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New Therapeutic Strategy for Mood Disorders

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Current Medicinal Chemistry, 2011, 18, ????-???? 1 New Therapeutic Strategy for Mood Disorders

R. Crupi1, A. Marino2 and S. Cuzzocrea*,1,3

1Dept. of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy 2Dept. of Life Sciences “M. Malpighi”- Section of General Physiology and Pharmacology, University of Messina, Italy 3IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy Abstract: The development of new treatments for mood disorders, as anxiety and depression, is based on identification of neural sub- strates and the mechanisms underlying their etiology and pathophysiology. The heterogeneity of mood disorders indicates that its origin may lie in dysfunction of multiple brain regions (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex). The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests the contribute of new neurons to the biology of mood disorders that is still under debate. The production of new neurons, referred to as neurogenesis, occurs throughout life in discrete brain areas such as the dentate gyrus (DG) of the hippocampus and the subventricular zone/olfactory bulb. Findings describing that neurogenesis process in DG is increased by , like , and it is required for the behavioral effect of antidepres- sants, lead to a new strategy and drugs for the treatment of mood disorders. As many patients display poor response to therapy, research on depression and drugs is necessary. In this regard, focusing on neurogenesis and neuroplasticity processes in experimen- tal models is particularly interesting for the understanding of the pathophysiology of mood disorders and should define the role of adult- born neurons in hippocampal physiology. Different classes of drugs are currently prescribed for the treatment of mood disorders. Among them selective reuptake (SSRIs), monoamine oxidase inhibitors (MAOIs), specific norepinephrine reuptake inhibitors (SNRIs) and tricyclic acids (TCA) alleviate symptoms of mood disorders. Here we review different strategies that may be adopted for impairing mood disorders and that may be further developed for innovative therapeutic approaches. Keywords: Animal models, antidepressants, hippocampus, mood disorders, neurogenesis, neuroplasticity.

1. INTRODUCTION meta-analyses have also demonstrated a reduction in hippocampal volume related to age- and sex –matched controls [7]. In particular, Mood disorders (MD) impact 7% of the world’s population, and the magnitude of reduction in hippocampal volume reflects both the severe forms of depression affect 2% to 5% of the US population. frequency of depressive episodes and how the depression remains They are considered the fourth leading cause of disability world- untreated. Moreover pathohistological studies of post-mortem tissue wide and, according to the World Health Organization, may be- indicate that changes in neuropil and glial cell number may be re- come second only to cardiovascular diseases in the next two dec- sponsible for the reduced hippocampal volume [7]. For this reason ades[1]. A recent consensus document by the European Brain this specific brain area and its functions, depending on neurogenesis Council estimated the annual cost of MD at 106 billion EUR, with a and neuroplasticity processes, have been widely investigated as a prevalence of 21 million people across 28 European countries. De- pharmacological target in therapeutic strategies against MD. On this pressed mood, low self-esteem, feelings of hopelessness, anhedo- basis the development of new drugs in treating MD (i.e. antidepres- nia, neurovegetative symptoms, recurrent thoughts of suicide, cog- sants, ADs) has progressively become a critical point in pharmacol- nitive alterations (impairing working memory, bias towards nega- ogical research, taking also into account that a single-effect com- tive stimuli) are diagnostic features of MD [2]. According to the pound may not be effective in counteracting MD. Since ADs may Diagnostic and Statistical Manual of Mental Disorders, MD are induce side effects with serious damage to patients, drug develop- classified as major depressive disorders (MDD), commonly called ment has been recently propelled to discover novel compounds clinical depression or major depression, and bipolar disor- effective in MD treatment and with a low side effect profile. Such ders (BD), known as manic depression and characterized by inter- molecules, as reported by other authors [8, 9], specifically target mittent episodes of mania or hypomania, possibly associated with gene expression, synaptic transmission and neurogenesis, whose depressive episodes. Alterations exhibited by affected patients may alterations are actually involved in MD pathogenesis. The aim of display a notable heterogeneity, suggesting that a complex patho- the present article is to provide an updated review of classical and genesis underlies such disorders. Actually the pathogenesis of MD novel strategies as suitable therapeutic approaches to MD. is not completely defined and is still under intensive investigations by pharmacological and genetic tools and animal models. Multiple 2. PHARMACOLOGICAL THERAPY and distinct brain regions may be responsible for the heterogeneous nature of MD. Such hypothesis has been supported by human imag- Antidepressants (ADs) ing and post-mortem studies showing the involvement of different brain areas as prefrontal and cingulated cortex, hippocampus, stria- ADs are divided into first, second and third generation drugs tum, amygdala and thalamus [3]. Their involvement in MD and (see Table 1). First generation antidepressants (FGAs), available for emotionality has been demonstrated by studying the neural connec- therapy in the 1960s, include monoamino oxidase inhibitors tions between different brain areas as prefrontal cortex, amygdala (MAOIs) and tricyclic antidepressants (TCAs). and nucleus accumbens with hippocampus [4]. Moreover, with MAOIs (iproniazide or tranylcypromie) are irreversible inhibi- specific regard to this latter brain structure, a reduction in hippo- tors of the main metabolic enzymes of the monoamine neurotrans- campal volume in depressed patients has been assessed by func- mitters noradrenaline (NA), serotonin (5HT) and (DA), tional magnetic resonance imaging studies (fMRI) [5] reinforcing resulting thus in a generalized increase of monoamine levels the hypothesis that hippocampal alterations are linked to the patho- throughout the Central Nervous System (CNS) [10, 11] and, though genesis of MD [6]. In patients with recurrent depression, 2 their therapeutic efficacy, they have been limited due to the notable and potentially lethal side effects, such as hypertensive potential,

*Address correspondence to this author at the Dept of Clinical and Experimental Medi- that have been observed. cine and Pharmacology, School of Medicine, University of Messina, Italy, Torre Bi- TCAs comprise a variegated class of drugs deriving from phe- ologica- Policlinico Universitario, Via Consolare Valeria- Gazzi- 98100 Messina, Italy; nothiazines as , and . TCAs Tel: (39) 090 221 3644; Fax (39) 090 221 3300; E-mail: [email protected]

0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. 2 Current Medicinal Chemistry, 2011 Vol. 18, No. 2 Crupi et al.

Table 1. Pharmacotherapy of MD- Antidepressants

First generation

O O O H H H N N N N MAOIs N N H H H H N N N O N Iproniazide Nialamide H Procarbazine

O O

N

TCA H3C CH3 N N N NH CH3 H3C Amitriptyline

Second generation H N H N H H N H H3C O O O H Cl H SSRIs O

Cl Fluoxetine CF3 F OH OH S H N CH H C N 3 3 N H H O N CH3 CH3 SNRIs Cl O O CH3 H C 3

H N CH3 OH Cl H H H CH3 N N O O O NARIs H O O N O O O H H N O

Reboxetine

H3C N

N N N NaSSAs N

N N N O O O O N N N N N N N N N N N O SARIs H

Cl Cl F Lubazodone

Antidepressant Strategies in Therapy Against Anxiety and Depressive-Like Disorders Current Medicinal Chemistry, 2011 Vol. 18, No. 2 3

(Table 1). Contd…..

Third generation Multimodal agents Vilazone Lu AA21004

N Triple uptake inhibitors Cl

Sibutramine

NK1 antagonist CP-96345

NH2

Glutamate-based treatments CP-101606

Memantine

OH3C

NH

Nicotinic receptor-based treatments N

CP-96345

Antiglucocorticoid therapies NBI 30775 NBI 34041 main pharmacological properties consist in the inhibition of mono- considered. This drug has been approved by FDA in the USA on amines membrane transporters, leading to an increased extracellular 21-01-11 and acts with 5-HT1A receptor partial agonist activity and availability of monoamine neurotransmitters. Different classes of with the effects of an SSRIs [16]. Artigas and coworkers [17] report drugs, developed mainly in the 1980s-1990s, have been classified that Lu AA21004, a multimodal serotonergic agent, combines SSRI as second generation antidepressants (SGAs). They include selec- activity with 5-HT3 receptor antagonism and 5-HT1A agonist. tive serotonin reuptake inhibitors (SSRIs) and serotonin and The Triple uptake inhibitors(TUIs), as the weight loss drug noradrenalin reuptake inhibitors (SNRIs), noradrenalin reuptake sibutramine, combine inhibition of the serotonin, norepinephrine inhibitors (NARIs), noradrenergic and specific serotonergic antide- and dopamine transporters, targeting the for a pressants (NaSSAs) and 5HT2A antagonist/reuptake inhibitors more effective action [18, 19]. (SARIs). In general the SGAs action mechanism moves from the monoamino hypothesis with a primary mechanism consisting of NK1 antagonists are adopted in therapeutic approaches against monoamino reuptake inhibition and/or antagonism for selected MD, since inhibit NK1 receptors for substance P and neurokinin monoamino receptors. In particular fluoxetine, sertraline, paroxet- identified within human brain areas involved in the pathogenesis of ine, , and , known as SSRIs, MD [20, 21]. have replaced TCAs in clinical therapy, showing a reduced adverse effects profile. Venlafaxine and duloxetine (SNSRIs) [12], mirta- Glutamate-Based Treatments zapine (NaSSAs) [13] and (NARIs) [14] are also consid- ered as the first goal for treatment of MD. Novel compounds (third Glycine and glutamate are commonly known as excitatory neu- generation), in most cases characterized by non- rotransmitters in the CNS. mechanisms, have been successively developed and classified as Glycine is the primary inhibitory neurotransmitter in the spinal third generation drugs (TGAs) [15]. Amongst these, the main part cord and brain stem and is also an obligatory co-agonist at the exci- acts on peptidergic, glutamatergic or circadian rhythm-related tatory glutamate, N-methyl-D-aspartate receptor (NMDAR). The mechanisms, while only a few act with a monoaminergic mecha- post-synaptic action of glycine should be regulated to maintain a nism. These new compounds are divided into: multimodal sero- balance between its inhibitory and excitatory inputs. The glycine toninergic agents; triple uptake inhibitors; NK1 antagonists; gluta- concentration at the synapse is tightly regulated by 2 types of gly- mate-based treatments; nicotinic receptor-based treatments; neuro- cine transporters, GlyT1 and GlyT2, located on nerve terminals or genesis-based treatments; antiglucocorticoid therapies. astrocytes [22]. Multimodal serotoninergic agents include elements of inhibi- In particular they are involved in the activation of N-methyl-D tion of the and elements that either block sero- aspartate (NMDA), -amino-3.hydroxy-5-methil-4-isoxazole toninergic receptors, such as the serotonin 5-HT2A receptor, and/or propionate (AMPA), and kainate receptors as well as the type I, II act as a partial agonist of serotonergic receptors, such as the 5-HT1A and III metabotropic glutamate receptors [23]. Stahl and colleagues receptor. Amongst multimodal serotonergic agents, vilazone can be [24] have hypothesized that NMDA receptor antagonists may pos- 4 Current Medicinal Chemistry, 2011 Vol. 18, No. 2 Crupi et al. sess neuroprotective properties and, thus, antidepressant effects. tors, decreasing the chemical signal that drives psychotic behavior. Traxoprodil (CP 101 606), another NMDA That is, decrease neurotransmission by blocking targeting the NR2B subtype, has antidepressant effects in patients dopamine from binding to the receptors. Both conventional and unresponsive to SSRI [25]. The development and the use of NMDA second-generation antipsychotics are dopamine antagonists and are antagonists as antidepressants should be limited because of some therefore effective in treating the positive symptoms of psychosis. hallucinogenic properties even inducing psychotic-like symptoms In areas of the brain where antipsychotics have no therapeutic bene- in subjects with or without an history of psychosis [26]. Glutama- fits, they may produce side effects. tergic agents, such as , may benefit on cognition per- formance [27], being thus effective in the treatment of cognitive Second Generation Antipsychotics dysfunction in depression or in the treatment of MD. The ‘atypical antipsychotics’ are classified as psychotropic Nicotinic Receptor-Based Treatments agents that differ from classic antipsychotics for pharmacological and clinical aspects [39]. Atypical drugs possess a rather strong Some evidences account for the role of imipramine as nicotinic affinity to dopaminergic, serotoninergic, adrenergic, and choliner- receptor antagonists in depression [28]. Moreover, recent findings gic systems in the brain. Considering clinical aspects, atypical an- have shown TC-5214, the S-(+) –enantiomer of mecamylamine, a tipsychotics act similarly to typical drugs against positive symp- non competitive nicotinic receptor antagonist (42, and 7) to be toms, being more efficacious against negative symptoms. Moreover more effective in animal models of depression [29] and to be more the atypical antipsychotics improve cognitive functions. Studies by effective than placebo in augmenting SSRIs in treatment resistant Post and colleagues [40] showed that atypical antipsychotics are depression (TRD) in a phase 2b trial [30]. used in the treatment of schizophrenia and other related disorders such as MD. The use of these drugs in the therapy against depres- Antiglucocorticoid Therapies sion may be explained by the presence of concomitant psychotic symptoms. For this reason it is difficult to evaluate the real antide- It has been shown that in MD an increase in secretion of hypo- pressive effect of atypical antipsychotics. Nevertheless, the use of thalamic neuropeptides corticotrophin-releasing hormone (CRH) second generation antipsychotics in bipolar depression is justified and vasopressin occurs. In particular, CRH1 receptors are involved by different factors: the antidepressive effect, the impact on sero- in producing a number of anxiety- and depression-like symptoms toninergic transmission, and the effect [41]. An inter- [31]. Two examples of these compounds are the CRH1 receptor esting point is the possible use of antipsychotics in addition to the antagonist NBI-30775/R121919, presenting a clinical profile com- antidepressive treatment or even in substitution. There is still no parable to that of the antidepressant paroxetine, and NBI-34041. evidence definitively suggesting an answer to this question [42]. Such findings report that CRH1 receptor antagonists and other Amongst these drugs, has been employed against de- types of anti-glucocorticoid therapies are reasonably considered as pression and dysthymia, possessing several effects on depressive a novel therapeutic strategy against MD. Preliminary studies [32] symptomatology. Such effects have been shown to modulate the showed that alterations in the circadian rhythm affect the state of dopaminergic mechanisms in depression [43]. The action is evident mood. Successively a novel approach to depression involving the at lower doses, as described by Sachs et al. [44]. , act- circadian rhythm led to a new antidepressant therapy [33]. Actually ing as D2-receptor antagonist, has unique characteristics as a partial is not clear whether sleep disturbances affect the clinical expression agonist at D2 and 5HT1A receptors and an antagonist at 5HT2A re- of depression or is a causative factor. In this context, the ceptors [45, 46]. It also has a low propensity to produce extrapyra- is considered the first antidepressant in this class. It is midal syndrome (EPS), sedation, weight gain, and hyperprolacti- an agonist of MT1/MT2 melatonergic receptors and antagonist of nemia [47, 48]. The 5-HT1A agonistic effect of aripiprazole as well serotonin 5-HT2C receptors. This new compound induces resyn- as its efficacy in treating anxiety and depressive symptoms, in clini- chronization of circadian rhythm and is efficient in preclinical stud- cal trials with psychotic disorders, provide evidence for the use of ies with different animal models of depression. Moreover this drug aripiprazole as an adjunctive therapy to SSRIs against MD [49, 50]. has been tested in several clinical trials [34]. The efficacy of is a drug usually employed for the treatment of schizo- agomelatine treatment has been already proven though adverse phrenia and other psychosis [51]. Clinical studies and trials suggest effects were observed both in treated and untreated patients [35]. If olanzapine is superior to and also maybe superior to compared with others antidepressant drugs, agomelatine presents in terms of efficacy and side-effect profiles. The thera- clinical benefits such as respect of sexual function, absence of dis- peutic advantage of recent antipsychotics (so-called atypical antip- continuation symptoms, and no effect on body weight [36]. sychotics) has been attributed to alpha-2 adrenergic antagonist ef- fects . In vivo, olanzapine has potent antiserotoninergic activity as Antipsychotics evidenced by the inhibition of 5-hydroxytrytophan-induced head twitches increases in serum corticosterone in rats. Olanzapine ex- Drugs available for the treatment of MD include: first genera- hibits high affinity for dopamine D1 ,D2, D4, 5HT2A, 5HT2C, tion antipsychotics and second generation antipsychotics (see Table 5HT3, muscarinic, 1-adrenergic and histamine H1 receptors in rats 2) [37]. and human tissue and in cell lines transfected with human receptors [52-54]. Nevertheless, the study of olanzapine effects upon cogni- First-Generation Antipsychotics tive function is complex and under debate being reported contrast- ing evidences [55, 56]. More clinical trials studying olanzapine They represent an older class of antipsychotics that have been response in patients with depression use the combination of olan- the standard goal for treating psychotic disorders for many decades. zapine with an antidepressant, mainly with fluoxetine. In bipolar These drugs are often called typical or conventional antipsychotics depression, this combination has a satisfactory effect both in short- since, when compared with a newer class of second-generation term and long-term treatments, accompanied by a low risk for antipsychotics, they lack a wider spectrum of therapeutic activity. switch to mania [57]. drugs such as quetiap- Moreover, the conventional antipsychotics are associated with ine, dissociate from the D2 receptor in vitro and in vivo, with rapid many side effects and lack the tolerability of the newer antipsychot- dissociation times from the cloned D2 receptor [58], limiting the ics. Yet for patients in whom conventional antipsychotics are effec- clinical side effects. being a broad-acting agent, exhibit tive and tolerable, these continue to have a place in the affinity for a variety of DA receptors, and also for other me- treatment of mental disorders [38]. Antipsychotics work principally tabotropic receptors, e.g. those for serotonin (5-HT2A and 5-HT1), by blocking, or antagonizing, the action of dopamine at its recep- norepinephrine (NE), acetylcholine and histamine [59]. The thera- Antidepressant Strategies in Therapy Against Anxiety and Depressive-Like Disorders Current Medicinal Chemistry, 2011 Vol. 18, No. 2 5

Table 2. Pharmacotherapy of MD- Antipsychotics

First generation Second generation Cl

Cl

S N

N N H Phenotiazine H O N O

Aripiprazole

N

O N N

N S Butyrophenone H Olanzapine

N O N HO N O N N S

S S Quetiapine F O O O N S N N H

H2N O

F Amisulpride Diphenylbutylpiperidine

N O N NH2 N Cl

Benzamide N H peutic effects of quetiapine on the positive symptoms depends on in bipolar mania, schizophrenia, or schizoaffective disorders. [64, the inhibition of D2 receptors in mesolimbic areas [58]. On this 65]. basis, quetiapine is used in patients with MD due to both its effi- cacy and its favorable tolerance profile [60, 61]. As concerns 3. NON PHARMACOLOGICAL THERAPY risperidone, several clinical observations report that it induces minimal extrapyramidal side-effects compared to the classic antip- Non pharmacological therapy (electroconvulsive therapy, vagus sychotics (e.g., ) [50] and it is considered as an ad- nerve stimulation and transcranial magnetic stimulation) have been junctive therapy for MD [44, 60, 62, 63]. Available data for antide- considered as alternative options in patients affected by MD not pressant effects of described its efficacy and tolerability responding to conventional treatments. 6 Current Medicinal Chemistry, 2011 Vol. 18, No. 2 Crupi et al.

Electronconvulsive therapy (ECT) has been used for 70 years 4. NATURAL SUBSTANCES and it is considered the cornerstone for patients who do not respond to and psychotherapy. ECT is characterized by high The development of new treatments is likely to emerge from the efficacy accompanied by cognitive side effects [66]. Study con- identification of etiological mechanisms or of pivotal components ducted by UK research group [67] showed that ECT is considered of the pathophysiology of depression. The therapeutic action of an effective short-term treatment for depression. currently available chemical ADs is realized approximately 50-60% of patients with MDD and required weeks to months of chronic Vagus nerve stimulation (VNS) has been approved in July 2005, treatment [77, 78]. An improved understanding of the etiology and by FDA in US as adjunctive long-term treatment of pathophysiology of MDD and its subtypes will facilitate the devel- chronic/recurrent depression for adult patients refractory to ADs opment of novel, faster-acting, subtype-specific antidepressants. In therapy [68, 69]. Unfortunately the VNS use is limited for the ade- this context the use of natural or herbal remedies as a form of self- quacy of the clinical trial and the partial failure of treatment against treatment of different afflictions has become popular in Western depression. societies. The conventional medications have established efficacy and a broad spectrum of action among the MD, presenting caveats Transcranial Magnetic Stimulation (TMS) for their use. Many patients improve with treatment, however, Repetitive transcranial magnetic stimulation (rTMS) is a new many others remain symptomatic despite an initial intervention; brain stimulation technique that has been utilized as an additional many others are unable to tolerate the side effects that accompany treatment for patients with MDD [70]. rTMS is characterized by a treatment with conventional agents. Many patients often are reluc- focal cortical intervention that gives the possibility to involve key tant to use ‘‘synthetic agents’’ for prolonged periods of time or at depressed brain regions. After application of rTMS in depression, all. Natural remedies may be more appealing to these patients as the patients with MDD exhibit a reduction in resting activity in left they are perceived as safer and commonly have a more favorable dorsolateral prefrontal cortex (DLPC) on PET imaging [71]. Factors side effects profile [79]. Unfortunately there are only few data re- such as pulse number, frequency, intensity of stimulation, train garding efficacy, tolerability and safety of natural remedies for duration and intertrain interval, can all be varied in the provision of different psychiatric disorders. Among natural remedies we specifi- rTMS trials over time [72]. The effect of TMS on the site targeted cally focus on melatonin, Hypericum perforatum and omega-3 fatty will produce both local and distal effects that needed to normalize acids (Fig. 2). activity in the depression circuitry. In this technique the pulses are applied to the brain repeatedly at both high and low frequency. In Melatonin general low frequency usually refers to stimulation at 1 Hz and it is Melatonin is a neurohormone synthesized by the pineal gland often applied for 15-20 min. On the contrary, high-frequency rTMS during darkness; it is able to regulate seasonal and circadian refers to the stimulation with short burst of multiple pulses, com- rhythms [80]. The anti inflammatory activity of melatonin in central prised between 5 and 20 Hz. Fitzgeral and colleagues [66] demon- nervous system [81, 82] demonstrated that endogenous melatonin strated that after a single session of low-frequency there is a tran- synthesis depends on the suprachiasmatic nucleus responsible for sient reduction in cortical activity, while after high -frequency there noradrenalin release by sympathetic nerves in the pineal. Moreover, is a transient increase in local cortical excitability. Despite early exogenous melatonin can affect neurodegenerative diseases, im- studies have been conducted since 1990s, only in 2008 it has been mune function disorders and oxidative damage [80]. Melatonin approved by FDA for the treatment of depression [66, 73]. Unlike antidepressant actions have been described by Ergun et al., [83] and ECT, rTMS does not involve anesthetic or seizure. rTMS is consid- Crupi et al. 2010 [84]. Melatonin has been hypothesized to be al- ered safe and the most commonly side effects are transient head- tered in depressed patients as a consequence of a disturbance of the ache and discomfort at the site of stimulation [74]. Actually the noradrenergic transmission. In fact, there have been numerous re- studies regarding the use of rTMS in clinical have not been evalu- ports of abnormality in phase and amplitude of circadian rhythms in ated in a number of relevant subpopulations patients with depres- depressed patients [85]. Studies by Zhdanova [86] showed that low sion (adolescents, very old or pregnant). In this important field doses of melatonin have an anxiolytic-like effect in rats withdrawn further studies should be necessary to explore the optimal methods from chronic administration. Published data from our labo- of treatment administration in a large cohort of patients. ratory [84] identified melatonin as implicated in the treatment of Deep brain stimulation (DBS) is a surgical treatment used to depression in a mouse model of anxiety/depressive-like state. In our treat neurological, psychiatric disorders and movement. This tech- study and according to Ramirez-Rodriguez [87] this indoleamine is nique involves the implantation of a brain pacemaker, which sends able to stimulate hippocampal neurogenesis. electrical impulses to the specific brain areas. In DBS, a pair of electrodes is implanted in the brain and controlled by a generator Hypericum perforatum that is placed in the chest. Stimulation is continuous and its fre- quency and level is customized to the individual. DBS requires St. John’s Wort is a plant native to Europe, West Asia and brain surgery. The head is shaved and then attached with screws to North Africa. These extracts have been traditionally recommended a sturdy frame that prevents the head from moving during the sur- for different medical conditions. The modern-day use of St. John’s gery. Scans of the head and brain using MRI are taken. The surgeon wort is the treatment of depression [88]. In this respect, different uses these images as guides during the surgery. Patients are awake controlled trials have confirmed its efficacy in the treatment of during the procedure to provide the surgeon with feedback, but they mild-to-moderate depression [89]. Studies by Di Paola et colleagues feel no pain because the head is numbed with a local anesthetic. [90] demonstrated that Hypericum perforatum has anxiolytic and Once ready for surgery, two holes are drilled into the head. From anti-inflammatory effects. Due to its components (hypericin and there, the surgeon threads a slender tube down into the brain to pseudohypericin) Muller et al. [91] have demonstrated that Hy- place electrodes on each side of a specific part of the brain. In the pericum perforatum is able to inhibit the reuptake of several synap- case of depression, the part of the brain targeted is called Area 25. tosomal neurotransmitters such as serotonin, noradrenalin, dopa- This area has been found to be overactive in depression and other mine, with efficiencies similar to that affinity selective inhibitors mood disorders [75]. Recently DBS as been used in the treatment [92] and modulates neuronal excitability via glutamatergic and resistant depression [76]. Functional circuit involved in the different GABAergic mechanisms [93]. Recently in our laboratory[94] we mood disorders are critical steps for the DBS efficacy. have tested the Hypericum perforatum efficacy in a mouse model of depression. Our results showed the antidepressant activity of this Antidepressant Strategies in Therapy Against Anxiety and Depressive-Like Disorders Current Medicinal Chemistry, 2011 Vol. 18, No. 2 7 wort accompanied by improvement in synaptic plasticity and neu- sant medications act by normalizing this impairment [109]. The rogenesis. “hypothesis of neuroplasticity” integrates post-receptor intracellular signaling cascades with the mechanisms of gene expression and Omega-3 Fatty Acids several other processes, including synaptic mechanisms, neurotro- phic mechanisms and neurogenesis [8]. The network construction Omega-3 fatty acids are long-chain polyunsaturated fatty acids and reorganization occurs during neuronal remodeling, character- found in various plant and marine life [95]. Their recruitment is ized by new synapses formation and birth of neurons. These modi- essential for human health but the body can' t make them, so that fications can be clustered under the neuroplasticity term. This proc- they should be taken with food. Omega-3 fatty acids, also called as ess represents a complex of different adaptive response to both polyunsaturated fatty acids (PUFAs), play a crucial role in brain external and internal stimuli of various nature. Modifications of function and are known to have therapeutic potential in several gene expression (activation of neurotrophic factors), synaptic plas- neurological and psychiatric disorders. With regard to the depres- ticity (long term potentiation and long term depression) and neuro- sion studies, Smith [96] and Hibbeln and Salem [97] suggested that genesis, represent the most important target of neuroplasticity proc- the sharp rises in rates of depression and other neurological disor- ess [110]. It is known that chronic antidepressant administration ders in the 20th century are being fueled by increased consumption increases adult neurogenesis in the SGZ as observed by uptake of of vegetable oils rich in omega-6 fatty acids. Accordingly, findings bromo-deoxyuridine [111]. SSRIs, monoamino oxidase inhibitors, by [98] showed that high levels of inflammatory eicosanoids de- tricyclics and norepinephrine reuptake inhibitors increase adult rived from arachidonic acid in both patients with unipolar depres- neurogenesis in the SGZ and not in the SVZ suggesting a specific- sion and those with bipolar depression. In the CNS, eicosapen- ity of the antidepressants to regulate hippocampal neurogenesis taenoic acid (EPA) and docosahexaenoic acid (DHA), considered as [112]. The effects on cell proliferation are observed only after the two main omega (n)-3 fatty acids in fish oil, are characterized chronic treatment; this result is in accordance to the therapeutic by biological functions. In particular DHA is a major structural action of these classes of antidepressants in humans [111]. Studies component of neuronal membranes, and EPA has important physio- performed by Wang and colleagues [113] showed that chronic logical functions that can affect neuronal activity. Changes in the fluoxetine administration promotes the maturation of young neu- fatty acid composition of neuronal membranes lead to functional rons by increasing dendritic arborization. Other antidepressants changes in the activity of receptors, neurotransmitter channels and such as tianepine, agomelatine stimulated proliferation and survival other proteins embedded in the membrane phospholipids. Epidemi- in the adult hippocampus [114]. In particular chronic agomelatine ological studies, performed by Peet and Stokes, [99] and Connor treatment increased cell proliferation and survival in the ventral [100] indicate an association between depression and low dietary dentate gyrus, a region involved in emotionally behavior [114]. intake of n-3 fatty acids (EPA and DHA). In support to this hy- Moreover, chronic SSRI (sertraline, paroxetine, fluoextine and pothesis, clinical studies have shown reduced levels of n-3 fatty citalopram) [115, 116], NESRI (desipramine and reboxetine) [117, acids in red blood cell membranes and plasma in both depressive 118], and MAOI (tranylcypromine) [115] treatment notably in- and schizophrenic patients. Furthermore, EPA has been used to creased the expression of neurotrophine such as BDNF in the hip- treat depression [101]. n-3 fatty acids are able to affect neurogene- pocampus [115]. sis [102] via their anti-inflammatory, neurotransmitter regulating and neuroprotective effects [103, 104]. This mechanism includes Neurotrophic Factors that (a) n-3 fatty acids decrease the production of pro-inflammatory cytokines, such as TNF- and IL-1 [103], which have been impli- Neurotrophic factors are a family of proteins that can induce the cated in the mechanism that benefits neurogenesis and cell fate growth and survival of developing neurons in the CNS (central [105]; (b) n-3 fatty acids modulate the quaternary structure of nervous system) and PNS (peripheral nervous system) and control membrane proteins and membrane fluidity, which may benefit the the mature neurons maintenance. They are capable of re-growing binding of 5-HT [102]. 5-HT, in turn, stimulates neurogenesis in damaged neurons in test tubes and animal models [119]. Neurotro- both vertebrate and invertebrate species [106] (c) n-3 fatty acids up- phic factors are often released by the target tissue in order to guide regulate levels and expressions of neurotrophins, such as BDNF the growth of developing axons and can be divided into three fami- and its receptors [107]. Kawakita and colleagues [108] showed that, lies: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor DHA effectively promoted neurogenesis and enhanced the differen- family ligands (GFLs), and (3) neuropoietic cytokines [119] tiation of neural stem cells into neurons by promoting cell cycle exit and by suppressing cell death in adult rats. CREB The stimulation or inhibition of selected receptors for serotonin 5. ACTION MECHANISM FOR ANTIDEPRESSANT and noradrenalin may provoke adaptive changes in signaling path- THERAPY ways. A large number of transcription factors that regulate a wide Molecules employed in the therapy for MD have been devel- variety of physiological processes have been identified. Among oped based on studies progressively performed to ascertain the them, cAMP-response element binding protein (CREB1) can be pathogenesis of such alterations thus suggesting different hypothe- considered. Studies by Kandel [120] showed that it is implicated in sis for the onset of depressive phenotype. The “monoamine hy- different processes such as proliferation of neuronal precursors, pothesis” of depression, dealing with serotonergic, noradrenergic outgrowth of neuronal processes, learning and memory in both and dopaminergic system alterations, has explained the pathophysi- invertebrates and vertebrates, induction of neurotrophic and neuro- ology of depression for a long time. For this reason compounds as protective cellular programs and regulation of circadian rhythms. monoamine oxidase inhibitors (MAOIs) and tricyclics have been Nibuya and colleagues [121] found that chronic but not acute ad- adopted as ADs. Nevertheless, the modulation of dopaminergic, ministration of several drugs, representative of different classes of serotonergic and noradrenergic transmission does not totally ex- ADs, as well as electroconvulsive treatment (ECT), up-regulated plain the efficacy of ADs in treating MD. This hypothesis has been the expression of CREB mRNA in hippocampus. They also showed developed since the 1960s. Thereafter it has been modified based that following repetitive administration of fluoxetine (FLX), or on several experimental reports. In fact it has been suggested that ECT, the amount of CREB bound to CRE regulatory element, was major depressive disorders may be associated not only with altered increased, as detected by gelshift analysis. Another group con- neurotransmission and neuromodulation, but also with an impair- firmed this result [122]. All of these findings are consistent with the ment of neuroplasticity and cellular resilience, and that antidepres- hypothesis that the time-dependent therapeutic effect of these drugs 8 Current Medicinal Chemistry, 2011 Vol. 18, No. 2 Crupi et al. depend on modification of gene expression. However, it has been Both LTP and LTD of glutamatergic synapses are considered shown that the transcriptional activity of CREB is mainly induced cellular correlates for learning and memory but exhibit several dif- by its phosphorylation [123-125]. Therefore, in subsequent study, ferent features. For example, the amplitude of excitatory post syn- Duman and colleagues [126] investigated both the CRE-mediated aptic potential (EPSCs) is increased during LTP, while it is reduced gene transcription and the phosphorylation of CREB. FLX and during LTD [145]. Hippocampal LTP is accompanied by a higher tranylcypromine (TCP) (an inhibitor of monoamine oxidase) in- sensitivity of the postsynaptic membrane for exogenously applied creased it in cerebral cortex and hypothalamus and TCP only in DG agonists, while LTD is accompanied by a lower sensitivity [146]. A and CA3 hippocampal areas. Moreover it has been suggested that synaptic insertion of AMPA receptors occurs after the induction of the activation of multiple signaling cascades impinging on CREB is LTP, whereas a synaptic redistribution of AMPA receptors occurs required for induction of persistent changes in gene expression after the induction of LTD [147]. The single-channel conductance [127, 128]. This mechanism could be a way of signaling stimuli of of AMPA receptors is increased during LTP [148]. The late phase greater significance, deserving to leave a more persistent trace in of LTP is accompanied by an increased synthesis of AMPA recep- gene expression and cellular function. Different studies suggest that tors [149]. LTP induction is followed by an increase in spine den- CREB contributes to neurotrophin-mediated survival in the central sity [150]. Specific subunits of the AMPA receptor are more phos- nervous system by activating antiapoptotic gene expression and that phorylated during LTP and less phosphorylated during LTD [151, CREB Ser 133 phosphorylation is required for activation of CREB- 152]. Alterations in neuroplasticity may underlie some of the symp- regulated transcription by neurotrophins [129, 130]. toms of psychiatric disorders such as depression, schizophrenia and bipolar disorder [153]. Enhanced CA1 LTD was demonstrated in a BDNF rat model of depression and could be blocked by the antidepressant fluvoxamine [154]. It is well established that the triggering of LTP An interesting point regards the Brain-Derived Neurotrophic requires synaptic activation of postsynaptic N-methyl-d-aspartate Factor (BDNF). The role of this factor along with its receptor TrkB (NMDA) receptors, a subtype of ionotropic glutamate receptor. The in modulation of neuroplasticity and cognitive process has been role of glutamate in psychiatric disorders has been documented by widely investigated. The neurotrophic hypothesis of depression increased levels of glutamate in plasma and brain of patients with postulates that decreased levels of neurotrophic factors, in particular MD [155], elevation of glutamate neurotransmission and levels in BDNF, contribute to the hippocampal atrophy observed in de- cortical/limbic brain regions of depressed patients [156], atrophy of pressed patients and that antidepressant administration restores apical dendrites in CA3 hippocampal neurons induced by chronic their therapeutic effects through increased expression of neurotro- stress [157], alteration of NMDA receptors induced by chronic phic factors in the hippocampus [131-134]. In particular it has been stress [158]. Antidepressant therapy downregulates NMDA receptor shown that BDNF infusion in mice hippocampus mimics the anti- subunits [159], counteracts the effects of stress on LTP [160], re- depressant-like actions [131] and TrkB over expression provokes duces the depolarization-evoked release of glutamate in hippocam- antidepressant-like effects in behavioral paradigm as Forced pus by modifying pre-synaptic protein interactions regulating the Swimming Test (FST) [135]. BDNF polymorphism is often associ- exocytotic release [161]. Acute administration of fluoxetine, imi- ated with depressive symptoms: in particular a link between fatigue pramine, tianeptine re-establishes LTP after acute stress [162]. One [136] or impairment of working memory and depression or increase of the mechanisms of action of ADs is a stabilization of glutamate of anxiety has been described [137]. Other pathologies, such as release. Some evidences suggest that the functional relationship psychosis [138], substances dependence [139] and Alzheimer dis- between NMDA and AMPA glutamate receptors in cortical and ease [140] are associated with BDNF polymorphism. BDNF ex- limbic areas is involved in both the pathophysiology of MD and in pression is increased by different classes of antidepressants. In this antidepressant mechanisms [163]. In pre-clinical trials the chronic regard, experimental findings have shown that subfields of the hip- treatment with different ADs induces a reduction in the function or pocampus, including the granule cell layer and the CA1 and CA3 expression of the NMDA receptor [164]. In particular chronic pyramidal cell layers are involved [121]. Actually the upregulation fluoxetine and reboxetine induce in rat hippocampus downregula- of BDNF is modulated by different classes of ADs, as selective tion of subunit of NR1 only locally at synapses [165], similarly to serotonin reuptake inhibitors (SSRI), norepinephrine selective reup- what observed with escitalopram in a genetic animal model of de- take inhibitors (NESRI), monoamine oxidase inhibitors (MAOIs), pression [166]. atypical antidepressants, and electroconvulsive seizures (ECS) [115]. BDNF expression is also dependent on chronic antidepres- Hippocampal Neurogenesis sant treatment, consistent with the time course for the therapeutic action of ADs. Interestingly opiates, antipsychotics and psy- Studies by Goldman and Nottebohm [167] showed, for the first chostimulants do not modify hippocampal BDNF expression, sug- time, that in songbirds, new neurons are produced in the HVc gesting BDNF as a pharmacological target to treat MD [141]. Elec- (Hight Vocal center), a brain nucleus of the telencephalon involved troconvulsive seizures, monoamine oxidase inhibitors, SSRI and in vocal control. The production of new elemental components of NESRI antidepressants increase the hippocampal BDNF levels songs has been hypothesized to require new neurons [168]. In the depending on both dose and time of treatment [116, 118, 142]. 1990s, new detection methods have given renewal attention to the postnatal neurogenesis in the mammalian brain so that the subven- Synaptic Plasticity tricular zone (SVZ) has been recognized to a neurogenesis poten- tial. The newly born cells have been further reported to migrate and Neuronal functions underlying the modulation of behavioral differentiate into neurons of the olfactory bulb (OB) [169] . In par- neural circuits depend mainly on three mechanisms: (a) efficacy of ticular, these new cells in the SVZ migrate to the OB through the synaptic transmission at preexisting synapses, (b) growth of new rostral migratory stream (RMS) and differentiate into interneurons synaptic connections (c) excitability properties of single neurons. of the OB. In the OB these cells establish synaptic contacts and The first one specifically accounts for neuroplasticity processes. functional connections with neighboring cells [170]. This phe- Alterations of synaptic efficacy may be due to long-lasting activity- nomenon has been classified such as adult neurogenesis and it has dependent changes in synaptic strength. The most common forms been confirmed in a variety of species and in particular in humans are long-term potentiation (LTP), considered as long-lasting en- [171, 172]. Neurogenesis occurs in two specific brain areas: sub- hancement in signal transmission between two neurons resulting ventricular zone (SVZ) of the lateral ventricles and the subgranular from stimulating them synchronously [143], and long term depres- zone (SGZ) of the DG of the hippocampus and can be divided into sion (LTD), that represents an activity-dependent reduction in the discrete stages, each of which is defined by distinct physiological efficacy of neuronal synapses lasting hours or longer [144]. Antidepressant Strategies in Therapy Against Anxiety and Depressive-Like Disorders Current Medicinal Chemistry, 2011 Vol. 18, No. 2 9

Fig. (1). Mechanism of action of antidepressants. Chronic antidepressant treatment causes cellular and molecular manifestations of neuroplasticity in adult brain. Bottom panel shows the neuronal differentiation cascade in the DG. Quiescent positive radial glia-like progenitors (I) generate, through asymmetric divisions the amplifying neural progenitors (II). These cells, after symmetric divisions, exit the cell cycle within 1–3 days and become postmitotic neuroblasts type 1 cells (III). In the next 15-21 days these cells mature into neuroblasts type 2 (III) and then into immature neurons (IV). These cells are characterized by apical processes and basal axons and the soma is located in the granule cell layer. 10-15 days later, the immature neurons evolve in mature granule neurons (V). and morphological properties [6]. Five different stages can be dis- PSA-NCAM and DCX. They migrate a short distance into the tinguished [173]. Stage 1 or proliferation phase: the newly gener- granule cell layer of the DG. In the stage 4 or axonal and dendritic ated cells express the markers glial fibrillaryacidic protein (GFAP) targeting the immature neurons send their dendrites toward the and nestin [174]. These cells can be considered as putative stem molecular layer of the DG and extend their axonal projections to- cells and putative progenitor cells and represent, in the SGZ, a sub- ward the hippocampal CA3 pyramidal cell layer. During this stage, set of astrocytes that give rise to new granule cells [175]. These the newly generated neurons become postmitotic. The immature precursors share many characteristics with embryonic radial glia neurons still express DCX and PSA-NCAM [180]. The early post- cells [176], acting as neuronal progenitors during embryonic devel- mitotic neurons (at least in mice) transiently express the calcium- opment [177]. The resident hippocampal precursor has been re- binding protein calretinin [181] and the neuronal marker NeuN ported to be a progenitor capable of proliferation and multi- (neuron-specific nuclear protein) [181]. In the stage 5 or synaptic potential differentiation, but unable to self-renew and, thus, unable integration, the newly formed granule neurons establish their synap- to proliferate indefinitely [178]. The stem cell responsible for adult tic contacts for receiving inputs from the entorhinal cortex and for hippocampal neurogenesis may reside outside the hippocampus and sending outputs to the CA3 and hilus regions. Approximately 2– 3 produces progenitors that migrate into the SGZ and proliferate to weeks after the newly generated cells have become postmitotic, generate new neurons and glia [178]. Based on this view, the calretinin seems to be exchanged for calbindin in mature granule nestin/GFAP positive cells seen at stage 1 may represent progeni- cells [181, 182]. Calbindin is present in all mature granule cells tors but not stem cells. Alternatively, the stem cell might only exist [183], and the newly formed cells that express calbindin become shortly after birth to create a progenitor pool. According to this functionally integrated in the hippocampus [184]. These neurons model, the adult DG would have only a limited supply of dividing also express the postmitotic neuronal marker NeuN [185]. Neuro- progenitor cells. During the stage 2 or differentiation phase, the genesis process is completed when the mature neurons are inte- transient amplifying cells differentiate into immature neurons in the grated structurally and functionally into pre-existing neural net- SGZ. The cells of early stage 2 are nestin-positive but GFAP- works [186, 187]. Adult neurogenesis has become one of the most negative and highly proliferative [179]. During this phase, the cells rapidly growing areas in neuroscience research. It adds a new di- are also thought to commit to a neuronal lineage. At later time- mension of cellular plasticity to the familiar synaptic concept of points, the stage 2 cells transiently stop expressing nestin and start plasticity. Actually adult neurogenesis in the DG has been consid- to express doublecortin (DCX) and the polysialylated embryonic ered as a cellular substrate underlying the treatment of depression. form of the neural cell adhesion molecule (PSA-NCAM) [179]. In As stated above, the hippocampus is one of the several limbic struc- stage 3 or migration phase, the immature neurons express both tures that has been studied in patients with psychiatric and neuro- 10 Current Medicinal Chemistry, 2011 Vol. 18, No. 2 Crupi et al.

Fig. (2). Potential role for natural substances as a treatment for mood disorders. Melatonin, Hypericum perforatum and Omega-3 fatty acids, modulate brain inflammation, synaptic plasticity and neurogenesis in the treatment of mood disorders. logical disorders and represents a neural substrate that underlies the SGZ there are two different types of neuronal progenitors : type 1 response to ADs [188]. Altered hippocampal function probably and type 2. Type 1 possessed a radial process spanning the granule interferes with the activity of neural circuitry in the prefrontal cor- cell layer, expressing nestin, glial fibrillary acidin protein (GFAP), tex, amigdala and nucleus accumbens, structures that receive inputs and the Sry-related HMG box transcription factor Sox2 [196] . from the hippocampus and are associated with emotionality [4]. To Type 2 have a short processes and express Sox-2 but not GFAP understand the pathophysiological framework of depression and [187] and are considered to as transit-amplifying cells or intermedi- subsequent treatment, it is important to know the most relevant ate progenitors [197]. SSRIs are able to change metabolic activity molecular, cellular and circuit-levels of chronic antidepressant ac- of the subgenual cingulate cortex, hippocampus and prefrontal cor- tion accompanied by behavioral models. Thus the neurogenesis tex [198, 199]. Amongst Ads, SSRIs treatment is often linked with hypothesis of depression has become popular in the last years. Ac- a delayed onset of therapeutic efficacy that has long been thought to cording to this hypothesis, a decrease in the development of new- mimic the temporal profile of desensitization of specific serotonin born granule cells in the DG of the hippocampus is linked to the autoreceptors [200, 201]. Richardson-Jones and colleagues [202] pathophysiology of depression and hippocampal neurogenesis is recently suggested that serotonergic tone prior to the onset of treat- required for the behavioral effect of ADs [112]. This hypothesis is ment is likely more important for governing this delay than autore- at least partially true. In fact, the decrease of neurogenesis alone is ceptor desensitization. Another alternative for this hypothesis had not sufficient to drive a depression-like phenotype since there adult previously suggested that structural changes in neural circuitry, neurogenesis is required to mediate the beneficial effects of antide- such as adult neurogenesis, also underlie this delay [6, 131]. Ac- pressant therapy. cording to this hypothesis adult neurogenesis, only in the SGZ is Several studies showed that the hippocampus, amygdala and increased by chronic, not acute, antidepressant therapy. This find- prefrontal cortex are involved in the regulation of mood for their ing, obtained for different drugs (SSRIs, MAOIs, TCAs) is impor- contribute to the central regulation of the hypothalamic-pituitary- tant because suggests a specificity of the ADs to modulate hippo- adrenal (HPA) axis [189]. In particular, hippocampal neurogenesis campal neurogenesis. In particular Wang et al. [113] demonstrated is directly involved in this phenomenon. It is known that exposure that chronic fluoxetine administration stimulates neural hippocam- of different forms of chronic stress can modify adult neurogenesis pal proliferation and accelerates the dendritic arborization in young in different species [190]. Stress suppresses adult neurogenesis in neurons. Like antidepressant therapy, electro convulsive seizures the hippocampus by activation of the HPA axis and consequent (ECS) or environmental enrichment [203, 204] increase neurogene- glucocorticoid levels elevation [191, 192]. Antidepressant therapy sis. To clarify the role of antidepressant therapy in adult hippocam- increases proliferation and survival stages in the adult hippocampus pal neurogenesis, several methods have been used. In particular [114] (Fig. 1). Recently it has been shown that ADs could differen- focal X-irradiation of the hippocampus [112] in mice does not in- tially affect various stages of neurogenesis in the dorsal and ventral fluence anxiety-related behavior, as reviewed in Novelty Sup- hippocampus. In this regard 3 weeks agomelatine administration pressed Field (NSF) or in conflict-based tests (Elevated Place stimulated cell proliferation and survival in the ventral DG [114]. Maze, Open Field). The loss of adult hippocampal neurogenesis Atypical antidepressant, such as tianepine, is able to increase prolif- after irradiation is not sufficient to induce anxiety/depressive-like eration and survival of new neurons in the adult hippocampus behavior and does not aggravate the behavioral alteration provoked [193]. Wang and colleagues [113] demonstrated that chronic by stress. This finding shows that adult hippocampal neurogenesis fluoxetine administration increases both proliferation and survival is important in mediating the antidepressant response. To better of immature neurons. Moreover an important fraction of double- clarify this conclusion, several depression and anxiety–related be- cortin positive cells (DCX+) presented tertiary dendrites with more havioral effects induced by chronic stress or corticosterone admini- complex dendritic arborization. Newborn neurons showed an accel- stration are counteracted by chronic antidepressant therapy in a erated maturation after chronic fluoxetine administration, as re- neurogenesis-dependent manner [194, 205]. Mice in which neuro- vealed by the increased proportion of newborn cells that ceased to genesis is ablated by genetic manipulation (GFAP-TK mice) are express the immature neuronal marker DCX [194] . Adult NSCs responsive to antidepressant treatment behaviorally [206]. In this can differentiate into astrocytes and oligodendrocytes [195]. In the context a genetic manipulation also demonstrated a requirement in mediating the antidepressants response. Different factors modulate Antidepressant Strategies in Therapy Against Anxiety and Depressive-Like Disorders Current Medicinal Chemistry, 2011 Vol. 18, No. 2 11 adult hippocampal neurogenesis, among which neurotrophic fac- REFERENCES tors, such as BDNF and VEGF, have a critical role [207]. 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