A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy

Biomedicine & Pharmacotherapy 79 (2016) 263–272

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A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy Muhammad Zahid Khan* Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 February 2016 Received in revised form 16 February 2016 Accepted 16 February 2016

Zinc the essential trace element, plays a significant role in the brain development and in the proper brain functions at every stage of life. Misbalance of zinc (Zn2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as Alzheimer's disease, Depression, and Epilepsy. In brain, Zn2+ has been identified as a ligand, capable of activating and inhibiting the receptors including the NMDA-type glutamate receptors (NMDARs), GABAA receptors, nicotinic acetylcholine receptors (nAChRs), glycine receptors (glyR) and serotonin receptors (5-HT3). Recently GPR39 has been identified as a zinc-specific receptor, widely expressed in brain tissues including the frontal cortex, amygdala, and hippocampus. GPR39, when binding with Zn2+ has shown promising therapeutic potentials. This review presents current knowledge regarding the role of GPR39 zinc sensing receptor in brain, with a focus on Alzheimer’s disease and Epilepsy. Although the results are encouraging, further research is needed to clarify zinc and GPR39 role in the treatment of Alzheimer's disease and Epilepsy. ã 2016 Elsevier Masson SAS. All rights reserved.

Keywords: Zinc GPR39 receptor Alzheimer's disease Epilepsy

Contents 1. 2. 3. 4.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression of GPR39 receptor in brain . . . . . . . . . . . . . . . . . . . . . Ligands for GPR39 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc, GPR39 receptor and Alzheimer's disease . . . . . . . . . . . . . . . Zinc and Alzheimer's disease (AD) . . . . . . . . . . . . . . . . . . 4.1. Proposed GPR39 signaling pathway in Alzheimer disease 4.2. 4.3. CREB synaptic therapy approach in alzheimer disease . . . BDNF (brain-derived neurotrophic factor) . . . . . . . . . . . . . 4.4. 4.5. Oxidative stress, GPR39 receptor and Alzheimer disease . Zinc, GPR39 receptor and epilepsy . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Zinc and epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GPR39 receptor and epilepsy . . . . . . . . . . . . . . . . . . . . . . . 5.2. Association between epilepsy and alzheimer disease . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

* Corresponding author at: Department of Pharmacology, China Pharmaceutical University, No. 24 Tong Jia Xiang, Nanjing 210009, Jiang Su, China. E-mail address: [email protected] (M.Z. Khan). http://dx.doi.org/10.1016/j.biopha.2016.02.026 0753-3322/ ã 2016 Elsevier Masson SAS. All rights reserved.

Zinc is a necessary component of hundreds of enzymes and other proteins in organisms. It is required for intracellular message transmission, protein synthesis, maintenance of cell membranes, cellular and intracellular transmembrane transport and is involved in regulation of the neuronal, endocrinal and immunological systems [1]. The average zinc concentration in brain is between 10

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and 15 mg/g wet tissue [2], however, it may vary in different brain parts. The highest zinc level in the brain was found in hippocampus, amygdala and cerebellum [2,3].The adequate zinc level is critical for CNS development and the differentiation of nervous stem cells in mammals [4,5]. The sustainable zinc homeostasis is necessary for the proper development of brain, especially for cerebellum, stellate, basket and also for Purkinje and granule cells. Zinc regulative role in the cortical plasticity is important for brain development and functioning of processes like learning and memory [5,6]. Disturbances of zinc homeostasis are considered as important factors in neurodegenerative brain disorders. Adequate zinc intake is crucial for proper cognitive functions, especially in children and elderly human [3,5,7,8–10] (Fig. 1). In mammals zinc containing vesicles were found mostly in the glutamatergic neurons in cortex, hippocampus and amygdala, brain compartments responsible for learning, memory, cognition and mood regulation [7,8,11]. During the neuronal activity, when zinc with glutamate is released from synaptic vesicles into synaptic cleft, zinc interactions with postsynaptic receptors, neuronal ion channels and transporters may occur and therefore can modulate synaptic transmission [12–15]. Extracellular zinc in synaptic cleft may be reuptake by both pre and postsynaptic neurons and also glial cells [16]. Depending on the target, zinc can exert either positive or negative modulatory effects, with varying potency. NMDA-type glutamate receptors (NMDARs) stand out for their exquisite and complex zinc sensitivity. Zinc inhibition of NMDA receptors in synapses occurs through two mechanisms, voltage independent allosteric inhibition, which reduce ion channel opening frequency, and voltage dependent inhibition by blocking open channels [6,17]. NMDA receptors comprised of NR2A subunits display the highest sensitivity to the extracellular zinc concentration and are inhibited in the nanomolar range [18]. Another interaction mechanism consists of inhibition of GABA receptormediated response, which leads to reduction of neuronal excitability. The GABAA receptors are members of the ligandgated ion channel gene superfamily and form anion-selective channels [19–21]. Zinc ions are concentrated in the central nervous system and regulate GABA(A) receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABA(A) receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition

[22,23]. At physiological concentrations, zinc can also modulate nicotinic acetylcholine receptors (nAChRs), glycine receptors (glyR) and serotonin receptors (5-HT3) [24]. Zinc-specific receptors can be subdivided into ionotropic and metabotropic types. The zinc-activated ion channel, or ZAC receptor, displays the key elements of cys-loop receptors with a large N-terminal domain and the 4TM domains typical of this family of receptors [25]. The GPR39 gene is widely expressed in tissues including the digestive tract, pancreas, liver, kidney and the brain, and encodes the metabotropic zinc GPCR, mZnR [26]. GPR39 was thought to be the gene for the cognate receptor for obestatin and a member of the ghrelin and neurotensin receptor family. Subsequently, it was found to encode a GPCR that was sensitive to zinc and coupled to the Gas and, consequently, to multiple intracellular pathways [27]. The potency and efficacy of Zn2+ as an agonist suggest it to be a physiologically relevant modulator of GPR39 in vivo [28]. Functional studies are now beginning to yield more information regarding the physiological and neuropthological roles of GPR39 in brain. In this review, i have briefly discussed the significance of zinc and GPR39 receptor for neurodegenerative diseases including Alzheimer's disease and epilepsy. 2. Expression of GPR39 receptor in brain The GPR39 receptor is widely expressed in the body, including the central nervous system [29]. GPR39 is widely expressed in brain tissues such as the frontal cortex, amygdala, and hippocampus [30]. The expression of the GPR39 receptor was observed in the frontal cortex of mice by [31,32]. Decreased hippocampal and cortical GPR39 expression was observed in suicide victims [33]. Immunofluorescent analysis showed that GPR39 expression is highly enriched in hippocampal CA3 neurons of mice [34]. 3. Ligands for GPR39 receptor Studies over the last decade showed that zinc may activate metabotropic GPR39 receptor [28,34–36]. It was initially considered that GPR39 is an orphan receptor [37]. Study by Zhang et al., [38] indicated that obestatin is a natural endogenous ligand for this metabotropic receptor, but nobody has confirmed these findings [28,35,39]. Finally it was proved that the natural ligand for the

Fig. 1. Explain interaction of zinc with various receptors and their subtypes in synaptic cleft. Zinc ions inhibit NMDA receptors (NR2A, NR2B), inhibit GABA(A) receptor functions, modulate nACHRs receptors functions by inhibition and P/I and activate GPR39 receptor in synapses. Abbreviations; Inh indicates inhibition; P/I: indicates potentiation at lower concentration and inhibition at higher concentration.

M.Z. Khan / Biomedicine & Pharmacotherapy 79 (2016) 263–272

GPR39 receptor is zinc [35,28,36]. According to Hershfinkel et al., this receptor is capable of sensing extracellular Zn2+, thereby activating diverse signal-transduction pathways [27]. Recent studies have demonstrated that synaptically released zinc can also directly act on a postsynaptic metabotropic zinc receptor/G protein-linked receptor 39 (mZnR/GPR39) [40,41]. The unique binding of Zn2+ to GPR39 suggests that Zn2+ is a real ligand rather than an allosteric regulator [42]. Indeed, Zn2+ does not act in analogy to other small molecule agonists in the classical manner by directly stabilizing an active conformation of the transmembrane domain but by binding to His17 and His19 located in the N-terminal extension and by engaging Asp313 in a tridentate metal-ion binding site [43]. Recently Peukert et al., identified a highly potent and orally bioavailable GPR39 agonist (2-Pyridylpyrimidines) [44]. 4. Zinc, GPR39 receptor and Alzheimer's disease 4.1. Zinc and Alzheimer's disease (AD) Alzheimer’s disease (AD) is a neurodegenerative disease, with progressing cognitive disorders accompanied by the degeneration of synapses and significant loss of neurons in the brain cortex and cholinergic basal nuclei. It is supposed now that the main triggers of these disorders are A-beta and a hyperphosphorylated intracellular tau protein; the accumulation of these substances is associated with a misbalance of extra and intracellular contents and distribution of zinc and copper ions, and possibly also of iron ions [45]. The role of zinc in AD pathogenesis has begun to be intensively studied when it has been shown that zinc, above 300 nM, precipitates A-beta and induces beta-amyloid aggregation in senile plaque [46]. Zinc has been linked to a possible role in the pathogenesis of Alzheimer's disease (AD), but a causal role in AD has not yet been definitively demonstrated [47]. At present, the role of zinc in the development of AD is unclear. For instance, on binding with A-beta, Zn2+ shields the molecule’s sites of proteolytic cleavage and thus inhibits the degradation of A-beta with the participation of metalloproteases. At the same time, zinc inhibits activity of g-secretases, which are also involved in the generation of A-beta [48]. Zinc ions in AD interact with A-beta and are accumulated inside amyloid plaques. A-beta plaques and oligomers capture zinc that leads to a decrease in the intraneuronal zinc level and in some cases to its excess in the neurons nearest to Abeta plaques [49]. Zn2+ dysfunctional homeostasis can be a potent trigger for Ab oligomerization and NFT formation, as well as overproduction of reactive oxygen species (ROS) [50], all of which are factors critically involved in AD-related neurodegeneration. The maintenance of brain Zn2+ homeostasis is crucial for neuronal functioning. Perturbations of this equilibrium may be a contributing factor in AD development and progression. Excessive Zn2+ facilitates Ab oligomerization as well as overproduction of reactive oxygen species (ROS), thereby promoting synaptic dysfunction and neuronal death. However, Zn2+ deficiency may also be deleterious as decreased bioavailability of the cation leads to reduced activation of neuroprotective BDNF signaling. Zn2+ deficiency in fact decreases the maturation of Pro-BDNF to BDNF and reduces the transactivation of the BDNF receptor, TrkB [51]. It should be

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noted that the level of Zn2+ is significantly decreased in blood serum of patients with AD [52], although other authors have reported its increased level in cerebrospinal fluid [53]. Zn2+ deficiency was also found in elderly persons, but at present there are insufficient data to conclude that additions of zinc would be useful for preventative care and treatment of AD, and zinc insufficiency or an excess of zinc could be a risk factor of AD development [54]. Post-mortem analysis of zinc amounts in AD brain also appears contradictory, because some part of literature reports increased brain zinc levels in AD [55–60]. However, other authors have found unchanged or even decreased zinc levels [61– 63], Hence, the matter is still rather controversial and the apparent effect of zinc on AD pathology may be paradoxical [64,65] (Table 1). In the past few years, efforts have also been made to address AD-related Zn2+dyshomeostasis. To date, the most promising class of drugs developed for counteracting Zn2+ deregulation are so called metal-protein attenuation compounds (MPACs). Metal protein attenuating compounds (MPACs) differ from traditional chelators. They have only moderate affinity for metal ions and are capable of crossing the blood-brain barrier. Rather than systemic binding and removal of metals from tissues, they correct abnormal metal interactions and have subtle effects on metal homeostasis, inhibiting Zn2+ and Cu2+ induced oligermisation of A-beta. This promotes the solubilisation (and clearance) of A-beta and inhibits redox reactions that generate neurotoxic hydrogen peroxide. Consequently MPACs might provide a viable therapeutic strategy for slowing or preventing the progression of Alzheimer’s dementia [66]. The issue of handling AD-dependent Zn2+ deregulation also poses the question of when and how to intervene. In that respect, a recent study in a transgenic AD model showed that restoring brain Zn2+ levels with dietary supplementation in a pre-symptomatic stage of the disease can effectively counteract the development of hippocampus-dependent cognitive deficits. The beneficial effects of Zn2+ supplementation appear to be linked to the action of the cation in increasing BDNF levels and by its activity in counteracting age-dependent mitochondrial dysfunction [67]. 4.2. Proposed GPR39 signaling pathway in Alzheimer disease Activation of GPR39 triggers diverse neuronal pathways, resulting in stimulation of phospholipase C(PLC) activity and cAMP production. Currently, no single study exist which can highlight the role of Zn+2 and GPR39 receptor in AD mice model. As ZnR activity induces metabotropic release of Ca2+ mediated by a Gaq protein, GPR39, and the IP3 pathway, leading to phosphorylation of extracellular-regulated kinase (ERK1/2) and Ca2+/calmodulin kinase (CAMKII) in the CA3 hippocampal region of mice [34]. I suggest that the function of GPR39 receptor in AD mice model must be studied and it should be observe that whether activation of GPR39 receptor in hippocampus can leads to activation (ERK1/2) and Ca2+/calmodulin kinase (CAMKII) pathways or not. If it is proved that GPR39 receptor activation can leads to activation (ERK1/2) and Ca2+/calmodulin kinase (CAMKII) pathways in hippocampus of AD mice model then this knowledge will be highly valuable for understanding of GPR39 receptor function in AD. Activation (ERK1/2) and Ca2+/calmodulin kinase

Table 1 Zinc status in Alzheimer’s disease (AD) and epilepsy patients. Disease

Decreased

Alzheimer’s disease (AD) Decreased zinc levels in blood and brain Alzheimer’s disease (AD) Epileptic disorders patients

Deficiencies in plasma Zn2+ levels have been associated with human epileptic disorders

Increased Increased brain zinc levels (Post-mortem analysis)

References [61–63] [55–60] [150–153]

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(CAMKII) pathways in hippocampus can leads to phosphorylation of CREB. CREB (cAMP response element- binding protein) belongs to the family of leucine zipper transcription factors. It binds to certain DNA sequences called cAMP response elements (CRE) and regulate the transcripation of various genes including BDNF (Brainderived neurotrophic factor), c-fos, neuropeptides (such as somatostatin, enkephalin, VGF and corticotropin-releasing hormone) and tyrosine hydroxylase [68]. CREB regulates cell proliferation, differentiation, and survival in the developing brain, and mediates such responses as neuronal plasticity, learning and memory in the adult brain [69]. CREB play significant role in the neuronal plasticity and long term memory formation in the brain [70]. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Many studies on invertebrates and vertebrates revealed that CREB is significant for long-term memory [71]. The contribution of CREB and the upstream signaling pathways leading to its activation in learningassociated plasticity makes them attractive targets for drugs aimed at improving memory function in both diseased and healthy individuals [72] (Fig. 2). 4.3. CREB synaptic therapy approach in alzheimer disease Many researchers have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories [73]. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes [74]. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. Most importantly, targeting the enzymatic pathways and the transcription machinery leading to memory formation may be a useful strategy for treating AD [73]. Here we will discuss the literature supporting the idea of targeting two enzymatic pathways leading to CREB phosphorylation upon GPR39 receptor activation including the cAMP/protein kinase A (PKA)/ CREB cascade and ERK1/2 Mitogen-Activated Protein Kinase Pathway for a therapy against AD. PKA is one of the canonical kinases involved in synaptic plasticity. Numerous studies showed PKA dysfunction in animal

models of AD, which may be induced through Ab- mediated oxidative stress [75], as well as through Ab- independent mechanisms, such as direct inhibition of the PKA pathway by b-secretase (BACE) 1 [76]. Pathologic (nanomolar) concentrations of Ab42 cause a rapid and sustained decrease in PKA activity and inhibition of CREB phosphorylation in hippocampal neuronal cultures in response to glutamate stimulation [77]. The antiamnestic effects of both caffeine and environmental enrichment in animal models of AD have been linked to promotion of PKA activity [78,79]. Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP into 50 AMP and 50 GMP, respectively [80]. In particular, PDE4 has been shown to be a major regulator of cAMP [81,82].Thus, PDE4 inhibition has been proposed as a therapeutic strategy that can lead to cAMP elevation and increased CREB phosphorylation. Rolipram is a prominent PDE4 inhibitor that has been tested in multiple animal models of AD for this reason [83]. Study by Cheng et al., found that rolipram treatment reversed the memory deficits seen in rats treated with Ab1- 40 [84]. These studies supports the use PDE4 inhibition as a treatment of memory dysfunction in AD. As an aside, some have questioned the use of rolipram as an antiamnestic in humans owing to its side effect of severe emesis [85]. In response, newer PDE4 inhibitors have been developed that improve memory without the side effects of rolipram [86]. Signaling cascades involving ERK1/2 constitute another pathway that leads to CREB phosphorylation [87]. Evidence suggests that ERK signaling plays a more complex role in AD. ERK can be activated by multiple mechanisms and, in turn, can act on multiple targets [75]. In some cases data suggest that the effect of ERK signaling on AD is likely to be beneficial, and in others that it is likely to be detrimental. Elevated levels of ERK have been reported in the cerebrospinal fluid of patients with AD [88] and increased levels of activated ERK have been found in postmortem AD brains [88–90]. However, given that ERK is required for normal learning and memory and normal synaptic plasticity [91,92], the extent to which these increases represent contributory or compensatory mechanisms for AD-related impairments remains unclear. However, given that ERK is required for normal learning and memory and normal synaptic plasticity [91,92]. Obviously, the ERK pathway and ERK-mediated CREB phosphorylation play a critical role in AD. While significant progress has been made in unraveling its complex molecular interactions, we still lack a complete understanding of all the ways in which this pathway affects the development and progression of the disease [75]. This understanding will be critical for the future development of AD therapeutic strategies that target this pathway.

Fig. 2. Proposed signaling pathway of GPR39 receptor in AD. Activation of the GPR39 triggers diverse neuronal pathways leading to CREB phosphorylation. Enhanced CREB expression after GPR39 activation may increase BDNF and TrkB receptor levels and contribute to synaptic plasticity, short-term memory, long-term memory and memory persistence. Abbreviations; DAG 1,2-diacylglycerol; PKC protein kinase C; MAPK mitogen activated protein kinase; CREB cAMP responsive element binding protein; PLC, phospholipase C; TrkB, tropomyosin receptor kinase B; BDNF, brain-derived neurotrophic factor.

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4.4. BDNF (brain-derived neurotrophic factor)

4.5. Oxidative stress, GPR39 receptor and Alzheimer disease

Brain-derived neurotropic factor, also known as BDNF a member of neurotrophin family. BDNF is a secreted protein encoded by the gene that is also called BDNF, in humans this gene is located on the chromosome 11 [93,94]. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active and most widely distributed neurotrophin in the central nervous system [95–97]. CREB regulate the transcripation of BDNF gene [70]. Neurotrophins are potent molecules, minute quantities of these secreted proteins exert robust effects on neuronal survival, synapse stabilization, and synaptic function. Key functions of the neurons rely on these proteins being expressed at the right time and in the right place. This is especially true for BDNF [98]. BDNF is extensively expressed and active in the hippocampus, cerebral cortex, and basal forebrain-areas very important to learning, memory and higher thinking [99]. BDNF is present in high concentration in hippocampus, cerebral cortex and also found in human saliva [100]. BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses [101,102]. BDNF binds to at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB and the LNGFR (for low-affinity nerve growth factor receptor, also known as p75) [103]. Various studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer's disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Low level of plasma BDNF was detected in the late onset of Alzheimer's disease and lowest level of BDNF was detected in the demented patients affected by diabetes [104]. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants. Higher serum BDNF levels may protect against future occurrence of dementia and AD. BDNF play significant role in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons [105]. Currently, various studies showed a direct connection between GPR39-Zn(2+)-sensing receptor, CREB, BDNF pathways in depression. However there is no single study which can explain this connection in AD. We believe that future studies for evaluating this connection in AD will be highly valuable.

Oxidative stress is caused by imbalance between prooxidant and antioxidant in favor of prooxidant [106]. Oxidative stress is a primer factor underlying the pathogenesis of neurodegenerative diseases, which are characterized by a gradual and selective loss of neurons [107]. Oxidative stress is a major component of the harmful cascades activated in the development of aging-related neurodegenerative disorders, including AD [108]. It is known that AD has a long latent period before symptoms appear and a diagnosis can be made. Recent studies demonstrated that the onset of AD is commonly preceded by an interim phase known as mild cognitive impairment (MCI), when there is no significant increase of senile plaques and NFTs [109–111]. Indeed, MCI subjects exhibited significant oxidative imbalance compared with agematched controls [112]. A large body of research has demonstrated that lipid peroxidation is greatly enhanced in AD. Lipid peroxidation refers to the process in which lipids are attacked by ROS through a free radical chain reaction mechanism to generate lipid peroxidation products [113]. The most extensive lipid peroxidation products studied in AD are reactive aldehydes including 4hydroxynonal, malondialdehyde (MDA). It was reported that the 4-hydroxynonal levels are significantly elevated in hippocampus [114–116], entorhinal cortex [116], temporal cortex [116] (amygdala [114,115], parahippocampal gyrus [115], ventricular fluid [117], and plasma [118] in AD patients compared with agematched control subjects. Significant increase of MDA was also reported in hippocampus [114], pyriformcortex [114], temporal cortex [119,120], occipital cortices [121], and erythrocytes [122] from AD patients. Oxidative modifications of proteins have also been extensively reported in AD. The most widely studied markers of protein oxidation are protein carbonyls and 3-nitrotyrosine. A significant increase of protein carbonyl content was reported in hippocampus [123,124] parietal lobe [125], and superior middle temporal gyri in AD patients [124]. The other major protein oxidative modification, 3-nitrotyrosine, is the end product of the interaction of peroxynitrite with tyrosine residues and was found to be significantly increased in AD in various brain regions [126– 132]. and cerebrospinal fluid [129]. Numerous studies have provided evidence that oxidative damage of DNA/RNA was increased in AD. Oxidative damage of DNA can cause DNA double strand breaks, DNA/DNA or DNA/protein crosslinking, and base modification. High levels of DNA breaks were found in both AD hippocampus [133] and AD cerebral cortex [134] (Fig. 3).

Fig. 3. Explain protective role of GPR39 receptor against oxidative, ER, and mitochondrial stress. Activation of GPR39 receptor can results into coupling to Ga13 leading to activation of the RhoA pathway and secretion of the cytoprotective pigment epithelium- derived growth factor (PEDF).

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Recently Dittmer et al., highlighted the role of GPR39 receptor as a novel inhibitor of cell death. A hippocampal cell line over expressing GPR39 was more resistant to oxidative stress, endoplasmatic reticulum (ER) stress and direct activation of the caspase cascade. GPR39 indeed protected against glutamate toxicity, ER stress, and Bax-mediated cell death by coupling to Ga13 leading to activation of the RhoA pathway and secretion of the cytoprotective pigment epithelium- derived growth factor (PEDF) and other factors [135]. Pigment epithelium-derived factor (PEDF), a circulating glycoprotein with antiangiogenic, antioxidative, and anti-inflammatory properties [136]. PEDF has previously been reported to be secreted by adult SVZ endothelial and ependymal cells [137], as well as by astroglia and neurons [138,139], and to enhance self-renewal of adult murine SVZ precursor cells [137,139]. Application of PEDF may be helpful in designing new therapeutic strategies for neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease and brain ischemia [140].These findings suggest that GPR39 inverse agonists may have therapeutic implications for processes involving apoptosis or ER stress like cancer, ischemia/ reperfusion injury and neurodegenerative diseases including AD [44]. 5. Zinc, GPR39 receptor and epilepsy 5.1. Zinc and epilepsy Epilepsy is a common neurological disorder characterized by recurrent, spontaneous seizures. It affects 50 million people worldwide [141]. The treatment of choice for epilepsy is antiepileptic drug (AED) therapy. Approximately 70% epilepsy patients could attain long-term remission using currently available antiepileptic drugs (AEDs) [142], leaving about 30% of patients with drug-resistant seizures [143]. Moreover, AEDs are associated with multiple side effects, including gastrointestinal upsets, drowsiness, rashes, and the rare, but potentially fatal, anticonvulsant hypersensitivity syndrome [144,145]. There is still a need for new therapies for epilepsy. Zn is capable of exerting effects that could either inhibit or promote neuronal excitability, suggesting the possibility of both pro- and anticonvulsant properties [146,147]. Therefore, Zn homeostasis in the brain may be important for the development of seizures. In some studies, Zn showed anticonvulsant effect, although Zn has a proconvulsant effect depending on the type of seizure, animal species, and convulsant agents [148,149]. Systemic charges of Zn have shown anticonvulsant property in several experimental models [148]. Deficiencies in plasma Zn2+ levels have been associated with human epileptic disorders [150–163]. Moreover, studies in kindling models of epilepsy suggest that seizure activity can be moderated via Zn2+ administration [162,163]. Nonetheless, the pathways linking synaptically released Zn2+ to regulation of seizure activity are poorly understood. Several studies have shown that epileptic seizures increase hippocampal neurogenesis in the adult. Zinc chelation does not prevent neurodegeneration but does reduce seizure-induced progenitor cell proliferation and neurogenesis. Zinc has an essential role for modulating hippocampal neurogenesis after seizure [164] (Table 1). 5.2. GPR39 receptor and epilepsy Although it is well-recognized that epileptic activity is generally a self-limiting process, the precise molecular, cellular or intercellular events that lead to seizure termination are not completely defined [165]. However, some researchers proposed the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. GPR39 receptor is activated by

synaptic Zn2+ released from the mossy fibers and triggers an intracellular Ca2+ rise in hippocampal CA3 neurons, but not glia [34]. Activation of mZnR/GPR39 signaling leads to upregulation of K+/Cl co-transporter 2 (KCC2) surface expression and activity [41,42]. KCC2 is the major Cl extruding transporter in neurons, responsible for hyperpolarizing currents mediated by GABAA receptor channel activation [166–168]. KCC2 activity is essential for regulating neuronal inhibitory drive [169]. The activity of KCC2 is highly regulated by changes in its surface expression and phosphorylation [170,171], and interictal or seizure activity can induce such changes [172]. Gilad et al., proposed that mZnR/ GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition [172]. I suggest that this mechanism could be targeted as a potential novel approach to generating anti-epileptic therapeutic strategies (Fig. 4). 6. Association between epilepsy and alzheimer disease The possible association of epileptic activity to Alzheimer’s disease (AD) has been reported by means of animal and clinical studies [173,174]. From the clinical perspective, it has been shown that the incidence of unprovoked seizures in patients with AD is 6–10 times more common than age-matched healthy adults [175– 178]. In patients with AD, the reported incidence of seizures during the course of illness varies widely between studies, ranging from 5% to 64% [174,179]. Advanced stage of disease and younger diagnostic age of AD have been thought to be the two most consistent risk factors for developing seizures, although African-American ethnic background, greater cognitive impairment at baseline, antipsychotic use at baseline, diabetes and hypertension have been infrequently and inconsistently reported [179–181]. Some other reports have indicated that younger age was significantly associated with seizures in AD patients [182–184]. Preclinical studies of anti-epileptic drugs in mouse models and AD patients are another measure of support for a common mechanistic pathway between the two diseases. The antiepileptic drug valproic acid (VPA) has been identified as a potential treatment for AD using APdE9 mice [185]. In pre-clinical studies VPA treatment reduced Ab production both in vitro in APPSwe transfected HEK293 cells and in vivo in PDAPP tg mice [186]. VPA treatment also reduced amyloid plaque deposition in APP23 and APP23/PS45 mice compared to age-matched saline-treated controls [187]. The potential of VPA to exacerbate neurodegeneration and cognitive decline highlights the importance of cautious treatment of AD patients with anti-epileptic drugs. Promising mouse model studies have shown improved memory in models of aging and Alzheimer’s disease with levetiracetam (LEV) treatment [188,189]. Epileptiform activity in human AD patients responds best to LEV and lamotrigine (LTG) of the antiepileptic drugs tested [189]. 7. Conclusion It is an established fact that zinc is one of the most important trace element in our body, play significant physiological functions in the brain, and serve as agonist for the GPR39 receptor. GPR39 belong to a family of GPCRs which are currently considered as key targets for drug development [190,191]. GPR39 currently appears to be a potential target in the management of several neuropathological diseases such as Alzheimer's disease, Depression and Epilepsy. Many studies have shown that zinc and GPR39 signaling contribute to the anti oxidative stress effect, promote synaptic plasticity and hippocampal memory and play significant role in dampening epileptic seizure activity. However, there is a lack of

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Fig. 4. Explain role of GPR39 receptor in epilepsy. Activation of mZnR/GPR39 can triggers a Gq-mediated signaling pathways leading to ERK activation and enhanced KCC2 surface expression. A likely consequence of this process is decreased [Cl] and enhanced inhibitory drive resulting in an adaptive homeostatic mechanism for regulation of the excitatory/inhibitory balance. Abbreviations; K+/Cl cotransporter 2; PIP2 phosphatidylinositol; InsP3 inositol 1,4,5-triphosphate; PLCb phospholipase C-b; ER endoplasmic reticulum.

clear data supporting its role in Alzheimer's disease, therefore complementary studies are needed to fully clarify GPR39 functions in AD. This emphasizes the need to evaluate its role in the brain by using KO mice models and to develop new pharmacological tools to ascertain the functional role of GPR39 in physiological and neuropathlogical conditions. Further understanding of the connection between GPR39 receptor, epilepsy and Alzheimer’s will be beneficial for improving treatment strategies. Acknowledgements We gratefully acknowledge funding from National 12th Fiveyear Plan “Major Scientific and Technological Special Project for Significant New Drugs Creation” project of “Novel G proteincoupled receptor targeted drug screening system and key technology research”(NO.2012ZX09504001-001)and Program for New Century Excellent Talents in University (No.NCET-10-0817, which have supported aspects of our research covered in this article. The author would like to thank Professor Atlas khan for his contribution to English editing of this manuscript. References [1] A. Takeda, Movement of zinc and its functional significance in the brain, Brain Res. Rev. 34 (2000) 137–148. [2] W. Opoka, M. Jakubowska, B. Baú, M. Sowa- KuÊma, Development and validation of an anodic stripping voltammetric method for determination of Zn(2+) ions in brain microdialysate samples, Biol. Trace Elem. Res. 142 (2011) 671–682. [3] S. Pavlica, R. Gebhardt, Comparison of uptake and neuroprotective potential of seven zinc-salts, Neurochem. Int. 56 (2010) 84–93. [4] H. Xu, H.L. Gao, W. Zheng, N. Xin, Z.H. Chi, S.L. Bai, et al., Lactational zinc deficiency-induced hippocampal neuronal apoptosis by a BDNF-independent TrkB signaling pathway, Hippocampus 21 (2011) 495–501. [5] C.W. Levenson, D. Morris, Zinc and neurogenesis: making new neurons from development to adulthood, Adv. Nutr. 2 (2011) 96–100. [6] Y. Izumi, Y.P. Auberson, C.F. Zorumski, Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors, J. Neurosci. 26 (2006) 7181–7188. [7] G.J. Brewer, S.H. Kanzer, E.A. Zimmerman, E.S. Molho, D.F. Celmins, S.M. Heckman, et al., Subclinical zinc deficiency in Alzheimer's disease and Parkinson's disease, Am. J. Alzheimers Dis. Other Demen. 25 (2010) 572–575.

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