Recent Patents on CNS Drug Discovery, 2006, 1, 315-324
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Neuropeptide Y as an Endogenous Antiepileptic, Neuroprotective and ProNeurogenic Peptide Sara Xapellia, Fabienne Agassea, Raquel Ferreiraa, Ana P. Silvaa,b and João O. Malvaa,c,* a
Center for Neuroscience and Cell Biology of Coimbra, 3004-517 Coimbra, Portugal, bInstitute of Pharmacology and Therapeutics, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal, cInstitute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal Received: September 22, 2006; Accepted: September 28, 2006; Revised: October 6, 2006
Abstract: Neuropeptide Y (NPY) is a small peptide important in cardiovascular physiology, feeding, anxiety, depression and epilepsy. In the hippocampus, NPY is mainly produced and released by GABAergic interneurons and inhibits glutamatergic neurotransmission in the excitatory tri-synaptic circuit. Under epileptic conditions, there is a robust overexpression of NPY and NPY receptors particularly in the granular and pyramidal cells, contributing to the tonic inhibition of glutamate release and consequently to control the spread of excitability into other brain structures. Recently, an important role was attributed to NPY in neuroprotection against excitotoxicity and in the modulation of neurogenesis. In the present review we discuss the potential relevance of NPY and NPY receptors in neuroprotection and neurogenesis, with implications for brain repair strategies. Recent patents describing new NPY receptor antagonists directed to treat obesity and cardiovascular disorders were published. However, the NPYergic system may also prove to be a good target for the treatment of pharmaco-resistant forms of temporal lobe epilepsy, by acting on hyperexcitability, neuronal death or brain repair. In order to achieve new NPY-based antiepileptic and brain repair strategies, selective NPY receptor agonists able to reach their targets in the epileptic brain must be developed in the near future.
Keywords: NPY, NPY receptors, glutamate, epilepsy, excitotoxicity, neuroprotection, neurogenesis, brain repair. 1. INTRODUCTION Epilepsy is a group of neurological disorders characterized by the occurrence of spontaneous non-evoked seizure activity, widely distributed in human populations, affecting people of all ages, gender and social groups with an incidence of about 1-3% [1]. Several pre- and post-natal events may contribute to the pathogenesis of epilepsy [2,3] and epileptic crises are usually revealed several years after the epileptogenic insult, following a latent period free of crises [4]. In spite of the devastating consequences of these diseases, current medical therapy is largely symptomatic and poorly controlled by antiepileptic drugs [1,5,6]. Temporal lobe epilepsy (TLE) is one of the most common epilepsy forms in the adult human [7]. TLE can be acquired following brain aggression like stroke, trauma, and neurodegenerative diseases [8] but in the majority of the clinical cases the origin of epilepsy is not certain. TLE is a drug-resistant type of human adult focal epilepsy characterized by the spontaneous occurrence of complex partial seizures [9] with a well restricted epileptic focus (partial) accompanied with impairment of consciousness (complex) [5,10]. Changes in neuronal network structure and physiology have been associated with epileptogenesis and subsequent seizure expression including neuronal loss, increased excita*Address correspondence to this author at the Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal; Tel: +351 239 833369; Fax: +351 239 822776; E-mail:
[email protected] 1574-8898/06 $100.00+.00
tion, altered inhibition, circuitry reorganization and synapse abnormalities [8]. Patients with chronic TLE and animals subjected to chemo-convulsants display widespread neuronal cell death, axonal sprouting, enhanced neurogenesis and the activation and proliferation of astrocytes and resident microglia through the brain, gliosis and consequent hippocampal sclerosis [5,11-14]. TLE is characterized by several histological aberrations and functional recurrent excitatory circuits in the hippocampus [15]. In hippocampal tissues, from TLE patients [1622] and experimental models [16,23-28] an abnormal morphology of the axons of granule cells in the dentate gyrus (DG) i.e. sprouting of hippocampal mossy fibers can be observed. Mossy fiber sprouting is a pronounced expansion of the projections of the granule cell axons outside their normal targets into the supragranular layers of DG [16,17,19,25] and within the hilus [25,28]. The vast majority of newly formed asymmetric mossy fiber synapses terminates on dendritic spines of granule cells [29,30], suggesting the formation of new aberrant and recurrent excitatory synapses. Seizures have been documented in acute slices from kainic acid-treated epileptic rats with robust mossy fiber sprouting [31,32] and a positive correlation between mossy fiber sprouting and the frequency of spontaneous seizures has been reported in in vivo animal models [33,34]. in vitro Electrophysiological experiments conducted in hippocampal slices obtained from kainic acid-treated rats have shown that focal application of glutamate to the dentate molecular layer evokes excitatory postsynaptic currents (EPSCs) [35] or evokes excitatory postsynaptic potentials (EPSPs) [36] in granule cells distant from the application place. Taken together, these data support the idea that new © 2006 Bentham Science Publishers Ltd.
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mossy fiber synapses are mainly excitatory and contribute to the overall excitability of the hippocampal circuits. 2. NPY AND NPY RECEPTORS IN TLE 2.1. NPY in TLE Since the discovery of substance P, an 11-aminoacid peptide found in the human hippocampus, neocortex and in the gastrointestinal tract, there has been a profound interest in discovering new neuropeptides and targeting their biological function. One of the most attractive molecules to emerge was neuropeptide Y (NPY). Peptide YY (PYY) and pancreatic polypeptide (PP), gut endocrine peptides integrate the rest of this peptide family [37]. NPY has a preponderant role in stress-related behaviors (such as anxiety and depression), feeding, cardiovascular and memory functions and in the control of seizure activity [38,39]. NPY receptor family has six different subtypes which in turn belong to the G-protein coupled receptor superfamily. Y1, Y2, and Y5 receptors have shown to be the most prominent in the hippocampal formation. While Y3 has so far been detected in the solitary tract nucleus, Y4 binds preferentially to PP and y6 is functional only in the mouse and rabbit [40]. NPY is the most abundant peptide in the Central Nervous System (CNS) preferentially expressed in GABAergic interneurons but it is also present in long projecting neurons [41-43]. Following high frequency neuronal firing (such as that observed during an epileptic seizure) NPY is an efficient regulator of excitatory neurotransmission [44-46]. Although NPY is distributed broadly throughout the nervous system, seizure-related changes in NPY and NPY receptors are seen mostly in brain areas such as the hippocampus involved in the initiation and propagation of epileptic discharges [47,48]. In human epileptic brain a pronounced overexpression of NPY was observed in interneurons [16,49,50]. Moreover, in animal models of epilepsy, kainic-acid injected or kindled rats, NPY mRNA and immunoreactivity (ir) increase in the hippocampus, amygdala, striatum and entorhinal cortex as well as in other extralimbic areas [51-60]. NPY overexpression follows a distinct time-course after seizure induction in different brain areas and in distinct subsets of neurons [48,51,53-55]. Strong NPY-ir persists in granule cells of epileptic brain [61] including the brain of pilocarpine-treated epileptic rats [62] for several months. Moreover, NPY gene expression is also increased after multiple electroconvulsive stimulations (ECS) supporting the hypothesis that NPY can play a central role as an endogenous antiepileptic agent [63]. Accordingly, significant increase in Y1, Y2, and Y 5 receptors mRNA were found in the DG after ECS. Moreover, a recent study suggests that the mechanisms coupling NPY receptor stimulation to G-protein activation can be augmented after repeated ECS [64]. In addition, anticonvulsant drugs given acutely after kainic acid injection prevent both seizures and NPY overexpression [53-55]. Furthermore, NPY administration (intracerebroventricularly; icv) inhibits hippocampal seizures in vivo in DG, subiculum and in CA3 pyramidal cells [65,66]. NPY-deficient mice occasionally develop mild spontaneous seizures, and exhibit markedly enhanced susceptibility to motor seizures induced by convulsant agents. Accordingly, NPY (icv) infusion before kainic acid administration prevents death in these animals [67,68]. Additionally, during kindling epileptogenesis, NPY knoc-
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kout mice (KO) had higher seizure severity scores and longer after discharge periods than the wild type mice [69]. Tu and collaborators [70] have shown that a Y2 receptor antagonist (BIIE0246) not only blocked the effects of added NPY but also enhanced recurrent mossy fiber synaptic transmission, the frequency of mEPSCs, and the magnitude of mossy fiber-evoked granule cell epileptiform activity, implying that spontaneous release of NPY from the recurrent mossy fiber pathway is sufficient to regulate synaptic transmission. Also, in an adult model of generalized genetic epilepsy (Genetic Absence Epilepsy Rats of Strasbourg-GAERS) NPY was capable of suppressing absence seizures [71]. Another study has shown that endogenous NPY prevents recurrence of experimental febrile seizures since this effect was abolished by an NPY antagonist. The entorhinal cortex is an important relay station between the hippocampus and other brain areas, providing input to the DG and CA3 from its layer II, and receives outputs from the CA1 and subiculum to layer III [72]. The entorhinal cortex contains local NPY-positive fibers deriving from both local and external sources [73]. in vitro Studies demonstrated anti-epileptiform effects of NPY in mouse CA3, CA1 and subiculum [74,75] and frontal cortex [76-78]. Other studies show that NPY reversibly shortens the after potential duration of spontaneous epileptiform discharges in the mouse entorhinal cortex of two different mouse strains [79]. 2.2. Involvement of NPY Receptors in TLE 2.2.1. Y1 Receptors The highest levels of Y1 receptor mRNA in the brain of several mammalian species are consistently seen in forebrain regions including the cerebral cortex, the hippocampal formation, and several amygdaloid, thalamic, and hypothalamic nuclei [80-82]. Within the rat hippocampus, high to moderate levels of Y1 receptor mRNA is restricted to the CA3, CA2 and CA1 pyramidal cell layers but data on Y1 receptor mRNA on DG are discrepant [80,82,83]. Seizures markedly increase the density of Y2 receptors in the DG whereas the density of Y1 receptors declines [84,85] suggesting that down-regulation of Y1 receptors is a mechanism for protection against recurrent epileptic events and hyperexcitability [59]. In human epileptic dentate molecular layer a decrease in Y1 receptor binding was observed [49] whereas in kindled rats, Y1 receptor binding and mRNA are significantly reduced in DG, CA1 and CA3 areas [86,87]. Moreover, Y 1 receptors seem to mediate weak excitatory actions of NPY in rats, since the Y1 receptor antagonist (BIBP3236) inhibits kainic acid-induced seizures and delays kindling epileptogenesis while the Y1 receptor agonist ([Leu32, Pro34]-NPY) and NPY itself blocks these effects suggesting a proconvulsive role for the Y1 receptor [88-91]. However, other evidences do not support a direct role of Y1 receptors to limit synaptic excitation since exogenous Y1 receptor-preferring agonist cannot inhibit mossy fiber-to-CA3 field excitatory postsynaptic potentials (fEPSP) [74] and in vitro seizure activity are largely insensitive to exogenous Y1 receptor-preferring agonist [75,92]. Furthermore, Y1 receptors have also been shown to inhibit glutamate release from rat hippocampal synapto-
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somes [93] and to reduce seizure-like activity in neurons and hippocampal slices [76,94]. More recent studies support the proconvulsive role of Y 1 receptors and anticonvulsive role of Y2 receptors, since the recombinant adeno-associated viral vector overexpressing NPY (rAAV-NPY) led to a twofold reduction of seizures induced by kainic acid in wild type and Y1 receptor KO mice without affecting seizures in Y2 receptor KO [95].
the NPY-mediated inhibition of both glutamatergic transmission and of epileptiform discharges in two slice models of TLE [105]. Also, in vivo studies have demonstrated that intrahippocampal injections of Y2-preferring agonists inhibited seizures caused by intrahippocampal injection with kainate [105]. Moreover, a more recent study also showed that Y2 mediate the anti-excitatory actions of NPY, since the rAAV-mediated hippocampal overexpression was ineffective in Y2 receptor KO mice and the seizure-induced mortality rate increased in these KO animals [95]. These evidences suggest an endogenous neuroprotective effect of NPY mainly via Y2 receptor activation in epileptogenesis.
2.2.2. Y2 Receptors In the human brain, Y2 receptor mRNA is present in different cerebral cortical areas and also in the subcortical white matter [96,97]. In the hippocampal formation, the granular layer of the DG shows the highest signal of Y2 receptor mRNA [96,97] but high levels of the Y2 receptor mRNA are also found in the CA2 and CA3 regions [96,97].
2.2.3. Y5 Receptors In post-mortem human brain Y 5 receptor mRNA is found in several regions [106]. High levels of Y5 receptor mRNA are found in the amygdala, substantia nigra and hypothalamus [106]. In the hippocampus, moderate levels of Y5 mRNA are found in neurons of the CA2, CA3, and CA4 regions and DG with lower levels in CA1 [106]. A minor almost undetectable, Y 5 mRNA level is found in the cerebral cortex [106].
The co-localization of Y2 receptor mRNA with NPY mRNA in some neuronal cells supports pharmacological studies indicating a presynaptic localization of Y2 autoreceptors, able to inhibit the release of NPY and other neurotransmitters [93,97,98]. Accordingly, Y 2 receptors have been implicated in the anticonvulsant properties of NPY [40,59]. In human epileptic dentate hilus, Y 2 receptor binding increases [49] and NPY application suppresses epileptiform activity [99]. In kindled rats, Y2 receptor binding is upregulated in DG, down-regulated in CA3 and unchanged in CA1 area [86]. Moreover, Roder and collaborators [100] showed that Y2 receptor binding decreases in kainic acidtreated rats compared to control animals except in the hilus of DG where it remains elevated. High density of Y2 receptors is present at the Schaffer collateral terminals in the CA1 sector of the hippocampus where NPY exerts a potent inhibitory action on glutamate release [93,101,102]. In addition, up-regulated Y2 receptors on mossy fibers together with high expression of NPY in the same terminals may represent an additional crucial site for inhibition of glutamate release and consequently of epileptic activity [61,91]. Furthermore, Y 2 receptor KO mice show enhanced epileptic activity after intrahippocampal application of kainate [101,103] and activation of Y2 receptors suppresses seizure activity in hippocampal slices in vitro [76] and in vivo models [91]. In the CA3 area Y2 receptor activation has been shown to reduce both ictaform and interictaform activity and Y2 receptor-preferring agonist mimicked the inhibitory effect of NPY while Y2 receptor antagonist blocked the effect of both NPY and Y2 receptor agonist [78,92,104]. In fact, a recent study has shown that an Y 2 receptor-preferring agonist mimicked and the Y2 receptor-selective antagonist blocked,
The involvement of Y5 receptors in epilepsy has been a matter of debate. Kopp and collaborators [107] observed an up-regulation of NPY Y5 receptor mRNA after kindling epileptogenesis. In studies using levetiracetam as an anticonvulsant against kindled seizures an increase of the levels of Y 1- and particularly Y 5 receptors-ir was observed in DG. In CA1 and CA3 areas, levetiracetam increased Y1- and Y2 receptor-ir levels by approximately 20% while Y5 receptors-ir were increased by about 300% [86]. These results suggest that maintaining or elevating normal levels of Y5 receptors subtype may be of importance to the anticonvulsant and antiepileptogenic effect of levetiracetam [86]. On the contrary, a down-regulation of Y5 receptor in kainic acid-treated and kindled rats was observed by Bregola and collaborators [108]. Accordingly, in the hippocampus of kindled rats, Y5 receptor binding levels were lower than Y1 and Y2 binding levels [86]. NPY or Y2-preferring agonist had no effect on spontaneous epileptiform bursts elicited in zero-Mg bathing medium using acute hippocampal slices from Y5 receptor KO mice [75,109]. Interestingly, also Y5 receptor KO mice are more susceptible to seizures [75]. Accordingly, some in vivo studies have shown that NPY icv infusion is a powerful inhibitor of motor as well as electroencephalographic (EEG) seizures induced by kainic acid and that this effect was mediated via receptors with a pharmacological profile similar to the recently cloned rat Y5
Table 1 - NPY and NPY Receptor Changes in TLE TLE
Changes
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NPY
Y1 receptor
Y2 receptor
Human
Up-regulation interneurons [16,49,50,60]
Down-regulation dentate molecular layer [49]
Up-regulation DG [49]
Animal models
Up-regulation hippocampus, amygdala, striatum and entorhinal cortex [51-59]
Down-regulation DG, CA1 and CA3 [86,87]
Up-regulation DG [60,86]
Y5 receptor
Up-regulation [107] Down-regulation [108]
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receptor [110]. Another study revealed that NPY-mediated inhibition of fEPSC, evoked EPSC and evoked EPSC and spontaneous EPSC is absent in hippocampal slices from Y5 receptor KO mice [74]. Moreover, a Y5-preferring agonist was shown to completely suppress stimulus-train-induced bursting (STIB) in the CA3 region of hippocampal slices [78]. But, more recent studies have shown that the antiepileptic actions of NPY are mediated by Y2 receptors and not by Y 5 receptors [105]. In fact, El Bahh and collaborators [105] demonstrated that Y5 receptor-preferring agonists had small but significant effects in two slice models of TLE that were blocked by Y2 receptor antagonist but not by the Y5 receptor antagonists. Also, in vivo intrahippocampal injections of Y5 receptor-preferring agonists inhibited seizures, induced by kainic acid, but again the Y5 receptor antagonist did not block this effect. It is possible that Y5 receptor activation may regulate excitability in other brain regions, since recent evidences in rats, in vivo, indicate that the threshold for hippocampal rapid kindling can be reduced using an Y5 receptor agonist and that this effect is blocked by Y5 receptor antagonists [111]. 2.3. Modulation of Glutamate Release by NPY Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Within the brain, this excitatory neurotransmitter is synthesized by presynaptic neurons and stored in synaptic vesicles. Upon neuronal activity synaptic vesicles fuse with the plasma membrane and glutamate is released into the synaptic cleft [112]. As reviewed by Baraban and Tallent [113] neuropeptides play a pivotal role in neuronal excitability as they have a presynaptic site of action and in some cases they inhibit the release of glutamate. The modulation of postsynaptic excitatory neurotransmitter receptors mediated by peptides is rarely seen in experimental studies. Synaptic transmission at the CA3 and CA1 synapse was shown to be inhibited presynaptically by NPY in the rat hippocampus through the action of Y2 receptors that cause inhibition of voltage-dependent calcium channels [102]. The role of NPY and NPY receptors targeting K+ and Ca channels was described by Sun and colleagues [114] in rat thalamic neurons. In addition, our group has provided increasing evidences for a role of NPY in the inhibition of intracellular Ca2+ changes and glutamate release. Silva and collaborators [93] demonstrated in rat hippocampal synaptosomes, the presynaptic modulation of intracellular Ca2+ concentration ([Ca 2+]i) by activating Y1 and Y2 receptors. Y 2 receptor activation showed the highest inhibition of the total glutamate release in the whole hippocampus, sustaining a NPY inhibitory effect over evoked-glutamate release via Y2 receptors. Accordingly, in rod bipolar cell axon terminals D’Angelo and Brecha [115] also showed how NPY modulates presynaptic levels of Ca2+ supporting the involvement of Y2 in glutamate release. 2+
Y1 receptor is thought to act as an autoreceptor regulating the release of NPY. Wang [116] provided evidences that NPY acting on Y1 receptor could inhibit Ca2+ entry leading to the inhibition of evoked glutamate release in the nerve terminals of rat cerebral cortex. Y2 receptors are located presynaptically and are believed to have an inhibitory effect
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on calcium-mediated release of glutamate. Our group has also provided evidences for the functional interaction of Y1 and Y 2 and Y 2 and Y 5 receptors, suggesting the formation of oligomers, in the presynaptic inhibition of glutamate release. Moreover, the inhibitory effect of NPY was achieved mainly via Y 2 receptors [117]. Y5 receptors seem to share with Y2 a role in the modulation of hippocampal excitability since NPY is not able to inhibit glutamate-mediated synaptic transmission in the absence of Y 5 as seen in Y 5 receptor KO mice. Its role in the modulation of neuronal excitability remains controversial while it is possible that micromolar concentrations of NPY agonists used in vitro may not be selectively enough to assign receptor subtype specific roles [44,113]. The study of NPY system has gained particular relevance in pathological conditions characterized by neuronal hyperexcitability such as epilepsy. The hippocampus is associated to the generation and propagation of seizure activity. As a likely candidate to regulate excitatory transmission several studies on the antiepileptic actions of NPY and its receptors have been performed. Exogenously applied NPY has anticonvulsant properties and NPY KO mice are more susceptible to seizures [118]. Also, repeated electroconvulsive stimulations reduce significantly NPY specific binding sites in the rat hippocampus [119]. Kopp and collaborators [107] had already suggested the contribution of Y2 in the suppression of hyperexcitability. As reviewed by Vezzani and Sperk [59], NPY release and presynaptic Y2 receptors seem to increase in epileptic tissue. Stimulation of Y2 and Y5 receptors had previously been shown to reduce acute seizures while blocking Y1 receptor assured protection using the kainic acid injection model in the rat [120]. These evidences in the animal model, taken together with studies conducted in human epileptic hippocampal tissue, support a neuromodulator role for NPY in the restriction and propagation of seizures [99]. The NPY system acts as an endogenous neuroprotective mechanism as NPY immunoreactive fibers are increased in sclerotic hippocampus of TLE patients along with an upregulation of Y2 receptors and downregulation of Y1 receptors [49]. The extensive distribution of NPY in the CNS and colocalization with other neurotransmitters and modulators propose a neuromodulator role for this peptide. Knowledge about NPY and its receptor family may unquestionably represent an important tool in the treatment of any pathology where glutamate receptor dysfunction may occur. 2.4. NPY and Neuroprotection Against Excitotoxicity Seizures are the result of an imbalance between inhibitory and excitatory transmission in neuronal circuits. This imbalance toward hyperexcitability is accompanied by excessive glutamate release that may be deleterious to neuronal survival, causing excitotoxicity. So, it is conceivable that synaptic modulators able to decrease glutamate release can exert a neuroprotective action against glutamateinduced neuronal death. Excitotoxicity corresponds to the supraphysiological stimulation of glutamate receptors that after a prolonged activation leads to an increase in the intracellular Ca2+ concentration that is sufficiently high to trigger downstream processes resulting in cell death [121]. Therefore, the
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receptors responsible for the excitotoxicity belong to the ionotropic glutamate receptors family. On the basis of pharmacological and electrophysiological properties this family has been divided into three subtypes: α-amino-3hydroxy-5methyl-isoxazole-4-propionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors. Thus, control of extracellular glutamate concentrations is a critical homeostatic function that can affect both neuronal signaling and neuronal survival [122]. Our group investigated the involvement of NPY receptors in mediating neuroprotection against excitotoxic insults (with AMPA or kainate) in organotypic cultures of rat hippocampal slices [117]. For dentate granule cells, selective activation of Y1, Y2, or Y5 receptors had a neuroprotective effect against AMPA-induced toxicity whereas only the activation of Y2 receptors was effective for CA1 pyramidal cells [117]. When the slice cultures were exposed to kainate, the CA3 pyramidal cells displayed significant degeneration and in this case the activation of Y1, Y2, and Y5 receptors was neuroprotective. For the kainic acid-induced degeneration of CA1 pyramidal cells, we again found that only the Y2 receptor activation is effective [117]. This is consistent with the findings that the selective activation of Y1 and Y5 receptors did not modulate glutamate release in CA1 [93]. NPY can also regulate excitotoxicity in other brain areas such as amygdala and cortex. NPY-ir increases locally in the rat somato-sensory cortex when the excitotoxic lesion with D,L-homocysteic acid is made in this area [123]. The amygdalar neurochemical changes including NPY-ir increase in the basolateral nucleus, were seen when the ipsilateral insular cortex was lesioned [123]. 3. NPY AND NPY RECEPTORS AS ANTIEPILEPTIC AND PATENT TARGETS ON DRUG DISCOVERY Studies concerning the alteration in the NPY system, in TLE, following treatment with anti-epileptic drugs are also important, since they can give more direct information about the mechanisms involved in the anti-epileptic effect of NPY. Anticonvulsant drugs thiopental or the excitatory amino acid antagonist (MK-801) given acutely after kainic acid injection prevent both seizures and the increase in NPY expression [55]. Also, Midgley and collaborators [124,125] reported that phencyclidine and MK-801 reduced the NPY levels. Similarly, daily injections of phenobarbital, starting 3 days after the initial status epilepticus, suppress the increase in NPY expression [126]. Kindling is associated with an upregulation of hippocampal NPY mRNA levels and pretreatment with the anticonvulsant levetiracetam markedly delays the progression of kindling [86,126] by inhibiting kindling-induced rise in NPY mRNA and increasing the expression of Y1- and particularly Y5-like receptors in all hippocampal subfields [86]. Other studies show that in seizure sensitive gerbil NPY-ir in the hippocampus was lower than NPY-ir in seizure resistant gerbil. Following treatment with the anticonvulsant vigabatrin, the number of NPY-ir neurons and NPY mRNA expression was increased in the hilus and in the hippocampus [127]. In contrast, zonisamide markedly elevated the density of NPY-ir fibers in the DG, an effect not observed in other hippocampal areas [127]. A recent study has also shown that chronic valproate administration to rats resulted in an increase in NPY mRNA
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and protein expression in the nucleus reticularis thalami and hippocampus, but not in the neocortex [128]. Taken together, these data indicate that some anticonvulsants suppress convulsions in TLE and this effect is accompanied by increasing synthesis of NPY that may contribute to the inhibition of hippocampal hyperexcitability. As discussed above, an important hallmark of TLE is the circuitry reorganization of the DG [17-23]. Moreover, the implication of NPY in epilepsy also came from the observed increase in NPY levels in rat models of epilepsy as well as from hippocampi removed surgically from human patients with TLE [16,49-59]. This elevation could represent a compensatory mechanism in response to hyperexcitability, supporting thus NPY as an endogenous anticonvulsant agent. In addition, co-release of NPY may explain, in part, why stimulation of the mossy fibers in vitro [32,129-131] or the perforant path in vivo [132] usually does not evoke reverberating excitation in the dentate gyrus, even in the presence of robust recurrent mossy fibers growth. Thus, de novo expression of NPY in the mossy fibers pathway may protect the hippocampus from seizures that originate in or involve the entorhinal cortex [70]. Taken together these results suggest that NPY and NPY receptors may represent a promising antiepileptogenic drug target or may help in the development of new anticonvulsants. Recently, NPY and NPY receptors [133] have been important targets for drug discovery. Several patents were published describing new splice variants of the pancreatic polypeptide family, including NPY, [134], new NPY receptor agonists [135], and the development of new antagonists of NPY receptors [136-144]. These inventions were directed to treat several diseases, including: rhinitis [135], arthritis [140], hypertension and cardio/cerebrovascular diseases [134,135,139,140,142,143], renal dysfunction [139,140], respiratory diseases [139], dyslipidemia [134], diabetes [134,140,141,144], cancer [142], sexual and reproductive disorders [136], depression [136], schizophrenia [142], Alzheimer’s disease [142], epilepsy [136] and specially obesity and eating disorders [134,136-144] where Y5 receptors have been a preferential target for research [136-138,144]. 4. NPY AND NEUROGENESIS 4.1. NPY and Hippocampal Neurogenesis Neuronal death and synaptic reorganization are some of the features of temporal lobe epilepsy. So, at the long-term, new strategies to replace dead neurons and aberrant synaptic circuits are required for the proper cure of the epileptic hippocampus. Neurogenesis proceeds continuously in the DG of the hippocampus. The subgranular zone (SGZ) of the DG harbours precursor cells that proliferate to generate neurons. Neurons produced in the SGZ migrate locally to the granule cell layer where they achieve their differentiation into new granule neurons; in the rat about 10 000 new neurons are produced each day from DG progenitor cells [145]. Accordingly, pharmacological suppression of hippocampal neurogenesis decreases learning capacity in rodent, demonstrating the physiological relevance of the phenomena [146,147].
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Hippocampal neurogenesis is under the tight control of factors that modulate SGZ neurogenesis. For instance, cystatin C, a fibroblast growth factor-2 (FGF-2) co-factor, and insulin-like growth factor-1 (IGF-1) are locally released and promote proliferation and neurogenesis [148,149]. In the rat DG, immature neurons secrete the stem cell-derived neural stem/progenitor cell supporting factor (SDNSF) that promotes progenitor cell survival and self renewal [150]. Sonic hedgehog, a factor vital for neural development, and the neurotransmitter acetylcholine promote proliferation in the hippocampus [151,152]. Astrocytes release factors, including pro-inflammatory cytonines, that stimulate hippocampal neurogenesis [153,154]. Moreover, the soluble factor neurogenesin-1 (Ng-1), an antagonist of bone morphogenetic protein ( BMP), is secreted by astrocytes and counteracts the neurogenic inhibitory effect of BMP-4 [155]. Recently, NPY has been shown to promote neurogenesis in the DG. DG interneurons are a source of NPY and DG cells express Y1 receptors [156]. In Y1 receptor KO mice, both proliferation of the progenitor cells and emergence of doublecortin positive neurons are reduced [157]. This study convincingly demonstrates that NPY supports neurogenesis in the DG. 4.2. NPY and Neurogenesis in the Olfactory Epithelium The olfactory epithelium (OE) is another, however less known, site of adult neurogenesis. Located in the nasal cavity, OE is a pseudostratified epithelium composed of sustentacular (or supporting) non-neuronal cells, neuronal sensory neurons called olfactory receptor neurons (ORNs) and basal cells. In the upper part of the epithelium - i.e. bordering the nasal fossa - olfactory receptor neurons present microvillosities bearing receptors for odour molecules. Odorant molecules carried into the nose, bind to receptors and trigger the activation of a signalling pathway involving G proteins, opening of cAMP ion gated channels and consequent depolarisation. Resulting action potentials are transmitted via axons of the olfactory receptor neurons that extend in the basal part of the epithelium and cross the cribriform plate to reach the olfactory bulb. ORNs are constantly regenerated. Indeed, basal cells have stem cell properties as they proliferate, generate olfactory receptor precursor neurons that develop into new ORNs [158]. Like in the DG of the hippocampus, ORNs production is modulated by local cues. Growth factors such as FGF-2, EGF, TGF-α, (EGF: epidermal growth factor; TGF: transforming growth factor) and IGF-I stimulate basal cells and/or olfactory receptor precursor neurons proliferation [159-160]. In turn, mature ORNs secrete the growth and differentiation factor 11 (GDF11), member of the TGF-β family, that limits the proliferation of olfactory receptor neuron precursors [161,162]. NPY also plays a role in OE neurogenesis. In the adult mice, sustentacular cells express NPY [163]. NPY KO mice present a significant reduction of the number of olfactory receptor precursor neurons as compared to wild type mice suggesting that NPY stimulate proliferation of the basal cells. The proliferative role of NPY has been shown to be mediated by Y1 receptors [164].
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4.3. NPY and Injury-Induced Neurogenesis Numerous factors are up-regulated in neurogenic niches upon injury and are able to promote injury-induced neurogenesis. For instance, the expression of FGF-2 is enhanced in the DG following seizure, stimulating DG neurogenesis [165]. Following olfactory bulb ablation, dying ORNs of the OE secrete leukaemia inhibitory factor (LIF) that stimulates the proliferation of olfactory receptor neuron precursors and by this way ORNs replacement [166]. However, some pieces of evidence suggest that NPY may play a crucial role into injury-induced neurogenesis. Indeed, following seizure activity, NPY is overexpressed in the hippocampus [60], and in parallel, neurogenesis is increased in the DG [167-169]. In depression disorders, neurogenesis is decreased in the DG. Antidepressants used in depression treatment, like lithium and electroconvulsive therapy, increase SGZ neurogenesis [170]. Decrease of NPY mRNA levels has been observed in rats from the strain Flinders sensitive line (FSL) which present depressive behaviour. Electroconvulsive treatments increase levels of NPY in the DG of FSL rats [171]. It is then tempting to speculate that there might be an association between increased neurogenesis and up-regulation of endogenous NPY upon antidepressive treatments. 5. CURRENT & FUTURE DEVELOPMENTS Important gaps concerning NPY and neurogenesis must be filled. Indeed, no data are available on the action of NPY on subventricular zone (SVZ), the major neurogenic niche in the rodent brain. Neuroblasts are produced in the SVZ during the whole lifespan, migrate towards the olfactory bulb where they differentiate into interneurons [172] improving odour discrimination and memory [173,174]. No study hitherto demonstrated modulation of SVZ neurogenesis by NPY, despite the wide expression of NPY in the rodent brain [175]. SVZ and DG neurogenic systems share structural similarities. Indeed, in both tissues, stem/progenitor cells have been identified as astrocytes [176,177]. In both areas, neurogenesis is controlled by similar cues. However highly speculative, NPY, might modulate SVZ neurogenesis, but to confirm this, a huge amount of work has to be done in this area. This work will be of interest as SVZ cells represent an ethical and reliable source of cells for brain repair purposes. NPY, as a modulator of neurogenesis, is of particular interest for the development of future cell-based therapies to replace dead neurons in TLE and major neurodegenerative diseases. ACKNOWLEDGMENTS This work was supported by the Foundation for Science and Technology, Portugal, and FEDER Grant SFRH/ BD/14163/2003, POCTI/SAU-FCF/58492/2004 and POCTI/ FCB/46804/2002. REFERENCES [1] [2]
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