Medical Hypotheses 82 (2014) 105–110
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Therapeutic potential of agomelatine in epilepsy and epileptic complications P.V. Vimala ⇑, P.S. Bhutada, F.R. Patel Sinhgad College of Pharmacy, Post-Graduate Research Department, Off Sinhgad Road, Vadgaon (Bk), Pune 411 041, Maharashtra, India
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Article history: Received 20 July 2013 Accepted 14 November 2013
a b s t r a c t Epilepsy is a chronic neurologic disorder which often induces numerous adverse long-term neurologic effects, such as behavioral and cognitive deficits, increased predisposition to additional seizures, and cell injury or death. Cognitive dysfunction, depression, anxiety and sleep disorders are some of the highly prevalent and most disabling complications of epilepsy. The mechanisms that lead to the generation of epileptic comorbidities are poorly understood. Treatment for epileptic complications still remains a challenge because of the poor adherence and drug interactions associated with multi drug prescriptions and also for the fear of worsening seizures by the individual medications for complications. Melatonin, an endogenous hormone secreted by pineal gland has a prominent role in epilepsy. Agomelatine is a novel antidepressant which acts as melatonin MT1 and MT2 receptor agonist and serotonin 5Ht2C receptor antagonist. The combined action at MT1/2 and 5HT2C receptors, reduction in the depolarization-evoked release of glutamate, strong neuroprotective action and possible antioxidant properties of agomelatine could make it a potential agent in the treatment of epilepsy. The effect of agomelatine on hippocampal neuronal cell survival and neurogenesis, neuroprotective effect in hippocampus and frontal cortex and the antioxidant potential may contribute to the protective action of agomelatine against epilepsy induced memory decline. Agomelatine is proven to be an antidepressant and it has relieved anxiety symptoms and improved the quality of sleep in patients with depressive disorder. The action of agomelatine as a melatonin agonist and the consequent circadian resynchronizing property as well as its action as 5-HT2C receptor antagonist, could possibly suggest an antidepressant and anxiolytic action of agomelatine in epilepsy induced depressive behavior and anxiety. Since one of the many causes of sleep disruption in epilepsy is circadian rhythm disturbances and sleep promoting and circadian effects of melatonin is attributed to the MT1and MT2 subtypes of human melatonin receptors, agomelatine may also have a promising effect on epilepsy induced sleep disruptions. Thus with all these potential pharmacological actions, agomelatine could be recommended as a potential drug to treat epilepsy and its complications. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Epilepsy is a chronic neurological disorder characterized by recurrent, spontaneous brain seizures. It is the most common serious neurological condition and approximately 50 million people worldwide suffer from epilepsy [1]. About 50% of patients continue to experience seizures despite optimized treatment with modern antiepileptic drugs [2]. Seizures can induce numerous adverse long-term neurologic effects, such as behavioral and cognitive deficits, increased predisposition to additional seizures, and cell injury or death [3]. In this article we are discussing some of the most commonly accompanied complications of epilepsy such as cognitive dysfunction, depres⇑ Corresponding author. Tel.: +91 08149780874/9538367391; fax: +91 020 4354720/21. E-mail addresses: [email protected], [email protected] (P.V. Vimala). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.017
sion, anxiety and sleep disorders with a proposal of possible therapeutic potentials of agomelatine in these conditions. Often Epileptic patients with co-morbidities are provided with multi drug prescriptions which lead to poor adherence and interactions between different medications. Unfortunately, treatment for epileptic complications is still a challenge to the medical field for the fear of worsening seizures by the individual medications for complications [4,5]. Coexistence of cognitive dysfunction in epilepsy Cognitive dysfunction is one of the most commonly associated complications of epilepsy. Patients with epilepsy report significantly more memory problems and consider their memory problems to be a greater nuisance than do individuals without epilepsy [6]. The prevalence of memory problems in patients with refractory epilepsy has been estimated as high as 20–50% [7]. Several factors such as biologic (underlying neuropathology, seizure
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type and etiology, age of onset, frequency, severity and duration of seizures, structural cerebral damage); psychologic problems and treatment with antiepileptic drugs (AEDs) have been attributed to cause cognitive impairment in epilepsy [8,9]. Neuroimaging studies in patients with epileptic syndrome and cognitive dysfunction show structural abnormalities which include malformation of cortical development, hippocampal volume loss, reduction in cortical gray and white matter volumes, temporal lobe abnormalities [3,10]. Hippocampus is one of the most vulnerable brain areas for epilepsy related brain damage and thus plays an important role in the development of memory impairment in epilepsy. Specific hippocampal dysfunctions, acting in concert with changes in other brain structures, might represent a possible causal link between seizures and memory impairment [11]. It is influenced powerfully by serotonergic projections from midbrain raphe nuclei which modulate hippocampal electrical activity, hippocampusdependent behaviors, and long-term potentiation (LTP), and ultimately memory formation [12]. Some studies have shown involvement of oxidative stress in the pathophysiology of epilepsy and this prolonged oxidative damage to various brain sites could be one of the likely causes of cognition impairment in epilepsy [9,13]. The glutamatergic neurotransmission system plays a crucial role in learning and memory mechanisms as well as in convulsions. An excessive stimulation of this system resulting in cell damage and cell death could partly be an explanation for the memory deficits in epilepsy [14]. Coexistence of depression in epilepsy Depression represents one of the most disabling co-morbidities of epilepsy and impacts profoundly negatively on the quality of life of patients with epilepsy [15–17]. Population-based studies have shown a 30–35% lifetime prevalence rate of depressive disorder in people with epilepsy [18]. Various Neurotransmitter systems such as acetylcholine, dopamine, GABA, glutamate, nor-epinephrine and serotonin play important roles in the comorbidity between depression and epilepsy. Other potential mechanisms include corticotropin-releasing hormone (CRHergic) and glutamatergic excesses and the role of key brain regions like the amygdala and hippocampus [17,19,20]. An abnormality in the central serotonin system (5HT) illustrates one of the major pathogenic mechanisms exist between depression and epilepsy [18,21]. Furthermore a dysfunction in the regulation of glutamate neurotransmission is suggested in the coexistence of depression and epilepsy [18,22]. Disrupted production of adult-born hippocampal granule cells in both disorders may also be suggestive of their unusually high coincidence [23]. An interconnection between circadian rhythms and depression is also well established but mechanisms underlying the specific biology of this interaction are yet to be studied [24]. Other mechanisms like the role of hypothalamic–pituitary–adrenal axis, neurotrophins, ion channels and hippocampal interleukin-1b have been suggested for future investigation in the context of comorbidity [16,17]. Coexistence of anxiety in epilepsy Anxiety is a very common and equally disabling complication of epilepsy but it is less well-studied as comorbidity in epilepsy [25]. People with epilepsy often suffer greatly from anxiety disorders. The prevalence of anxiety disorders in epilepsy is estimated at approximately 25% [26]. Though the neurobiological mechanisms of anxiety in epilepsy are not clearly understood, a common pathophysiology of both the disorders is suggested. The role of amygdala in epilepsy as well as in the production of anxiety symptoms seems to be important. Involvement of neurotransmitter systems including altered GABA, serotonin and dopamine activ-
ity in both epilepsy and anxiety is considered to be a pathophysiological similarity [20,27]. Particularly abnormal functioning of GABA-A receptors could be of great importance in the pathophysiology of epilepsy and anxiety disorders. Interestingly all these observations are supported by the fact that GABAergic drugs like gabapentin, vigabatrin, tiagabine as well as barbiturates and benzodiazepines, have both antiepileptic and anxiolytic properties [26]. Coexistence of sleep disorders in epilepsy Sleep disorders frequently coexist in patients with epilepsy. The relationship between sleep and epilepsy is complicated and reciprocal [28–30]. In a questionnaire based survey, the prevalence of subjectively reported sleep disturbance among adults with epilepsy (39%) was found to be significantly higher than among controls (18%) [31]. Patients with epilepsy suffer from a variety of treatable sleep disorders which in turn could lead to poor seizure control. Epilepsy patients experience alterations in total sleep, sleep architecture, sleep latency and spontaneous arousals with a higher incidence of sleep fragmentation and daytime drowsiness [31]. Various factors such as epilepsy per se, type and frequency of seizures, inadequate sleep hygiene, coexisting sleep disorders and circadian rhythm disturbances could be responsible for alterations of sleep architecture in epileptic patients [29,31]. Anti-epileptic drugs (AEDs) altering sleep in a negative way make the condition worse. Though the exact mechanism of sleep deprivation in epilepsy is still unclear, a GABA modulation and role of adenosine is suggested [31]. Despite the high prevalence and complexities of comorbid disorders in epilepsy, very little is known about their treatment options. Unfortunately, there are only a few earlier attempts to find an ideal drug which may have protective action against both epilepsy and associated complications. A study by Genkova and Bakarova in 1992 has shown that four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) at doses known to exert antiamnestic effect decrease the intensity of pentylenetetrazole (PTZ) kindled seizures and completely prevent appearance of postictal depression in rats [32]. But advances in this regard are very limited. Hypothesis Melatonin, an endogenous hormone secreted by pineal gland has a prominent but variable effect in epilepsy. Melatonin exerts a depressive effect on brain excitability and has been shown to exert an anticonvulsant activity in various animal models such as chemically (pilocarpine, pentylenetetrazole and kainate) and electrically induced seizures [28,33–36]. Patients with untreated complex partial epilepsy are found to have an increased melatonin production and it was concluded that overproduction of melatonin was possibly an attempt by the brain to produce a natural down regulator of cerebral epileptiform activity [28]. Also there is evidence suggesting that high doses of melatonin may exert proconvulsive activity and in low doses, melatonin has been shown to possess anticonvulsant action. This is because low doses of melatonin have been shown to increase hypothalamic and cortical GABA levels, accounting for its anticonvulsant action. But melatonin at high concentrations, decreases GABA levels at these sites. Thus the proconvulsive activity of melatonin may possibly be due to the decrease in brain GABA levels [36–38]. All these evidences suggest the potential role of melatonin in epilepsy. Furthermore, a very recent study by Tchekalarova et al. in 2013, demonstrated that melatonin alleviated seizure frequency during the period of treatment and provided protection against deleterious behavioral
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alterations, memory deficit, and neuronal damage during the chronic epileptic state in a kainate model of temporal lobe epilepsy [39]. Enhanced 5-HT2C gene expression and receptor binding in hippocampus has been demonstrated in an animal model of epilepsy and an antagonism of these effects is suggested for therapeutic effect in the management of epilepsy [12]. Agomelatine is a novel antidepressant which acts through a unique mechanism since it is a melatonin MT1 and MT2 receptor agonist as well as serotonin 5HT2C receptor antagonist. It has been studied extensively and the antidepressant, anxiolytic, memory enhancing and sleep improving effects of agomelatine are well established [40–44]. Taken all these findings into account, it is postulated that agomelatine can have beneficial effects to treat epilepsy and many of the complications associated with epilepsy. Therapeutic potential of agomelatine to treat epilepsy The pineal hormone melatonin has a prominent role in epilepsy. Melatonin has found to be acting as an anticonvulsant in various animal models [28,33–36]. Several studies revealed that, GABAergic and serotonergic mechanisms may play an important role in mediating the anticonvulsant activity of melatonin and the GABAergic effect possibly depends on the combined effect of membrane ion permeability and increasing chloride ion influx through GABA A-dependent chloride channels (Fig. 1) [28,36–38,45]. Neurotransmitter levels that mediate the epileptic activity are also known to be influenced by circadian cycles [46]. Also it has been suggested that anticonvulsant activity of melatonin is mediated through activation of MT1 receptors [47]. Agomelatine, a naphthalene analog melatonin, is found to act as an agonist at melatonin MT1/2 receptors and as an antagonist at serotonin 5HT2C receptors. Hence it might also possess the anticonvulsant potential as that of melatonin. One of the very recent studies by Aguiar et al. in 2012 strongly supports this statement. In their study, agomelatine is shown to increase latency to convulsion, in an acute PTZ and pilocarpine induced seizure model in rats. Also they have concluded that the anticonvulsant action of agomelatine may be due to its combined action at MT1/2 and 5HT2C receptors [45]. Also there are studies suggesting that chronic treatment with agomelatine reduced depolarization-evoked release of glutamate
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but not GABA release in rat hippocampus, suggesting a dampening of excitatory neurotransmission [48,49]. The decrease in glutamate release may also account for its anticonvulsant action. Furthermore, in a newborn mouse model of excitotoxic white matter lesions, agomelatine displayed potent neuroprotective properties [50]. The neuroprotective action of agomelatine may provide protection against seizure induced brain damage and the further incidence of seizures. Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy [9,51]. Some studies demonstrated that mitochondrial dysfunction is associated with chronic oxidative stress and may have an essential role in the epileptogenesis process [52]. It has also been shown that seizures result in increased oxidative damage and lipid peroxidation (increased MDA and NO level), and decreased antioxidant defense mechanisms (SOD and GSH) in a PTZ induced experimental model [53]. Melatonin is found to be a powerful antioxidant and exerts protective effect against the oxidative and nitrosative damages [54,55]. This may further suggest that agomelatine could possibly have the antioxidant potential as that of melatonin [55,56]. This needs to be studied and characterized further. This possible antioxidant property of agomelatine can further protect against cell injury and cell death associated with seizures. Therapeutic potential of agomelatine to treat memory dysfunction in epilepsy Agomelatine is proven to have a memory facilitating effect in novel object recognition task [44]. It is well established that chronic agomelatine treatment can stimulate several stages of adult neurogenesis in the hippocampus [57] and it has been shown to reverse the decrease in hippocampal cell survival induced by chronic mild stress [58]. These actions may account for its memory improving effect. AlAhmed and Herbert, in 2010 suggested that the action of agomelatine on neurogenesis is likely to reside in its antagonism of the 5HT2C receptor [42], while Soumier et al. demonstrated that the joint actions of agomelatine on melatonergic (MT1, MT2) and 5-HT2C receptors are needed for its effects on neurogenesis [57]. Thus it can also be proposed that with its potential role in hippocampal neuronal cell survival and neurogenesis, which is a part crucial for memory formation and consolidation, agomelatine may
Fig. 1. Mechanisms explaining therapeutic potential of agomelatine in epilepsy and epileptic complications.
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reverse the memory impairment associated with recurrent seizures. Further, agomelatine is found to have a neuroprotective effect in hippocampus and frontal cortex in a rat model of depression in Alzheimer’s disease and in cortisol aggression [59]. Additionally agomelatine could possibly have the antioxidant potential as melatonin as stated earlier [55,56]. Earlier literature shows that, agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats [60]. All these effects may together contribute to the protective action of agomelatine against epilepsy induced memory decline. Therapeutic potential of agomelatine to treat depression in epilepsy Agomelatine is a novel and clinically effective drug used in major depressive disorder. It is the first antidepressant that was developed based on hypotheses relating circadian rhythms and depression [61]. Preclinical studies have shown that agomelatine exerts antidepressant activity in several animal models such as forced swim test, chronic mild stress, learned helplessness test and a transgenic mouse model of depression [41,62]. Clinically agomelatine is proven to be efficacious as a safer drug in depressive patients [63,64]. Clinical studies undertaken on patients with major depression, bipolar disorders and seasonal affective disorder have revealed the effectiveness of agomelatine in ameliorating depressive symptoms with a good tolerability and safety profile [65]. And it was suggested that antidepressant activity agomelatine involves a combination of both its melatonin agonist and 5-HT2C receptor antagonist properties. Since regulation of circadian rhythms plays an important role in the pathophysiology of depressive disorders, resynchronization of the disrupted circadian rhythms by agomelatine is suggested as one of the mechanisms for its antidepressant effect [65,66]. Also neurogenesis in animal models of depression is identified as another action [65]. All these evidence can be further extended to hypothesize that agomelatine may also be effective in protecting against epilepsy induced depressive behavior. Therapeutic potential of agomelatine to treat anxiety in epilepsy Anxiolytic properties of agomelatine are shown in animal models as well as in humans [67–72]. A normalization of disturbed circadian rhythms partly accounts for its anxiolytic properties [69]. Various studies indicate that antagonists at 5HT2C receptor subtype exhibit anxiolytic-like properties in different animal models [67,73]. This implies that the anxiolytic effect of agomelatine could be attributed to its 5HT2C antagonism. Further in a study by Loiseau et al. in 2006, it was shown that melatonin and agomelatine potentiated the anxiolytic action of diazepam [68]. But the involvement of GABA-BZD receptors in the anxiolytic action of agomelatine is not characterized further. Therapeutic potential of agomelatine to treat sleep disorders in epilepsy The sleep promoting effect of agomelatine is well established. Patients with seizures not only have a reduction in total sleep time but also REM sleep when compared with patients without seizures. It is also suggested that seizures affect the circadian pattern responsible for REM sleep, thus delaying its onset. Thus one of the many causes of sleep disruption in epilepsy is circadian rhythm disturbances [31]. Additionally, it has also been shown that the antagonistic action of antidepressants on serotonergic 5-HT2 receptors improves sleep continuity and promotes slow wave sleep [74]. This is how agomelatine can have an important role in the treatment of sleep disturbances in epilepsy. It is been proven that
the sleep promoting and circadian effects of melatonin have been attributed to the two subtypes of human melatonin receptors (MT1and MT2) [75]. Since agomelatine is an agonist at both MT1and MT2 receptors, it may also possess the sleep promoting effect of melatonin. Further, in a study Racagni, has shown that agomelatine resynchronized disrupted circadian rhythms and antagonized the effect of stress on the total amount of REM sleep [76]. Also there are evidences from clinical trials suggesting that agomelatine was superior to venlafaxine and sertraline in ‘‘getting to sleep and quality of sleep’’ [64,77–79]. Moreover patients with depressive disorder, treated with agomelatine, also benefit from improved quality of sleep [64,80–83]. Thus the characteristics of agomelatine also include a rapid onset of action and a pronounced effectiveness for improving sleep efficiency and correcting circadian rhythm abnormalities [84]. Furthermore, agomelatine promotes the ability to go to sleep and improves sleep quality without associated daytime drowsiness [64,79,81] which would be a favorable characteristic, if used in epilepsy. All these findings together support the idea that agomelatine could be used in epileptic patients to prevent sleep disruptions and promote sleep.
Testing the hypothesis This hypothesis could be tested in various animal models such as chemical or electrical kindling. Kindling induced with the chemoconvulsant pentylenetetrazole (PTZ) represents a model of primary generalized epilepsy. This animal model represents the convulsive component of epilepsy as well as secondary alterations in the field of cognition and thus a serving as a screen for potential treatments for the cognitive and emotional deficits that are observed in human epilepsy [85]. Further, clinical studies would also be possible since agomelatine is already proven to be safe. Potential interactions affecting agomelatine are matter of importance in case of clinical studies. Medicinal products that interact with the isoenzymes CYP1A2 and CYP2C9/19 may decrease or increase the bioavailability of agomelatine. Thus co-administration of agomelatine with fluvoxamine and ciprofloxacin is contraindicated and propranolol, grepafloxacin and enoxacin should be prescribed with caution. But further studies are needed for more information on drug interactions of agomelatine.
Conclusion Agomelatine, a novel antidepressant clinically used to treat major depressive disorders possesses many other pharmacological actions. Literature reveals that, it has also potential to treat epilepsy and epileptic complications such as memory dysfunction, depression, anxiety, sleep disorders and pain. The combined action on MT1/2 and 5HT2C receptors, circadian resynchronizing, glutamate release reducing, neuroprotective and neurogenesis enhancing actions and the possible antioxidant potential of agomelatine can contribute to protection against epilepsy and its complications.
Conflicts of interest None declared.
Acknowledgment The authors would like to thank Ms. Vanisree P.V for her valuable comments.
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Therapeutic potential of agomelatine in epilepsy and epileptic complications P.V. Vimala ⇑, P.S. Bhutada, F.R. Patel Sinhgad College of Pharmacy, Post-Graduate Research Department, Off Sinhgad Road, Vadgaon (Bk), Pune 411 041, Maharashtra, India
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Article history: Received 20 July 2013 Accepted 14 November 2013
a b s t r a c t Epilepsy is a chronic neurologic disorder which often induces numerous adverse long-term neurologic effects, such as behavioral and cognitive deficits, increased predisposition to additional seizures, and cell injury or death. Cognitive dysfunction, depression, anxiety and sleep disorders are some of the highly prevalent and most disabling complications of epilepsy. The mechanisms that lead to the generation of epileptic comorbidities are poorly understood. Treatment for epileptic complications still remains a challenge because of the poor adherence and drug interactions associated with multi drug prescriptions and also for the fear of worsening seizures by the individual medications for complications. Melatonin, an endogenous hormone secreted by pineal gland has a prominent role in epilepsy. Agomelatine is a novel antidepressant which acts as melatonin MT1 and MT2 receptor agonist and serotonin 5Ht2C receptor antagonist. The combined action at MT1/2 and 5HT2C receptors, reduction in the depolarization-evoked release of glutamate, strong neuroprotective action and possible antioxidant properties of agomelatine could make it a potential agent in the treatment of epilepsy. The effect of agomelatine on hippocampal neuronal cell survival and neurogenesis, neuroprotective effect in hippocampus and frontal cortex and the antioxidant potential may contribute to the protective action of agomelatine against epilepsy induced memory decline. Agomelatine is proven to be an antidepressant and it has relieved anxiety symptoms and improved the quality of sleep in patients with depressive disorder. The action of agomelatine as a melatonin agonist and the consequent circadian resynchronizing property as well as its action as 5-HT2C receptor antagonist, could possibly suggest an antidepressant and anxiolytic action of agomelatine in epilepsy induced depressive behavior and anxiety. Since one of the many causes of sleep disruption in epilepsy is circadian rhythm disturbances and sleep promoting and circadian effects of melatonin is attributed to the MT1and MT2 subtypes of human melatonin receptors, agomelatine may also have a promising effect on epilepsy induced sleep disruptions. Thus with all these potential pharmacological actions, agomelatine could be recommended as a potential drug to treat epilepsy and its complications. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Epilepsy is a chronic neurological disorder characterized by recurrent, spontaneous brain seizures. It is the most common serious neurological condition and approximately 50 million people worldwide suffer from epilepsy [1]. About 50% of patients continue to experience seizures despite optimized treatment with modern antiepileptic drugs [2]. Seizures can induce numerous adverse long-term neurologic effects, such as behavioral and cognitive deficits, increased predisposition to additional seizures, and cell injury or death [3]. In this article we are discussing some of the most commonly accompanied complications of epilepsy such as cognitive dysfunction, depres⇑ Corresponding author. Tel.: +91 08149780874/9538367391; fax: +91 020 4354720/21. E-mail addresses: [email protected], [email protected] (P.V. Vimala). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.017
sion, anxiety and sleep disorders with a proposal of possible therapeutic potentials of agomelatine in these conditions. Often Epileptic patients with co-morbidities are provided with multi drug prescriptions which lead to poor adherence and interactions between different medications. Unfortunately, treatment for epileptic complications is still a challenge to the medical field for the fear of worsening seizures by the individual medications for complications [4,5]. Coexistence of cognitive dysfunction in epilepsy Cognitive dysfunction is one of the most commonly associated complications of epilepsy. Patients with epilepsy report significantly more memory problems and consider their memory problems to be a greater nuisance than do individuals without epilepsy [6]. The prevalence of memory problems in patients with refractory epilepsy has been estimated as high as 20–50% [7]. Several factors such as biologic (underlying neuropathology, seizure
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type and etiology, age of onset, frequency, severity and duration of seizures, structural cerebral damage); psychologic problems and treatment with antiepileptic drugs (AEDs) have been attributed to cause cognitive impairment in epilepsy [8,9]. Neuroimaging studies in patients with epileptic syndrome and cognitive dysfunction show structural abnormalities which include malformation of cortical development, hippocampal volume loss, reduction in cortical gray and white matter volumes, temporal lobe abnormalities [3,10]. Hippocampus is one of the most vulnerable brain areas for epilepsy related brain damage and thus plays an important role in the development of memory impairment in epilepsy. Specific hippocampal dysfunctions, acting in concert with changes in other brain structures, might represent a possible causal link between seizures and memory impairment [11]. It is influenced powerfully by serotonergic projections from midbrain raphe nuclei which modulate hippocampal electrical activity, hippocampusdependent behaviors, and long-term potentiation (LTP), and ultimately memory formation [12]. Some studies have shown involvement of oxidative stress in the pathophysiology of epilepsy and this prolonged oxidative damage to various brain sites could be one of the likely causes of cognition impairment in epilepsy [9,13]. The glutamatergic neurotransmission system plays a crucial role in learning and memory mechanisms as well as in convulsions. An excessive stimulation of this system resulting in cell damage and cell death could partly be an explanation for the memory deficits in epilepsy [14]. Coexistence of depression in epilepsy Depression represents one of the most disabling co-morbidities of epilepsy and impacts profoundly negatively on the quality of life of patients with epilepsy [15–17]. Population-based studies have shown a 30–35% lifetime prevalence rate of depressive disorder in people with epilepsy [18]. Various Neurotransmitter systems such as acetylcholine, dopamine, GABA, glutamate, nor-epinephrine and serotonin play important roles in the comorbidity between depression and epilepsy. Other potential mechanisms include corticotropin-releasing hormone (CRHergic) and glutamatergic excesses and the role of key brain regions like the amygdala and hippocampus [17,19,20]. An abnormality in the central serotonin system (5HT) illustrates one of the major pathogenic mechanisms exist between depression and epilepsy [18,21]. Furthermore a dysfunction in the regulation of glutamate neurotransmission is suggested in the coexistence of depression and epilepsy [18,22]. Disrupted production of adult-born hippocampal granule cells in both disorders may also be suggestive of their unusually high coincidence [23]. An interconnection between circadian rhythms and depression is also well established but mechanisms underlying the specific biology of this interaction are yet to be studied [24]. Other mechanisms like the role of hypothalamic–pituitary–adrenal axis, neurotrophins, ion channels and hippocampal interleukin-1b have been suggested for future investigation in the context of comorbidity [16,17]. Coexistence of anxiety in epilepsy Anxiety is a very common and equally disabling complication of epilepsy but it is less well-studied as comorbidity in epilepsy [25]. People with epilepsy often suffer greatly from anxiety disorders. The prevalence of anxiety disorders in epilepsy is estimated at approximately 25% [26]. Though the neurobiological mechanisms of anxiety in epilepsy are not clearly understood, a common pathophysiology of both the disorders is suggested. The role of amygdala in epilepsy as well as in the production of anxiety symptoms seems to be important. Involvement of neurotransmitter systems including altered GABA, serotonin and dopamine activ-
ity in both epilepsy and anxiety is considered to be a pathophysiological similarity [20,27]. Particularly abnormal functioning of GABA-A receptors could be of great importance in the pathophysiology of epilepsy and anxiety disorders. Interestingly all these observations are supported by the fact that GABAergic drugs like gabapentin, vigabatrin, tiagabine as well as barbiturates and benzodiazepines, have both antiepileptic and anxiolytic properties [26]. Coexistence of sleep disorders in epilepsy Sleep disorders frequently coexist in patients with epilepsy. The relationship between sleep and epilepsy is complicated and reciprocal [28–30]. In a questionnaire based survey, the prevalence of subjectively reported sleep disturbance among adults with epilepsy (39%) was found to be significantly higher than among controls (18%) [31]. Patients with epilepsy suffer from a variety of treatable sleep disorders which in turn could lead to poor seizure control. Epilepsy patients experience alterations in total sleep, sleep architecture, sleep latency and spontaneous arousals with a higher incidence of sleep fragmentation and daytime drowsiness [31]. Various factors such as epilepsy per se, type and frequency of seizures, inadequate sleep hygiene, coexisting sleep disorders and circadian rhythm disturbances could be responsible for alterations of sleep architecture in epileptic patients [29,31]. Anti-epileptic drugs (AEDs) altering sleep in a negative way make the condition worse. Though the exact mechanism of sleep deprivation in epilepsy is still unclear, a GABA modulation and role of adenosine is suggested [31]. Despite the high prevalence and complexities of comorbid disorders in epilepsy, very little is known about their treatment options. Unfortunately, there are only a few earlier attempts to find an ideal drug which may have protective action against both epilepsy and associated complications. A study by Genkova and Bakarova in 1992 has shown that four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) at doses known to exert antiamnestic effect decrease the intensity of pentylenetetrazole (PTZ) kindled seizures and completely prevent appearance of postictal depression in rats [32]. But advances in this regard are very limited. Hypothesis Melatonin, an endogenous hormone secreted by pineal gland has a prominent but variable effect in epilepsy. Melatonin exerts a depressive effect on brain excitability and has been shown to exert an anticonvulsant activity in various animal models such as chemically (pilocarpine, pentylenetetrazole and kainate) and electrically induced seizures [28,33–36]. Patients with untreated complex partial epilepsy are found to have an increased melatonin production and it was concluded that overproduction of melatonin was possibly an attempt by the brain to produce a natural down regulator of cerebral epileptiform activity [28]. Also there is evidence suggesting that high doses of melatonin may exert proconvulsive activity and in low doses, melatonin has been shown to possess anticonvulsant action. This is because low doses of melatonin have been shown to increase hypothalamic and cortical GABA levels, accounting for its anticonvulsant action. But melatonin at high concentrations, decreases GABA levels at these sites. Thus the proconvulsive activity of melatonin may possibly be due to the decrease in brain GABA levels [36–38]. All these evidences suggest the potential role of melatonin in epilepsy. Furthermore, a very recent study by Tchekalarova et al. in 2013, demonstrated that melatonin alleviated seizure frequency during the period of treatment and provided protection against deleterious behavioral
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alterations, memory deficit, and neuronal damage during the chronic epileptic state in a kainate model of temporal lobe epilepsy [39]. Enhanced 5-HT2C gene expression and receptor binding in hippocampus has been demonstrated in an animal model of epilepsy and an antagonism of these effects is suggested for therapeutic effect in the management of epilepsy [12]. Agomelatine is a novel antidepressant which acts through a unique mechanism since it is a melatonin MT1 and MT2 receptor agonist as well as serotonin 5HT2C receptor antagonist. It has been studied extensively and the antidepressant, anxiolytic, memory enhancing and sleep improving effects of agomelatine are well established [40–44]. Taken all these findings into account, it is postulated that agomelatine can have beneficial effects to treat epilepsy and many of the complications associated with epilepsy. Therapeutic potential of agomelatine to treat epilepsy The pineal hormone melatonin has a prominent role in epilepsy. Melatonin has found to be acting as an anticonvulsant in various animal models [28,33–36]. Several studies revealed that, GABAergic and serotonergic mechanisms may play an important role in mediating the anticonvulsant activity of melatonin and the GABAergic effect possibly depends on the combined effect of membrane ion permeability and increasing chloride ion influx through GABA A-dependent chloride channels (Fig. 1) [28,36–38,45]. Neurotransmitter levels that mediate the epileptic activity are also known to be influenced by circadian cycles [46]. Also it has been suggested that anticonvulsant activity of melatonin is mediated through activation of MT1 receptors [47]. Agomelatine, a naphthalene analog melatonin, is found to act as an agonist at melatonin MT1/2 receptors and as an antagonist at serotonin 5HT2C receptors. Hence it might also possess the anticonvulsant potential as that of melatonin. One of the very recent studies by Aguiar et al. in 2012 strongly supports this statement. In their study, agomelatine is shown to increase latency to convulsion, in an acute PTZ and pilocarpine induced seizure model in rats. Also they have concluded that the anticonvulsant action of agomelatine may be due to its combined action at MT1/2 and 5HT2C receptors [45]. Also there are studies suggesting that chronic treatment with agomelatine reduced depolarization-evoked release of glutamate
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but not GABA release in rat hippocampus, suggesting a dampening of excitatory neurotransmission [48,49]. The decrease in glutamate release may also account for its anticonvulsant action. Furthermore, in a newborn mouse model of excitotoxic white matter lesions, agomelatine displayed potent neuroprotective properties [50]. The neuroprotective action of agomelatine may provide protection against seizure induced brain damage and the further incidence of seizures. Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy [9,51]. Some studies demonstrated that mitochondrial dysfunction is associated with chronic oxidative stress and may have an essential role in the epileptogenesis process [52]. It has also been shown that seizures result in increased oxidative damage and lipid peroxidation (increased MDA and NO level), and decreased antioxidant defense mechanisms (SOD and GSH) in a PTZ induced experimental model [53]. Melatonin is found to be a powerful antioxidant and exerts protective effect against the oxidative and nitrosative damages [54,55]. This may further suggest that agomelatine could possibly have the antioxidant potential as that of melatonin [55,56]. This needs to be studied and characterized further. This possible antioxidant property of agomelatine can further protect against cell injury and cell death associated with seizures. Therapeutic potential of agomelatine to treat memory dysfunction in epilepsy Agomelatine is proven to have a memory facilitating effect in novel object recognition task [44]. It is well established that chronic agomelatine treatment can stimulate several stages of adult neurogenesis in the hippocampus [57] and it has been shown to reverse the decrease in hippocampal cell survival induced by chronic mild stress [58]. These actions may account for its memory improving effect. AlAhmed and Herbert, in 2010 suggested that the action of agomelatine on neurogenesis is likely to reside in its antagonism of the 5HT2C receptor [42], while Soumier et al. demonstrated that the joint actions of agomelatine on melatonergic (MT1, MT2) and 5-HT2C receptors are needed for its effects on neurogenesis [57]. Thus it can also be proposed that with its potential role in hippocampal neuronal cell survival and neurogenesis, which is a part crucial for memory formation and consolidation, agomelatine may
Fig. 1. Mechanisms explaining therapeutic potential of agomelatine in epilepsy and epileptic complications.
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reverse the memory impairment associated with recurrent seizures. Further, agomelatine is found to have a neuroprotective effect in hippocampus and frontal cortex in a rat model of depression in Alzheimer’s disease and in cortisol aggression [59]. Additionally agomelatine could possibly have the antioxidant potential as melatonin as stated earlier [55,56]. Earlier literature shows that, agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats [60]. All these effects may together contribute to the protective action of agomelatine against epilepsy induced memory decline. Therapeutic potential of agomelatine to treat depression in epilepsy Agomelatine is a novel and clinically effective drug used in major depressive disorder. It is the first antidepressant that was developed based on hypotheses relating circadian rhythms and depression [61]. Preclinical studies have shown that agomelatine exerts antidepressant activity in several animal models such as forced swim test, chronic mild stress, learned helplessness test and a transgenic mouse model of depression [41,62]. Clinically agomelatine is proven to be efficacious as a safer drug in depressive patients [63,64]. Clinical studies undertaken on patients with major depression, bipolar disorders and seasonal affective disorder have revealed the effectiveness of agomelatine in ameliorating depressive symptoms with a good tolerability and safety profile [65]. And it was suggested that antidepressant activity agomelatine involves a combination of both its melatonin agonist and 5-HT2C receptor antagonist properties. Since regulation of circadian rhythms plays an important role in the pathophysiology of depressive disorders, resynchronization of the disrupted circadian rhythms by agomelatine is suggested as one of the mechanisms for its antidepressant effect [65,66]. Also neurogenesis in animal models of depression is identified as another action [65]. All these evidence can be further extended to hypothesize that agomelatine may also be effective in protecting against epilepsy induced depressive behavior. Therapeutic potential of agomelatine to treat anxiety in epilepsy Anxiolytic properties of agomelatine are shown in animal models as well as in humans [67–72]. A normalization of disturbed circadian rhythms partly accounts for its anxiolytic properties [69]. Various studies indicate that antagonists at 5HT2C receptor subtype exhibit anxiolytic-like properties in different animal models [67,73]. This implies that the anxiolytic effect of agomelatine could be attributed to its 5HT2C antagonism. Further in a study by Loiseau et al. in 2006, it was shown that melatonin and agomelatine potentiated the anxiolytic action of diazepam [68]. But the involvement of GABA-BZD receptors in the anxiolytic action of agomelatine is not characterized further. Therapeutic potential of agomelatine to treat sleep disorders in epilepsy The sleep promoting effect of agomelatine is well established. Patients with seizures not only have a reduction in total sleep time but also REM sleep when compared with patients without seizures. It is also suggested that seizures affect the circadian pattern responsible for REM sleep, thus delaying its onset. Thus one of the many causes of sleep disruption in epilepsy is circadian rhythm disturbances [31]. Additionally, it has also been shown that the antagonistic action of antidepressants on serotonergic 5-HT2 receptors improves sleep continuity and promotes slow wave sleep [74]. This is how agomelatine can have an important role in the treatment of sleep disturbances in epilepsy. It is been proven that
the sleep promoting and circadian effects of melatonin have been attributed to the two subtypes of human melatonin receptors (MT1and MT2) [75]. Since agomelatine is an agonist at both MT1and MT2 receptors, it may also possess the sleep promoting effect of melatonin. Further, in a study Racagni, has shown that agomelatine resynchronized disrupted circadian rhythms and antagonized the effect of stress on the total amount of REM sleep [76]. Also there are evidences from clinical trials suggesting that agomelatine was superior to venlafaxine and sertraline in ‘‘getting to sleep and quality of sleep’’ [64,77–79]. Moreover patients with depressive disorder, treated with agomelatine, also benefit from improved quality of sleep [64,80–83]. Thus the characteristics of agomelatine also include a rapid onset of action and a pronounced effectiveness for improving sleep efficiency and correcting circadian rhythm abnormalities [84]. Furthermore, agomelatine promotes the ability to go to sleep and improves sleep quality without associated daytime drowsiness [64,79,81] which would be a favorable characteristic, if used in epilepsy. All these findings together support the idea that agomelatine could be used in epileptic patients to prevent sleep disruptions and promote sleep.
Testing the hypothesis This hypothesis could be tested in various animal models such as chemical or electrical kindling. Kindling induced with the chemoconvulsant pentylenetetrazole (PTZ) represents a model of primary generalized epilepsy. This animal model represents the convulsive component of epilepsy as well as secondary alterations in the field of cognition and thus a serving as a screen for potential treatments for the cognitive and emotional deficits that are observed in human epilepsy [85]. Further, clinical studies would also be possible since agomelatine is already proven to be safe. Potential interactions affecting agomelatine are matter of importance in case of clinical studies. Medicinal products that interact with the isoenzymes CYP1A2 and CYP2C9/19 may decrease or increase the bioavailability of agomelatine. Thus co-administration of agomelatine with fluvoxamine and ciprofloxacin is contraindicated and propranolol, grepafloxacin and enoxacin should be prescribed with caution. But further studies are needed for more information on drug interactions of agomelatine.
Conclusion Agomelatine, a novel antidepressant clinically used to treat major depressive disorders possesses many other pharmacological actions. Literature reveals that, it has also potential to treat epilepsy and epileptic complications such as memory dysfunction, depression, anxiety, sleep disorders and pain. The combined action on MT1/2 and 5HT2C receptors, circadian resynchronizing, glutamate release reducing, neuroprotective and neurogenesis enhancing actions and the possible antioxidant potential of agomelatine can contribute to protection against epilepsy and its complications.
Conflicts of interest None declared.
Acknowledgment The authors would like to thank Ms. Vanisree P.V for her valuable comments.
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