[69] [70] [71] [72] [73] [74] [75] [76] [77] [78] In traditional medicine, the plant has [79] therapeutic properties for the [80] nervous system diseases. [81] [82] [83] [84] In Cameroon, N. latifolia is used in the treatment of fever, yellow fever, [85] malaria, and diseases of the central [86] nervous system like epilepsy. It is also used in the treatment of anxiety agitation, cerebral deficit, and behavioral disturbances in children with mental retardation.

G.J.M. Ketcha Wanda et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

Table 1 Summary of some medicinal plants and their traditional use as antidepressant, sedative anxiolytic, and anticonvulsant.

(continued on next page) 5

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Names

Families

Common or vernacular names

Distribution

Nauclea latifolia Smith

Models tested and effects Significant, anticonvulsant, anxiolytic, and sedative properties Behavioral activity of the decoction of the roots on different experimental models (FST, horizontal wire test and hole-board test) for detecting antidepressant, myorelaxant, and antianxiety properties Antidepressant and anxiolytic-like effects of hydroalcoholic (extract leaves and flowers) using forced swimming test, elevated plus maze, dark–light test, and open field In the EPM, the plant extract increased the percentage of time that mice spent in the open arms as well as the percentage of entries into these arms. In the dark–light test, the extract significantly increased the time spent in the light space. Diminution of immobility time of mice exposed to the forced swimming test Reduce immobility time in FST and TST Extension phase in MES test

Salvia elegans Vahl

Lamiaceae

“Mirto” (Mexico), pineapple sage, and pineapple-scented sage

Central and South America, Central Asia, and Mediterranean Eastern Asia

Terminalia belerica

Combretaceae

Beleric, Bahera Bastard myrobalan

Plains of Southeast Asia

Passiflora foetida

Passifloraceae

Stinking passion flower, wild water lemon, love-in-a-mist, or running pop

Southwestern United States, Central America, South America, and Southeast Asia

Reduce immobility time in FST and TST

Juglans regia

Juglandaceae

Great Britain and United States

Apocynum venetum

Apocynaceae

Decreased the duration of immobility in the FST and TST Reduced immobility time in FST and TST

Cassia occidentalis

Fabaceae

Common walnut and California walnut Basikurumon (Japan), Oshoro Town weed, and Dogbane leaf Coffee senna, negro coffee, coffee weed, and stinking weed

Daucus carota

Apiaceae

Wild carrot or Queen Anne's lace

Japan and China

India, thorough tropical and subtropical regions

Northern America

Decrease in the time spent immobile by rodents in FST and TST Increase the motor activity in OF test and time spent in the open arms of the EPM Reduced the duration of immobility in both TST and FST; showed

Models of epilepsy

Proposed active compounds

Delay the onset of clonic convulsions induced by PTZ test and reduce tonic hind limb

Tannic acid and polyphenols

Reduced the severity of seizures in PTZ -induced seizures

Alkaloids and flavonoids

Omega-3 fatty acid Flavonoids and kaempferol Flavonoids

Other traditional uses or potential health effects

Authors

Used in Mexican traditional medicine for the treatment of different central nervous system diseases, principally, anxiety

[87]

Used as laxative, diuretic, and aphrodisiac, also for pharyngitis, anemia, HIV infection, vaginal infection, liver problems, and epilepsy Antidepressant activity Used for diarrhea, liver disorders, tumors, fever, skin diseases (India); asthma (Malasia); and epilepsy (Argentina) Astringent, antifungicide, and antiseptic Used for hypertension and as antioxidant

[88]

Purgative, laxative, anti-inflammatory, analgesic, and antiepileptic

[12] [93]

Anticonvulsant, antidiabetic, antiestrogenic, antihistaminic,

[15]

[89] [90]

[91] [92]

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Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

Table 1 (continued)

Euphorbiaceae

Gooseberry, Phyllanthus emblica, Emblica, and Indian gooseberry

Aegle marmelos

Rutaceae

Bengal quince, golden apple, stone apple, wood apple, and bili

Ocimum basilicum

Lamiaceae

Ocimum gratissimum

Lamiaceae

Hedranthera barteri Hook. F

Apocynaceae

Hypericum perforatum Linné

Clusiaceae

Morus mesozygia

Moraceae

Alternanthera brasiliana (L) Kuntze

Amaranthaceae

Randia Nilotica Stapf.

Rubiaceae

Northern and south western India

India, Sri Lanka; Southeast Asia, Increased time spent on and number Malaysia, Tropical Africa, and the of entries into open arms while United States decreased number of stretch attend postures and head dips in closed arms of EPM. Decrease duration of immobility both in the TST and FST Sweet basil, basil, and Thai China, India, New Guinea ,and Protect central nervous system basil Southeast Asia against oxidative damages of electromagnetic field Decrease in immobility score and increase in swimming in FST Clove basil, African basil, wild Madagascar, Hawaii, Mexico, At low doses, enhanced mouse basil, Efinrin (Yoroba) Panama, West Indies, Brazil, locomotor activity Daidoya in (Hausa) Bolivia, and Southern Asia Induced a depressed-like behavior in the TST Dog's penis (Yoruba) South Nigeria, Ghana, North/Reduced the immobility in FST and West Cameroon, Congo TST Brazzaville, and Benin Increased time spent in opened arms of the EPM Increased the time spent in the light chamber in the dark–light test St. John's wort, Klamath Europe, Asia, USA, and Western Delayed the onset of tonic weed, common goat weed, Cape of South Africa convulsion and protect the and Tipton weed mice against mortality in PTZ-induced seizures Wonton (Ghana), Aye Found on the edge of the humid The extract reduced immobility in (Nigeria), and Kankate rain forests from Senegal to the FST and TST compared with (Zaire) Cameroon and Gabon; also in dry imipramine. savanna formations and in southern Europe Penicillina, terramicina, Central America, the Caribbean Increase the number and duration of Reduce the duration of alternanthera, Brazilian and tropical South America head poking in HB test; rearing and seizures in PTZ test joyweed, calico plant, indoor lines crossed in OF test; clover, Joseph's coat, and joy Increased the entries and time spent weed in opened arms of EPM “Shagart elmarfaen”; in Sudan central and east Africa as Sudan and northern Nigeria, well as Cameroon and Nigeria it is known as ‘barbaji’, ‘tsibra’, or ‘kwanarya’ The Fulanis call it ‘gial goti’

antioxidant, antiseptic, antispasmodic, and antianxiety

Polyphenols, flavonoids, ascorbic acid, and tannic acid

Alkaloids, cardenolides, flavonoids ,and saponins

Used as diuretic, aphrodisiac, laxative, astringent, and refrigerant and for anemia, jaundice, dyspepsia, hemorrhage disorders, diabetes, asthma, and bronchitis Constipation and some gastrointestinal problems

[94]

Used for supplementary treatment of asthma, stress, and diabetes; have potent antioxidant, antiviral, and antibacterial activities

[96]

Used as analgesic

[97] [98]

Used to treat dizziness, gonorrhea, and tumors, also as a vermifuge Anticonvulsant activity, antidepressant, and anxiolytic activity

[99]

Used as anti-inflammatory, astringent, antiepileptic, and antiseptic

[100]

Alkaloids, saponins, and flavonoids

[95]

[101]

Alkaloids, steroids, and triterpenes

Used as anti-inflammatory, analgesic, antitumor, immunomodulator and for epilepsy

[102]

Saponins, tannins, flavonoids, and cardiac glycosides

Mental breakdown and for convulsions Epilepsy and for madness depressant activity

[103]

G.J.M. Ketcha Wanda et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019

Emblica officinalis

opposite actions against hypothermia induced by apomorphine; had significant effect in potentiation of head twitches Reduction of immobility time in FST and TST

7

8

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imbalances in such neurotransmitters as GABA, glutamate, norepinephrine, and serotonin, which are presumed to occur in patients with epilepsy, may concurrently contribute to the evolution of depression [17, 104–106]. Animal models of the comorbidity between epilepsy and depression are established for several goals. Firstly, it is to examine whether depression developed under conditions of a commonly used model of TLE, namely, post-SE chronic epilepsy in the rat. Secondly (knowing that the post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression), in addition to characterizing the behavioral symptoms of depression, some neurochemical correlates of the comorbidity are studied. Among multiple candidate mechanisms, serotonergic transmission as a target for initial experiments has been selected. On the one hand, serotonin (5-HT) deficiency is not only a mechanism of depression [16,17] but also a defining approach in the treatment of the disease through the use of selective serotonin reuptake inhibitors (SSRIs). On the other hand, dysfunction of serotonergic transmission has been reported under conditions of TLE [18]. It was suggested that impairments in serotonergic transmission represent a pathophysiological link between epilepsy and depression [16]. Zobel et al. [107] in one clinical study emphasized comparable impairments in the functioning of the hypothalamic–pituitary– adrenocortical system in patients with epilepsy and those with depression. A number of clinical reports have implicated hippocampal neurodegeneration [108,109] or dysfunction [110] in the development of depression in patients with epilepsy, although few studies have suggested otherwise [111,112]. Studies by Mazarati et al. [17] showed that some patients that suffer from epilepsy-induced depression do not respond well to selective serotonin reuptake inhibitors that included fluoxetine. The findings that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways [17]. Gladiolus dalenii administration caused a significant increase in the level of hippocampal BDNF compared with saline and fluoxetine even though a substantial number of preclinical studies have failed to show these changes induced by antidepressants [113,114]. However, their findings were in agreement with previous reports demonstrating how chronic administration of several antidepressants, including selective serotonin reuptake inhibitors, increases BDNF expression in the hippocampus [115–117]. The normalization of depressive behavior by herbals and wellcharacterized substances can be due to their ability to correct the hyperactivity of the HPA axis. It is known that excessive activation of the HPA axis is reversed by selective serotonin reuptake inhibitors and other antidepressants [14,118]. 5. Conclusion In conclusion, mood disorders and epilepsy are two important diseases because of distribution and their incidence in the world population. To test chemical and herbal therapies that may be potentially effective, animal models have been developed and are continually becoming more sophisticated. As clinical evidence continues to mount that there is a relationship between mood disorders and epilepsy, more studies are needed to develop valuable models of the comorbidity of depression and epilepsy. On the other hand, it is necessary to look at the comorbidity with epilepsy and other mood disorders such as bipolar disturbance. In this review, we presented methods for testing plant-derived substances for their potential antidepressant and anxiolytic effects. Future studies should take into consideration the fact that both depression and anxiety can co-occur in a patient with epilepsy, recognizing that the comorbidity of mood disorders and epilepsy in patients remains an area of active investigation. While progress has been made in understanding the mechanisms of action of medicinal plants that

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Please cite this article as: Ketcha Wanda GJM, et al, Botanicals for mood disorders with a focus on epilepsy, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.08.019