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Leptin as a neuroprotective agent
Available online at www.sciencedirect.com
Biochemical and Biophysical Research Communications 368 (2008) 181–185 www.elsevier.com/locate/ybbrc
Mini Review
Leptin as a neuroprotective agent Bor Luen Tang * Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore Received 7 December 2007 Available online 28 January 2008
Abstract Leptin is a hormone produced by adipocytes that regulates satiety (food uptake) and energy homeostasis by activating receptors expressed in neurons of the hypothalamus. Leptin receptors are also found in other brain regions such as the hippocampus and cerebral cortex, and have known roles in regulating neural development and neuroendocrine functions. Recent evidence indicates that leptin could be neuroprotective, enhancing neuronal survival both in vitro and in vivo. Intriguingly, administration of leptin protects against neuronal death in animal models of cerebral ischemic injury and hemiparkisonism. Activation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT), phosphatidylinositol (PI) 3-kinase and the extracellular signal regulated kinase (ERK) pathways are known downstream events of leptin receptor signaling, all of which are pro-survival and anti-apoptotic. The relative ease of leptin’s accessibility to the brain by peripheral administration makes it a potential drug candidate in the development of therapeutics for brain injuries and neurodegeneration. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Leptin; Neuroprotection; Neuroregeneration; JAK-STAT
The adipostatic hormone leptin is a 16 kDa peptide that acts as a feedback signal from the body’s main energy store, namely the adipose tissue, to the brain in the regulation of food uptake and energy homeostasis [1–3]. Leptin synthesis is regulated largely at the transcription and translation level, with the peptide itself being secreted constitutively. Circulating leptin levels is dependent on the feeding status of the animal and adipose tissue mass. Leptin deficiency phenotype and function are first defined by the obese (ob) and diabetes (db) mutant mice, which carry recessive mutations of leptin and leptin receptor (Ob-R), respectively [4]. These mice are hyperphagic, obese and diabetic. They also suffer from neuroendocrine problems such as hypothalamic hypogonadism, hypothyroidism, decrease immune functions and increase glucocorticoids. Rare human cases of congenital lipodystrophy, or mutations of leptin or leptin receptor, have mirroring symptoms that can be cor-
*
Fax: +65 67791453. E-mail address: [email protected]
0006-291X/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2008.01.063
rected by exogenous administration of leptin [5,6]. Under physiological conditions, leptin levels decreases during starvation, and increases with feeding. In the fed state, adequate circulating leptin levels would suppress feeding and divert energy expenditure to growth, reproduction and various functions of the neuroendocrine and immune systems. Multiple splice isoforms of the leptin receptor are generated from a single obr gene. With the exception of the soluble isoform Ob-Re, all are membrane-spanning proteins differing in the sequences of their intracellular domains [7]. The longest isoform, Ob-Rb, has a 302 amino acid intracellular domain, and is considered to be essential and responsible for the principle functions of leptin. It is the isoform affected by the mouse db mutation, and transgenic expression of this form reversed many of the phenotype of db mutants. Structurally, the leptin receptor belongs to the family of hematopoietic growth factors, or type-1 cytokine receptors [8,9]. Ligand binding results in receptor homo-oligomerization and activation of the Janus kinase (JAK) JAK2. The activated kinase in turn phosphorylates itself, as well as several tyrosine residues at the
182
B.L. Tang / Biochemical and Biophysical Research Communications 368 (2008) 181–185
leptin receptor’s intracellular domain. The phosphorylated tyrosines then become a platform for the recruitment of various signaling proteins. These include insulin receptor substrate-1 (IRS-1), signal transducers and activators of transcription (STAT), SH2 domain-containing proteintyrosine phosphatase 2 (Shp2) and growth factor receptor-bound protein 2 (Grb2). Leptin receptor signaling culminates in the activation, to varying degrees depending on the cell context, of several signaling pathways. These include the JAK2-STAT3, phosphatidylinositol 3 (PI3)kinase-AKT kinase and the Ras-Raf-mitogen activated protein kinase (MAPK) (or extracellular signal regulated kinase (ERK)), and the 50 -AMP-activated protein kinase (AMPK) pathways [10–14]. Leptin receptor expression is not confined exclusively to central nervous system (CNS) neurons, but it is very much CNS-enriched and its activity at the CNS is pivotal to leptin’s role in energy homeostasis. In line with its role in neuroendocrine regulation of food intake, particularly high levels of leptin receptors are found in the neurons of the hypothalamus [15–20]. However, leptin receptor is also highly expressed in some other regions of the brain [15– 21]. Other than their known neuroendocrine functions [22,23] associated with energy homeostasis, reproduction, thyroid function and sympathetic nervous system activity, leptin and its receptor have some rather intriguing roles in the brain. At the hippocampus, for example, leptin could influence the excitability of hippocampal neurons through its ability to increase the activity of large conductance Ca2+-activated potassium (BK) channels [24]. On the other hand, leptin could also mediate a mode of NMDA receptor-dependent long-term depression (LTD) in the CA1 region of the hippocampus [25,26]. In view of the fact that signaling pathways activated by leptin are largely pro-survival and growth-promoting in nature, it would not be surprising if lectin has some degree of neurotrophic and anti-apoptotic functions in the CNS. Recent findings have now provided strong evidence that leptin may indeed be neuroprotective. This neuroprotective potential of leptin of CNS neurons and its possible clinical implications are discussed in the paragraphs below.
Emerging evidence for the neuroprotective effects of leptin Leptin appears to have a general survival and proliferation promoting effect, which has been documented in a wide array of tissue and cell types. Continuous exposure of osteoblasts to leptin promoted collagen synthesis, mineralization, as well as cell survival and transition into preosteocytes [27]. In the immune system, leptin is known to modulate T-cell immune response [28], and is a survival and anti-apoptotic factor for T lymphocytes [29–31]. Leptin’s anti-apoptotic effect has been likewise demonstrated in ovarian follicular cells [32], pancreatic beta cells [33], hepatic stellate cells [34] and various cancer cells [35–37]. Intriguingly, leptin administration was recently shown to
reduce cardiac infarct size in a mouse ischemia-reperfusion injury model [38]. One of the first hints that leptin may be neuroprotective is suggested by a decreased in brain weight, impaired myelination and inhibited neural cell type maturation in leptin/ leptin receptor mutant mice [39]. Dicou and colleagues [40] showed that systemically administered leptin reduced cortical lesions and white matter cysts induced by ibotenate-mediated excititoxicity. Leptin also protected mouse cortical neurons in culture against N-methyl-D-aspartate (NMDA) cytotoxicity. Russo et al. [41] demonstrated that leptin stimulated the proliferation of SH-SY5Y neuroblastoma cells, and reduced apoptosis caused by serum withdrawal. The underlying anti-apoptotic mechanism appears to be the activation of the JAK-STAT, PI3-kinase, and ERK pathways. These resulted in a down-regulation of caspase-10 and the TNF-related apoptosis-inducing ligand (TRAIL), as revealed by gene expression profiling. A protective function by leptin against specific neurotoxins have also been demonstrated using the same cell line, as leptin also inhibited 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cell death [42]. Several very recent studies have provided further evidence of leptin’s neuroprotective property, and hinted at its potential therapeutic applications pertaining to neuronal injury and neurodegeneration. Chen and colleagues [43] found that rat cortical neurons express leptin receptor isoforms. Leptin attenuated apoptotic neuronal death in vitro induced by a combined oxygen-glucose deprivation protocol. Extending their studies to a mouse middle cerebral artery occlusion (MCAO) focal cerebral ischemia model, the authors showed that leptin significantly reduced cerebral infarct volume, even when administered 90 min after the onset of ischemia. Leptin administration also improved neurologic deficits and body weight recovery after 7 days. The authors found that leptin has exerted its neuroprotective effect primarily though ERK1/2 signaling. Accordingly, intracerebral infusion of the ERK1/2-activating mitogen extracellular kinase (MEK) inhibitor PD98059 blocks both ERK phosphorylation and the neuroprotective effect. In a related study, the same laboratory had investigated possible neuroprotective effects of leptin on dopaminergic neurons using models of Parkinson’s disease [44]. The authors found that the toxicity of 6-hydroxydopamine (6OHDA) on MN9D, a mouse dopaminergic cell line, was significant attenuated by leptin. Again, leptin appears to exert this protective effect via ERK1/2 activation. Importantly, intracranial injection of leptin reduced loss of tyrosine hydroxylase-positive dopaminergic neurons induced by 6-OHDA. This rescue effect of leptin is also reflected by a significant attenuation of the 6-OHDA-induced behavioral deficits (assessed by apomorphine-induced rotations). The results of these studies are intriguing because they indicate that leptin administration is neuroprotective using rather established animal models of CNS ischemic injury and neurodegeneration, and suggest that leptin
B.L. Tang / Biochemical and Biophysical Research Communications 368 (2008) 181–185
could perhaps confer a beneficial effect in CNS-associated ailments. Signaling mechanisms underlying leptin’s enhancement of neuronal survival The recent observations pertaining to the neuroprotective effect of leptin highlighted above requires some clarifications in terms of the mechanism(s) underpinning the neuroprotection. As mentioned earlier, the leptin receptor (Ob-Rb) signals principally through the activation of JAK2, which then phosphorylates tyrosine residues on itself, as well as the cytoplamic domain of Ob-Rb. These tyrosine residues then engage STAT3 and other signal adaptors such as SHP-2 and Grb2 (which activates the ERK pathway) and IRS-1 (which activates the PI3kinase-AKT kinase pathway). For the neuroblastoma SH-SY5Y cells (a dopaminergic line), inhibitor studies indicated that all three pathways appeared to contribute to leptin’s anti-apoptotic effect after serum withdrawal [41]. For MPTP-induced neurotoxicity, however, inhibitor studies indicated that activation of the PI3-kinase-AKT kinase pathway in SH-SY5Y cells is essential for rescue [42]. It is unclear if MPTP treatment somehow attenuated the activation of the other survival pathways, or that these other pathways are in fact activated but for unknown reasons did not contribute to rescue. In all the systems examined by Chen and colleagues (namely rat cortical neurons, the mouse dopaminergic cell line MN9D, mouse cortical neurons and mouse substantia nigra dopaminergic neurons), ERk1/2 activation appears to be pivotal in mediating leptin’s beneficial effects. For the dopaminergic MN9D cells and the substantia nigra dopaminergic neurons, the authors have shown further that ERK1/2 activation impinges on the transcription factor cAMP response element binding (CREB) protein. CREB is a known mediator of multiple signaling events elicited by various growth factors. In CNS neurons, it is known to play roles in processes ranging from neuronal regeneration to learning and memory. One of CREB’s downstream transcriptional targets is the brain-derived growth factor (BDNF) [45], which is a known neuroprotective factor for dopaminergic neurons [46]. ERK1/2 activation thus seems to be the main survival signaling pathway activated by leptin both in cortical neurons and mid-brain dopaminergic neurons. Although leptin almost certainly activated the JAK2-STAT3 pathway, ascertaining a definitive role for this pathway may be more difficult, especially in vivo. In the focal ischemia model, for example, STAT3 phosphorylation and its activity in neurons could be masked by its predominant activation in surrounding glia cells as a response to injury. It should however be noted that not all CNS neurons respond to leptin in the same way that cortical or dopaminergic neurons do. Recent work by Mattson and colleagues provided an illustration of possible diversity in leptin survival signaling in different types of neurons [47]. Working
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with rat hippocampal neurons, the authors showed that leptin protected these against cell death induced by growth factor withdrawal and oxidative insults. While JAK-STAT pathway blockers and PI3-kinase inhibitors blocked this rescue, an MEK inhibitor did not. They have also noted that leptin treatment elevated anti-apoptotic molecules such as Bcl-XL and the manganese superoxide dismutase, which probably protected the cells against mitochondriabased apoptotic mechanisms. Leptin’s signaling effect in neurons and neuron-like cells is therefore clearly cell context dependent. Leptin’s potential as a neuroprotective drug against CNS injury and neurodegeneration The evidence for leptin’s neuroprotective effect highlighted above, particularly in the more established neurological disease models, suggests that it may be use as a therapeutic agent in acute brain injury as well as chronic neurodegenerative diseases. Studies on the effect of leptin on other CNS injury animal models, and of neurodegenerative such as Huntington’s disease, Alzheimer’s disease and motor neuron disorders, may soon appear in the literature. These studies will provide a more comprehensive understanding of how different neurons respond to leptin in vitro and in vivo. Another probable and longer-term beneficial effect of leptin is enhancement of CNS neuronal regeneration. JAK-STAT signaling through the leukemia inhibitory factor (LIF) [48] and interleukin-6 (IL-6) [49] had both been implicated in the enhancement of neuronal regeneration after CNS injury [50]. It is conceivable that JAK-STAT signaling from leptin may have a similar effect. Leptin treatment has the advantage that it readily crosses the blood brain barrier. Its effective local concentration in the CNS after peripheral administration needs to be ascertained. Leptin’s effect on multiple organs and tissues would mean that careful dose monitoring is necessary and one needs to be wary of potential systemic side effects. Bearing leptin’s effect on cancer cell survival in mind, its potential oncogenic effect in long-term administrations has to be carefully assessed. However, considering that the effect of leptin administration has already been under intense scrutiny in clinical trials of leptin deficiency and leptin resistance [51,52], it is perhaps not too far fetch to imagine it being part of a combined therapy for stroke or neurodegeneration in the future. Acknowledgment The author declares no financial conflict of interest. References [1] J.M. Friedman, J.L. Halaas, Leptin and the regulation of body weight in mammals, Nature 395 (1998) 763–770. [2] A. Coll, I. Farooqi, S. O’Rahilly, The hormonal control of food intake, Cell 129 (2007) 251–262.
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Biochemical and Biophysical Research Communications 368 (2008) 181–185 www.elsevier.com/locate/ybbrc
Mini Review
Leptin as a neuroprotective agent Bor Luen Tang * Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore Received 7 December 2007 Available online 28 January 2008
Abstract Leptin is a hormone produced by adipocytes that regulates satiety (food uptake) and energy homeostasis by activating receptors expressed in neurons of the hypothalamus. Leptin receptors are also found in other brain regions such as the hippocampus and cerebral cortex, and have known roles in regulating neural development and neuroendocrine functions. Recent evidence indicates that leptin could be neuroprotective, enhancing neuronal survival both in vitro and in vivo. Intriguingly, administration of leptin protects against neuronal death in animal models of cerebral ischemic injury and hemiparkisonism. Activation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT), phosphatidylinositol (PI) 3-kinase and the extracellular signal regulated kinase (ERK) pathways are known downstream events of leptin receptor signaling, all of which are pro-survival and anti-apoptotic. The relative ease of leptin’s accessibility to the brain by peripheral administration makes it a potential drug candidate in the development of therapeutics for brain injuries and neurodegeneration. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Leptin; Neuroprotection; Neuroregeneration; JAK-STAT
The adipostatic hormone leptin is a 16 kDa peptide that acts as a feedback signal from the body’s main energy store, namely the adipose tissue, to the brain in the regulation of food uptake and energy homeostasis [1–3]. Leptin synthesis is regulated largely at the transcription and translation level, with the peptide itself being secreted constitutively. Circulating leptin levels is dependent on the feeding status of the animal and adipose tissue mass. Leptin deficiency phenotype and function are first defined by the obese (ob) and diabetes (db) mutant mice, which carry recessive mutations of leptin and leptin receptor (Ob-R), respectively [4]. These mice are hyperphagic, obese and diabetic. They also suffer from neuroendocrine problems such as hypothalamic hypogonadism, hypothyroidism, decrease immune functions and increase glucocorticoids. Rare human cases of congenital lipodystrophy, or mutations of leptin or leptin receptor, have mirroring symptoms that can be cor-
*
Fax: +65 67791453. E-mail address: [email protected]
0006-291X/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2008.01.063
rected by exogenous administration of leptin [5,6]. Under physiological conditions, leptin levels decreases during starvation, and increases with feeding. In the fed state, adequate circulating leptin levels would suppress feeding and divert energy expenditure to growth, reproduction and various functions of the neuroendocrine and immune systems. Multiple splice isoforms of the leptin receptor are generated from a single obr gene. With the exception of the soluble isoform Ob-Re, all are membrane-spanning proteins differing in the sequences of their intracellular domains [7]. The longest isoform, Ob-Rb, has a 302 amino acid intracellular domain, and is considered to be essential and responsible for the principle functions of leptin. It is the isoform affected by the mouse db mutation, and transgenic expression of this form reversed many of the phenotype of db mutants. Structurally, the leptin receptor belongs to the family of hematopoietic growth factors, or type-1 cytokine receptors [8,9]. Ligand binding results in receptor homo-oligomerization and activation of the Janus kinase (JAK) JAK2. The activated kinase in turn phosphorylates itself, as well as several tyrosine residues at the
182
B.L. Tang / Biochemical and Biophysical Research Communications 368 (2008) 181–185
leptin receptor’s intracellular domain. The phosphorylated tyrosines then become a platform for the recruitment of various signaling proteins. These include insulin receptor substrate-1 (IRS-1), signal transducers and activators of transcription (STAT), SH2 domain-containing proteintyrosine phosphatase 2 (Shp2) and growth factor receptor-bound protein 2 (Grb2). Leptin receptor signaling culminates in the activation, to varying degrees depending on the cell context, of several signaling pathways. These include the JAK2-STAT3, phosphatidylinositol 3 (PI3)kinase-AKT kinase and the Ras-Raf-mitogen activated protein kinase (MAPK) (or extracellular signal regulated kinase (ERK)), and the 50 -AMP-activated protein kinase (AMPK) pathways [10–14]. Leptin receptor expression is not confined exclusively to central nervous system (CNS) neurons, but it is very much CNS-enriched and its activity at the CNS is pivotal to leptin’s role in energy homeostasis. In line with its role in neuroendocrine regulation of food intake, particularly high levels of leptin receptors are found in the neurons of the hypothalamus [15–20]. However, leptin receptor is also highly expressed in some other regions of the brain [15– 21]. Other than their known neuroendocrine functions [22,23] associated with energy homeostasis, reproduction, thyroid function and sympathetic nervous system activity, leptin and its receptor have some rather intriguing roles in the brain. At the hippocampus, for example, leptin could influence the excitability of hippocampal neurons through its ability to increase the activity of large conductance Ca2+-activated potassium (BK) channels [24]. On the other hand, leptin could also mediate a mode of NMDA receptor-dependent long-term depression (LTD) in the CA1 region of the hippocampus [25,26]. In view of the fact that signaling pathways activated by leptin are largely pro-survival and growth-promoting in nature, it would not be surprising if lectin has some degree of neurotrophic and anti-apoptotic functions in the CNS. Recent findings have now provided strong evidence that leptin may indeed be neuroprotective. This neuroprotective potential of leptin of CNS neurons and its possible clinical implications are discussed in the paragraphs below.
Emerging evidence for the neuroprotective effects of leptin Leptin appears to have a general survival and proliferation promoting effect, which has been documented in a wide array of tissue and cell types. Continuous exposure of osteoblasts to leptin promoted collagen synthesis, mineralization, as well as cell survival and transition into preosteocytes [27]. In the immune system, leptin is known to modulate T-cell immune response [28], and is a survival and anti-apoptotic factor for T lymphocytes [29–31]. Leptin’s anti-apoptotic effect has been likewise demonstrated in ovarian follicular cells [32], pancreatic beta cells [33], hepatic stellate cells [34] and various cancer cells [35–37]. Intriguingly, leptin administration was recently shown to
reduce cardiac infarct size in a mouse ischemia-reperfusion injury model [38]. One of the first hints that leptin may be neuroprotective is suggested by a decreased in brain weight, impaired myelination and inhibited neural cell type maturation in leptin/ leptin receptor mutant mice [39]. Dicou and colleagues [40] showed that systemically administered leptin reduced cortical lesions and white matter cysts induced by ibotenate-mediated excititoxicity. Leptin also protected mouse cortical neurons in culture against N-methyl-D-aspartate (NMDA) cytotoxicity. Russo et al. [41] demonstrated that leptin stimulated the proliferation of SH-SY5Y neuroblastoma cells, and reduced apoptosis caused by serum withdrawal. The underlying anti-apoptotic mechanism appears to be the activation of the JAK-STAT, PI3-kinase, and ERK pathways. These resulted in a down-regulation of caspase-10 and the TNF-related apoptosis-inducing ligand (TRAIL), as revealed by gene expression profiling. A protective function by leptin against specific neurotoxins have also been demonstrated using the same cell line, as leptin also inhibited 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cell death [42]. Several very recent studies have provided further evidence of leptin’s neuroprotective property, and hinted at its potential therapeutic applications pertaining to neuronal injury and neurodegeneration. Chen and colleagues [43] found that rat cortical neurons express leptin receptor isoforms. Leptin attenuated apoptotic neuronal death in vitro induced by a combined oxygen-glucose deprivation protocol. Extending their studies to a mouse middle cerebral artery occlusion (MCAO) focal cerebral ischemia model, the authors showed that leptin significantly reduced cerebral infarct volume, even when administered 90 min after the onset of ischemia. Leptin administration also improved neurologic deficits and body weight recovery after 7 days. The authors found that leptin has exerted its neuroprotective effect primarily though ERK1/2 signaling. Accordingly, intracerebral infusion of the ERK1/2-activating mitogen extracellular kinase (MEK) inhibitor PD98059 blocks both ERK phosphorylation and the neuroprotective effect. In a related study, the same laboratory had investigated possible neuroprotective effects of leptin on dopaminergic neurons using models of Parkinson’s disease [44]. The authors found that the toxicity of 6-hydroxydopamine (6OHDA) on MN9D, a mouse dopaminergic cell line, was significant attenuated by leptin. Again, leptin appears to exert this protective effect via ERK1/2 activation. Importantly, intracranial injection of leptin reduced loss of tyrosine hydroxylase-positive dopaminergic neurons induced by 6-OHDA. This rescue effect of leptin is also reflected by a significant attenuation of the 6-OHDA-induced behavioral deficits (assessed by apomorphine-induced rotations). The results of these studies are intriguing because they indicate that leptin administration is neuroprotective using rather established animal models of CNS ischemic injury and neurodegeneration, and suggest that leptin
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could perhaps confer a beneficial effect in CNS-associated ailments. Signaling mechanisms underlying leptin’s enhancement of neuronal survival The recent observations pertaining to the neuroprotective effect of leptin highlighted above requires some clarifications in terms of the mechanism(s) underpinning the neuroprotection. As mentioned earlier, the leptin receptor (Ob-Rb) signals principally through the activation of JAK2, which then phosphorylates tyrosine residues on itself, as well as the cytoplamic domain of Ob-Rb. These tyrosine residues then engage STAT3 and other signal adaptors such as SHP-2 and Grb2 (which activates the ERK pathway) and IRS-1 (which activates the PI3kinase-AKT kinase pathway). For the neuroblastoma SH-SY5Y cells (a dopaminergic line), inhibitor studies indicated that all three pathways appeared to contribute to leptin’s anti-apoptotic effect after serum withdrawal [41]. For MPTP-induced neurotoxicity, however, inhibitor studies indicated that activation of the PI3-kinase-AKT kinase pathway in SH-SY5Y cells is essential for rescue [42]. It is unclear if MPTP treatment somehow attenuated the activation of the other survival pathways, or that these other pathways are in fact activated but for unknown reasons did not contribute to rescue. In all the systems examined by Chen and colleagues (namely rat cortical neurons, the mouse dopaminergic cell line MN9D, mouse cortical neurons and mouse substantia nigra dopaminergic neurons), ERk1/2 activation appears to be pivotal in mediating leptin’s beneficial effects. For the dopaminergic MN9D cells and the substantia nigra dopaminergic neurons, the authors have shown further that ERK1/2 activation impinges on the transcription factor cAMP response element binding (CREB) protein. CREB is a known mediator of multiple signaling events elicited by various growth factors. In CNS neurons, it is known to play roles in processes ranging from neuronal regeneration to learning and memory. One of CREB’s downstream transcriptional targets is the brain-derived growth factor (BDNF) [45], which is a known neuroprotective factor for dopaminergic neurons [46]. ERK1/2 activation thus seems to be the main survival signaling pathway activated by leptin both in cortical neurons and mid-brain dopaminergic neurons. Although leptin almost certainly activated the JAK2-STAT3 pathway, ascertaining a definitive role for this pathway may be more difficult, especially in vivo. In the focal ischemia model, for example, STAT3 phosphorylation and its activity in neurons could be masked by its predominant activation in surrounding glia cells as a response to injury. It should however be noted that not all CNS neurons respond to leptin in the same way that cortical or dopaminergic neurons do. Recent work by Mattson and colleagues provided an illustration of possible diversity in leptin survival signaling in different types of neurons [47]. Working
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with rat hippocampal neurons, the authors showed that leptin protected these against cell death induced by growth factor withdrawal and oxidative insults. While JAK-STAT pathway blockers and PI3-kinase inhibitors blocked this rescue, an MEK inhibitor did not. They have also noted that leptin treatment elevated anti-apoptotic molecules such as Bcl-XL and the manganese superoxide dismutase, which probably protected the cells against mitochondriabased apoptotic mechanisms. Leptin’s signaling effect in neurons and neuron-like cells is therefore clearly cell context dependent. Leptin’s potential as a neuroprotective drug against CNS injury and neurodegeneration The evidence for leptin’s neuroprotective effect highlighted above, particularly in the more established neurological disease models, suggests that it may be use as a therapeutic agent in acute brain injury as well as chronic neurodegenerative diseases. Studies on the effect of leptin on other CNS injury animal models, and of neurodegenerative such as Huntington’s disease, Alzheimer’s disease and motor neuron disorders, may soon appear in the literature. These studies will provide a more comprehensive understanding of how different neurons respond to leptin in vitro and in vivo. Another probable and longer-term beneficial effect of leptin is enhancement of CNS neuronal regeneration. JAK-STAT signaling through the leukemia inhibitory factor (LIF) [48] and interleukin-6 (IL-6) [49] had both been implicated in the enhancement of neuronal regeneration after CNS injury [50]. It is conceivable that JAK-STAT signaling from leptin may have a similar effect. Leptin treatment has the advantage that it readily crosses the blood brain barrier. Its effective local concentration in the CNS after peripheral administration needs to be ascertained. Leptin’s effect on multiple organs and tissues would mean that careful dose monitoring is necessary and one needs to be wary of potential systemic side effects. Bearing leptin’s effect on cancer cell survival in mind, its potential oncogenic effect in long-term administrations has to be carefully assessed. However, considering that the effect of leptin administration has already been under intense scrutiny in clinical trials of leptin deficiency and leptin resistance [51,52], it is perhaps not too far fetch to imagine it being part of a combined therapy for stroke or neurodegeneration in the future. Acknowledgment The author declares no financial conflict of interest. References [1] J.M. Friedman, J.L. Halaas, Leptin and the regulation of body weight in mammals, Nature 395 (1998) 763–770. [2] A. Coll, I. Farooqi, S. O’Rahilly, The hormonal control of food intake, Cell 129 (2007) 251–262.
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